OA20777A - Stable antibody formulation. - Google Patents

Abstract

The present disclosure provides stable pharmaceutical formulations comprising a human antibody that specifically binds to Ebola Virus (EBOV). In certain embodiments, the formulations contain, in addition to an anti-EBOV antibody, a buffer, an amino acid, a non-ionic surfactant, and a stabilizer. The pharmaceutical formulations of the present disclosure exhibit a substantial degree of antibody stability upon stress, for example, agitation during transport, and storage, for example, storage at temperatures greater than 40°C.

Description

STABLE ANTIBODY FORMULATION

GOVERNMENT LICENSE RIGHTS

[0001] This invention was made with Government support under Agreement

HHSO100201500013C and HHSO 100201700016C awarded by the U.S. Department ofFIealth and Human Services, The government has certain rights in the invention,

SEQUENCE LISTING

[0002] An official copy of the sequence listing is submitted concurrently with the spécification electronically via EFS-Web as an ASCII formatted sequence listing with a file name of “10668W001_Sequence_Listing_ST25.txt”, a création date ofJanuary 22, 2021, and a size of about 36KB. The sequence listing contained in this ASCII formatted document is part ofthe spécification and is herein incorporated by référencé in its entirety.

FIELD OF THE INVENTION

[0003] The present disclosure relates to the field of therapeutic antibody formulations. More specifically, the present disclosure relates to the field of pharmaceutical formulations comprising one or more human antibodies that specifically bind to Ebola virus (EBOV).

BACKGROUND

[0004] Therapeutic macromolecules (e.g, antibodies) must be formulated in a manner that not only makes the molécules suitable for administration to patients, but also maintains their stability during storage and subséquent use. For example, therapeutic antibodies in liquid solution are prone to dégradation, aggregation or undesired Chemical modifications unless the solution is formulated properly. The stability of an antibody in liquid formulation dépends not only on the kinds of excipients used in the formulation, but also on the amounts and proportions of the excipients relative to one another. Furthermore, other considérations aside from stability must be taken into account when preparing a liquid antibody formulation. Examples of such additional considérations include the viscosity ofthe solution and the concentration of antibody that can be accommodated by a gîven formulation, and the visual quality or appeal ofthe formulation, Thus, when formulating a therapeutic antibody, great care must be taken to arrive at a formulation that reniai ns stable, contains an adéquate concentration of antibody, and possesses a suitable viscosity as well as other properties which enable the formulation to be conveniently administered to patients. Antîbodies to the Ebola virus (EBOV) are one example of a therapeutically relevant macromoiecule that requires proper formulation. Anti-EBOV antîbodies are clinical[y useful for the prévention and/or treatment of Ebola virus infection. Exemplary anti-EBOV antîbodies are described, inter alia, in US Patent/Publication Nos. 10,501,526 10,081,670, 9,771,414, 6,630,144, 6,875,433, 7,335,356, and 8,513,391, and in WO 2016/123019, EP1539238, EP2350270, and EP8513391.

[0005] Although anti-EBOV antîbodies are known, there remains a need in the art for novel pharmaceutical formulations comprising anti-EBOV antîbodies that are sufficiently stable and suitable for administration to patients, including patients located in remote environments or environments lacking access to réfrigération for therapeutics.

B RIE F SUMMARY

[0006] The présent disclosure satisfies the aforementioned need by providing stable pharmaceutical formulations comprising a human antibody that specifically binds to Ebola virus (EBOV).

[0007] In one aspect, a stable liquid pharmaceutical formulation is provided comprising: (a) a stabiliser comprising a sugar; (b) a buffer comprising histidine; (c) an organic cosolvent comprising polysorbate; and (d) at least one antibody which binds specifically to Ebola virus (EBOV).

[0008] In varions embodiments, the at least one antibody that specifically binds to EBOV is provided at a concentration from about 5 ± 0.75 mg/mL to about 250 ± 37.5 mg/mL. In some embodiments, 250 mg/mL is the maximum protein concentration in the formulation. In some aspects, the 250 mg/mL protein comprises up to three antîbodies. In some aspects, a maximum protein concentration in a formulation comprising three antîbodies would range from about 5 ± 0.75 mg/mL to about 250 mg/mL ± 37.5 mg/mL.

[0009] The ratio of the two or three antîbodies présent in the formulation can be modified depending on outcome measurements. In some aspects, the two antîbodies are présent in a 1:1 ratio. In some aspects, the antîbodies are présent in a 1:2 ratio. In some aspects, the two antîbodies are présent in a ratio of about 1 to 10:1. In some aspects, the three antîbodies are présent in a 1:1:1 ratio. In some aspects, the three antîbodies are présent in a 1:2:1 ratio. In some aspects, the three antîbodies are présent in a 2:1:1 ratio. In some aspects, the three antîbodies are présent in a 1:1:2 ratio. In some aspects, the antîbodies are présent in a ratio of about 1 to 10:1 to 10:1 to 10.

[00010] In some embodiments, the dosage is about 3000 mg, about 2000 mg, about 1500 mg, 1000 mg, about 800 mg, about 750 mg, about 500 mg, about 250 mg, about 200 mg, about 150 mg, about 100 mg, about 75 mg, about 50 mg, or about 25 mg. In some aspects, a dosage comprises one antiEBOV antibody. In some aspects, a dosage comprises two anti-EBOV antibodies. In some aspects, a dosage comprises three anti-EBOV antibodies. In one embodiment, the co-formulated antibodies are delivered intravenousiy over a time period of about 2 hours.

[00011] In one embodiment, the at least one antibody is provided at a concentration of 12.5 mg/mL ± 1.85 mg/mL, or about 12.5 mg/mL. In one embodiment, the at least one antibody is provided at a concentration of 25 mg/mL ± 3.75 mg/mL, or about 25 mg/mL. In another embodiment, the at least one antibody is provided at a concentration of 50 mg/mL ± 7.5 mg/mL, or about 50 mg/mL. In another embodiment, the at least one antibody is provided at a concentration of 100 mg/mL ± 15 mg/mL, or about 100 mg/mL. In another embodiment, the at least one antibody is provided at a concentration of 125 mg/mL ± 18.75 mg/mL, or about 125 mg/mL. In one embodiment, the at least one antibody is provided at a concentration of 150 mg/mL ± 22.5 mg/mL, or about 150 mg/mL. In another embodiment, the at least one antibody is provided at a concentration of 175 mg/mL ± 26.25 mg/mL, or about 175 mg/mL. In another embodiment, the at least one antibody is provided at a concentration of 200 mg/mL ± 30 mg/mL, or about 200 mg/mL. In another embodiment, the at least one antibody is provided at a concentration of 250 mg/mL + 37.5 mg/mL, or about 250 mg/mL.

[00012] In some embodiments, each antibody is administered at 50 mg/kg of body weight. In one embodiment, three antibodies are co-formulated such that the final formulation provides for each antibody to be administered at 50 mg/kg of body weight. Accordingly, the final dose to be administered to the patient is 150 mg/kg of body weight, with the three antibodies in the formulation at a 1:1:1 ratio. In one embodiment, the co-formulated antibodies are delivered intravenously over a time period of about 2 hours.

[00013] In certain embodiments, the formulation comprises any one or more of the anti-EBOV antibodies disciosed in US Patent Application Publication No: 2016/0215040, incorporated herein in its entirety. In certain embodiments, the anti-EBOV antibody comprises (a) a heavy chain variable région (HCVR) comprising heavy chain complementarity determining régions 1, 2 and 3 (HCDRIHCDR2-HCDR3) each comprising a sequence of SEQ ID NO: 4, SEQ ID NO: 6, and SEQ ID NO: 8, respectively; and (b) a light chain variable région (LCVR) comprising light chain complementarity determining régions 1,2 and 3 (LCDR1-LCDR2-LCDR3) each comprising a sequence of SEQ IDNO: 12, SEQ ID NO: 14, and SEQ ID NO: 16, respectively. In one embodiment, the antibody comprises a HCVR comprising the amino acid sequence of SEQ ID NO:

and a LCVR comprising the amino acid sequence of SEQ ID NO: 10. In one embodiment, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 17 and a light chain comprising the amino acid sequence of SEQ ID NO: 18. In one embodiment, the antibody comprises a HCVR having at least 90% sequence identity to SEQ ID NO: 2. In one embodiment, the antibody comprises a LCVR having at least 90% sequence identity to SEQ ID NO: 10. In one embodiment, the antibody comprises a HCVR having at least 95% sequence identity to SEQ ID NO: 2 and a LCVR having at least 95% sequence identity to SEQ ID NO: 10.

[00014] In certain embodiments, the anti-EBOV antibody comprises (a) a heavy chain variable région (HCVR) comprising heavy chain complementarity determining régions I, 2 and 3 (HCDR1HCDR2-HCDR3) each comprising a sequence of SEQ ID NO: 22, SEQ ID NO: 24, and SEQ ID NO: 26, respectively; and (b) a light chain variable région (LCVR) comprising light chain complementarity determining régions I, 2 and 3 (LCDR1-LCDR2-LCDR3) each comprising a sequence of SEQ ID NO: 30, SEQ ID NO: 32, and SEQ ID NO: 34, respectively. In one embodiment, the antibody comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 20 and a LCVR comprising the amino acid sequence of SEQ ID NO: 28. In one embodiment, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 35 and a light chain comprising the amino acid sequence of SEQ ID NO: 36. In one embodiment, the antibody comprises a HCVR having 90% sequence identity to SEQ ID NO: 20. In one embodiment, the antibody comprises a LCVR having 90% sequence identity to SEQ ID NO: 28. In one embodiment, the antibody comprises a HCVR having 95% sequence identity to SEQ ID NO: 20 and a LCVR having 95% sequence identity to SEQ ID NO: 28.

[00015] In certain embodiments, the anti-EBOV antibody comprises (a) a heavy chain variable région (HCVR) comprising heavy chain complementarity determining régions 1, 2 and 3 (HCDR1HCDR2-HCDR3) each comprising a sequence of SEQ ID NO: 40, SEQ ÏD NO: 42, and SEQ ID NO: 44, respectively; and (b) a light chain variable région (LCVR) comprising light chain complementarity determining régions 1,2 and 3 (LCDR1-LCDR2-LCDR3) each comprising a sequence of SEQ ID NO: 48, SEQ ID NO: 50, and SEQ ID NO: 52, respectively. In one embodiment, the antibody comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 38 and a LCVR comprising the amino acid sequence of SEQ ID NO: 46. In one embodiment, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 53 and a light chain comprising the amino acid sequence of SEQ ID NO: 54. In one embodiment, the antibody comprises a HCVR having 90% sequence identity to SEQ ID NO: 38. In one embodiment, the antibody comprises a LCVR having 90% sequence identity to SEQ ID NO: 46. In one embodiment, the antibody comprises a HCVR having 95% sequence identity to SEQ ID NO: 38 and a LCVR having 95% sequence identity to SEQ ID NO: 46.

[00016] In one embodiment, the pH of the liquid formulation is pH 6.0 ± 0.5, pH 6.0 ± 0.4, pH 6.0 ± 0.3, pH 6.0 ± 0.2, pH 6.0 ±0.1, pH 6.0 ± 0.05, pH 6.0 ± 0.01, or pH 6.0. In one embodiment, the pH of the liquid formulation is about pH 6.0 ± 0.3.

[00017] In one embodiment, the buffer comprises histidîne. In certain embodiments, the histidine buffer is at a concentration of from 5 mM ± 1 mM to 50 mM ± 10 mM, or from 5 mM ± 1 inM to 25 mM ± 5 mM. In one embodiment, the histidine buffer is at a concentration of 10 mM ± 2 mM or about 10 mM. In one embodiment, the histidine buffer is at a concentration of 20 mM ± 4 mM or about 20 mM. In one embodiment, the histidine buffer is at a concentration of 40 nM ± 8 mM or about 40 nM. In certain embodiments, the histidine buffer comprises L-hîstidine and L-histidine monohydrochloride monohydrate. In one embodiment, L-histidine is at a concentration of from 2 mM ± 0.4 mM to 25 mM ± 5 mM, preferably from 4 mM ± 0.8 mM to 20 mM ± 4 mM. In one embodiment, L-histidine monohydrochloride monohydrate is at a concentration of from 2 mM ± 0.4 mM to 25 mM ± 5 mM, preferably from 4 mM ±0.8 mM to 20 mM ± 4 mM. In one embodiment, the buffer comprises L-histidine at a concentration of 4.8 mM ± 0.96 mM and L-hîstidine monohydrochloride monohydrate at a concentration of 5.2 mM ± 1.04 mM. In one embodiment, the buffer comprises histidine at a concentration of 10 mM ± 2 mM, wherein the histidine comprises Lhistidine at a concentration of 4.8 mM ± 0.96 mM and L-histidine monohydrochloride monohydrate at a concentration of 5.2 mM ± 1.04 mM.

[00018] In certain embodiments, the organic cosolvent is a nonionic polymer containing a poiyoxyethylene moiety. In one embodiment, the organic cosolvent is a surfactant. In some embodiments, the organic cosoivent is any one or more of polysorbate, poloxamer 188 and polyethylene glycol 3350. In one embodiment, the organic cosolvent is polysorbate 80. In one embodiment, the organic cosolvent is polysorbate 20.

[00019] In one embodiment, the organic cosolvent is at a concentration of from about 0.01% + 0.005% to about 1% ± 0.5% “weight to volume” or “w/v”, wherein, e.g,, 0. ] g/ml = 10% and 0.01 g/ml = 1%. In certain embodiments, the organic cosolvent is polysorbate at a concentration of from 0.05% ± 0.025% to 0.5% ± 0.25% (w/v). In one embodiment, the organic cosolvent is polysorbate 80, which is at a concentration of 0.2% ± 0.1% w/v, or about 0.2%. In another embodiment, the organic cosolvent is polysorbate 80, which is at a concentration of 0.1% ± 0.05% w/v or about 0.1% 5 w/v. In one embodiment, the organic cosolvent is polysorbate 20, which is at a concentration of 0.2% ±0.1% w/v, or about 0.2%. in another embodiment, the organic cosolvent is polysorbate 20, which îs at a concentration of 0.1% ± 0.05% w/v or about 0.1% w/v.

[00020] In certain embodiments, the stabilizer is a sugar. In one embodiment, the sugar is sucrose. In varions embodiments, the stabilizer is at a concentration of from 1% ± 0.2% w/v to 20% ± 4% w/v, from 5% ±1% w/v to 15% + 3% w/v, or from 1% ± 0.2% to 10% ± 2% w/v. In one embodiment, the stabilizer is sucrose at a concentration of 5% ± 1% w/v or about 5% w/v. In another embodiment, the stabilizer is sucrose at a concentration of 9% ± 1.8% w/v or about 9% w/v. In another embodiment. the stabilizer is sucrose at a concentration of 10% ± 2% w/v or about 10% w/v.

[00021] In certain embodiments, the formulation does not need a viscosity modifier, i.e. the formulation lacks a viscosity modifier. In certain embodiments, the formulation comprises a viscosity modifier. In one embodiment, the formulation comprises a viscosity modifier and the viscosity modifier is an amino acid or a sait. In one embodiment, the viscosity modifier is L-proline. In certain embodiments, the viscosity modifier is at a concentration of from 1% ± 0.2% to 5% ± 1% w/v. In one embodiment, the viscosity modifier is proline at a concentration of 1.5% ± 0.3% or about 1.5%. In one embodiment, the viscosity modifier is proline at a concentration of 3% ± 0.6%, or about 3%.

[00022] In certain embodiments, the viscosity of the liquid pharmaceutical formulation at 25°C is less than or equal to about 15 cPoise ± 10%. In certain embodiments, the viscosity at 25°C is between 1,0 cPoise ± 10% and 20 cPoise ± 10%. In certain embodiments, the viscosity ofthe liquid pharmaceutical formulation is < 20 cPoise. In certain embodiments, the viscosity ofthe liquid pharmaceutical formulation is < 15 cPoise. In certain embodiments, the viscosity ofthe liquid pharmaceutical formulation is < 10 cPoise. In certain embodiments, the viscosity ofthe liquid pharmaceutical formulation is < 5 cPoise. In certain embodiments, the viscosity of the liquid pharmaceutical formulation îs < 2.5 cPoise. In certain embodiments, the viscosity at 25°C is about 2 cPoise ± 10%, 5 cPoise ± 10%, 6.0 cPoise ± 10%, 7.0 cPoise ± 10%, 7.1 cPoise ± 10%, 7.2 cPoise ± 10%, 7.9 cPoise ± 10%, 8.3 cPoise ± 10%, 9.0 cPoise ± 10%, 9.6 cPoise ± 10%, 10.0 cPoise ± 10%, 10.6 cPoise ± 10%, 11.4 cPoise ± 10%, 11.6 cPoise ± 10%, 11.8 cPoise ± 10%, 12.0 cPoise ± 10%, 13.0 cPoise ± 10%, 14.0 cPoise ± 10%, 15.0 cPoise ± 10%, or 16 cPoise ± 10%. In certain embodiments, the viscosity at 25°C is about 2.2 cPoise.

[00023] In one aspect, a stable liquid pharmaceutical formulation is provided, comprising: (a) from 6

5% + 1% to 15% ± 3% w/v sucrose, (b) from 5 mM ± 1 mM to 20 mM ± 4 mM histidine buffer, (c) from 0,01% ± 0.005% to 0.5% ± 0.25% w/v polysorbate, e.g, about 0.05% ± 0.025% to about 0.2% ± 0.1% w/v polysorbate, and (d) 50 mg/mL ± 7.5 mg/mL total anti-EBOV antibody, at pH 6.0 ± 0.3, In another aspect, a stable liquid pharmaceutical formulation is provided, comprising: (a) 10% ± 2% w/v sucrose, (b) lOmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ±7.5 mg/mL total antibody, at pH 6.0 ± 0,3. In another aspect, a stable liquid pharmaceutical formulation is provided, comprising: (a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ± 5 g/mL total antibody, at pH 6.0 ±0.3, [00024] In one aspect, a stable liquid pharmaceutical formulation is provided, comprising: (a) from 5% ± 1% to 15% ± 3% w/v sucrose, (b) from 5 mM ± 1 mM to 20 mM ± 4 mM histidine buffer, (c) from 0.01% ± 0.005% to 0.5% ± 0.25% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total antibody, at pH 6.0 ± 0.3, In another aspect, a stable liquid pharmaceutical formulation is provided, comprising: (a) 10% ±2% w/v sucrose, (b) lOmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total antibody, at pH 6.0 ± 0.3. In another aspect, a stable liquid pharmaceutical formulation is provided, comprising: (a) 10% ± 2% w/v sucrose, (b) 1 OmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 10 mg/mL total antibody, at pH 6.0 ± 0.3.

[00025] The anti-EBOV antibody comprises at least one antibody comprising three heavy chain complementarity determining régions (CDRs) (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in a heavy chain variable region/light chain variable région (HCVR/LCVR) amino acid sequence pair selected from the group consisting of (i) SEQ ID NOs: 2/10, (ii) SEQ ID NOs: 20/28, and (iii) SEQ ID NOs: 38/46, In some aspects, the formulation comprises the following: (î), (ii), (iii), (i)+(îî), (î)±(îîî), (îî)+(îîÎ), or (î)+(ii)±(iii), and the total anti-EBOV antibody présent in the formulation is 50 mg/mL ± 7,5 mg/mL. In some aspects, the formulation comprises the following: (i), (ii), (ni), (ί)+(ϋ), (i)±(iii), (iî)±(iii), or (î)+(it)±(iii), and the total anti-EBOV antibody présent in the formulation is 100 mg/mL ± 15 mg/mL.

[00026] In some embodiments, the at least one anti-EBOV antibody comprises a heavy chaîn variable région (HCVR) and a light chain variable région (LCVR) such that the HCVR/LCVR combination comprises heavy and light chaîn complementarity determining régions (HCDR1HCDR2-HCDR3 / LCDRI-LCDR2-LCDR3), which comprise the amino acid sequences selected 7 from the group consisting of SEQ ID NOs: 4-6-8 / 12-14-16, respectively; SEQ ID NOs: 22-24-26 / 30-32-34, respectively; and SEQ ID NOs: 40-42-44 / 48-50-52, respectively. In one embodiment, the anti-EBOV antibody comprises a heavy chain variable région (HCVR)/light chain variable région (LCVR) amino acid sequence pair selected from the group consisting of SEQ ID NOs: 2/10, 20/28, and 38/46. In certain embodiments, the anti-EBOV antibody comprises a Fc région elected from the group consisting of human IgGl, IgG2, IgG3, and IgG4 isotypes. In one embodiment, the antibody comprises a human IgGI isotype. In one embodiment, the antibody comprises a heavy chain comprising the amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 35, and 53; and a light chain comprising the amino acid sequence selected from the group consisting of SEQ IDNOs: 18, 36, and 54. In one embodiment, the antibody has a molecular weight of 145 kDa ± 15 kDa, for example, 144,804 Da, 145,905 Da, or 143,689 Da.

[00027] In certain embodiments, a stable, liquid pharmaceutical formulation is provided, comprising: (a) 10% ± 2% w/v sucrose, (b) lOmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ± 7.5 mg/mL total antibody that specifically binds to EBOV, at pH 6.0 ± 0.3; wherein the antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10. In one embodiment, the anti-EBOV antibody comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO: 10. In one embodiment, the anti-EBOV antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 17; and a light chain comprising the amino acid sequence of SEQ ID NO: 18.

[00028] In certain embodiments, a stable, liquid pharmaceutical formulation is provided, comprising: (a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ±7.5 mg/mL total antibody that specifically binds to EBOV, at pH 6.0 ± 0.3; wherein the antibody comprises three heavy chain CDRs (HCDRI, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28. In one embodiment, the anti-EBOV antibody comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 20 and a LCVR comprising the amino acid sequence of SEQ ID NO: 28. In one embodiment, the anti-EBOV antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 35; and a light chain comprising the amino acid sequence of SEQ ID NO: 36.

[00029] In certain embodiments, a stable, liquid pharmaceutical formulation is provided, comprising: (a) 10% ± 2% w/v sucrose, (b) lOmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ± 7.5 mg/mL total antibody that specifically binds to EBOV, at pH 6.0 ± 0.3; wherein the antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (iiî) SEQ ID NOs: 38/46. In one embodiment, the anti-EBOV antibody comprises a HCVR comprising the amino acid sequence of SEQ ID NO; 38 and a LCVR comprising the amino acid sequence of SEQ ID NO: 46. In one embodiment, the anti-EBOV antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 53; and a light chain comprising the amino acid sequence of SEQ ID NO: 54.

[00030] In certain embodiments, a stable, lîquid pharmaceutical formulation is provided, comprising: (a) 10% ± 2% w/v sucrose, (b) lOmM + 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ± 7.5 mg/mL total antibody that specifically binds to EBOV, at pl-l 6.0 ± 0.3; wherein a first antibody comprises three heavy chain CDRs (HCDRl, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10, and a second antibody comprises three heavy chain CDRs (HCDRl, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (il) SEQ ID NOs: 20/28. In one embodiment, the first anti-EBOV antibody comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO: 10; and the second anti-EBOV antibody comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 20 and an LCVR comprising the amino acid sequence of SEQ ID NO: 28.

[00031] In certain embodiments, a stable, liquid pharmaceutical formulation is provided, comprising: (a) 10% ± 2% w/v sucrose, (b) !0mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ± 7.5 mg/mL total antibody that specifically binds to EBOV, at pH 6.0 ± 0.3; wherein a first antibody comprises three heavy chain CDRs (FICDR l, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10, and a second antibody comprises three heavy chain CDRs (HCDRl, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46. In one embodiment, the first anti-EBOV antibody comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO: 10; and the second anti-EBOV antibody comprises an HCVR comprising the amino acid sequence of 9

SEQ ID NO: 38 and an LCVR comprising the amino acid sequence of SEQ ID NO: 46. [00032] In certain embodiments, a stable, liquid pharmaceutica! formulation is provided, comprising; (a) 10% ± 2% w/v sucrose, (b) lOmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ± 7.5 mg/mL total antibody that specifîcally binds to EBOV, at pH 6.0 ± 0.3; wherein a flrst antibody comprises three heavy chain CDRs (HCDRI, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (H) SEQ ID NOs: 20/28, and a second antibody comprises three heavy chain CDRs (HCDRI, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the I-ICVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46. In one embodiment, the first anti-EBOV antibody comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 20 and a LCVR comprising the amino acid sequence of SEQ ID NO: 28; and the second anti-EBOV antibody comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 38 and an LCVR comprising the amino acid sequence of SEQ ID NO: 46.

[00033] In certain embodiments, a stable, liquid pharmaceutical formulation is provided, comprising: (a) 10% + 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ± 7.5 mg/mL total antibody that specifîcally binds to EBOV, at pH 6.0 ± 0.3; wherein a first antibody comprises three heavy chain CDRs (HCDRI, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10, a second antibody comprises three heavy chain CDRs (HCDRI, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28, and a third antibody comprises three heavy chain CDRs (HCDRI, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46, In one embodiment, the first anti-EBOV antibody comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO: 10; the second anti-EBOV antibody comprises an HCVR comprising the amino acid sequence of SEQ ID NO; 20 and an LCVR comprising the amino acid sequence of SEQ ID NO: 28; and the third anti-EBOV antibody comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 38 and a LCVR comprising the amino acid sequence of SEQ ID NO: 46.

[00034] In certain embodiments, a stable, liquid pharmaceutical formulation is provided, comprising: (a) 10% + 2% w/v sucrose, (b) lOmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total antibody that specifîcally binds to EBOV, at pH 10 .0 ±0.3; wherein the antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10. In one embodiment, the anti-EBOV antibody comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO: 10. In one embodiment, the anti-EBOV antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 17; and a light chain comprising the amino acid sequence of SEQ ID NO: 18.

[00035] In certain embodiments, a stable, lîquîd pharmaceutical formulation is provided, comprising: (a) 10% ± 2% w/v sucrose, (b) lOmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total antibody that specifically binds to EBOV, at pH 6.0 ± 0.3; wherein the antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28. In one embodiment, the anti-EBOV antibody comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 20 and a LCVR comprising the amino acid sequence of SEQ ID NO: 28. In one embodiment, the anti-EBOV antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 35; and a light chain comprising the amino acid sequence of SEQ ID NO: 36.

[00036] In certain embodiments, a stable, liquid pharmaceutical formulation is provided, comprising: (a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total antibody that specifically binds to EBOV, at pH 6.0 ± 0.3; wherein the antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46. In one embodiment, the anti-EBOV antibody comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 38 and a LCVR comprising the amino acid sequence of SEQ ID NO: 46. In one embodiment, the anti-EBOV antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 53; and a light chain comprising the amino acid sequence of SEQ ID NO: 54.

[00037] In certain embodiments, a stable, liquid pharmaceutical formulation is provided, comprising: (a) 10% ± 2% w/v sucrose, (b) lOmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total antibody that specifically binds to EBOV, ai pH 6.0 ± 0.3; wherein a first antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and

HCDR3) and three light chain CDRs (LCDRl, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10, and a second antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDRl, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28. In one embodiment, the first anti-EBOV antibody comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO: 10; and the second anti-EBOV antibody comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 20 and an LCVR comprising the amino acid sequence of SEQ ID NO: 28.

(00038] In certain embodiments, a stable, liquid pharmaceuticaî formulation is provided, comprising: (a) 10% ±2% w/v sucrose, (b) lOmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total antibody that specifically binds to EBOV, at pH 6.0 ± 0.3; wherein a first antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDRl, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ IDNOs: 2/10, and a second antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDRl, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46. In one embodiment, the first anti-EBOV antibody comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO: 10; and the second anti-EBOV antibody comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 38 and an LCVR comprising the amino acid sequence of SEQ ID NO: 46.

[00039] In certain embodiments, a stable, liquid pharmaceuticaî formulation is provided, comprising: (a) 10% ± 2% w/v sucrose, (b) 10mM +2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total antibody that specifically binds to EBOV, at pH 6.0 ± 0.3; wherein a first antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDRl, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28, and a second antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDRl, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46. In one embodiment, the first anti-EBOV antibody comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 20 and a LCVR comprising the amino acid sequence of SEQ IDNO: 28; and the second anti-EBOV antibody comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 38 and an LCVR comprising the amino acid sequence of SEQ ID NO: 46.

[00040] In certain embodiments, a stable, liquid pharmaceutical formulation is provided, comprising: (a) 10% ± 2% w/v sucrose, (b) lOmM ± 2mM histîdine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total antibody that specifically binds to EBOV, at pH 6.0 ± 0.3; wherein a first antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10, a second antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28, and a thîrd antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (îiî) SEQ ID NOs: 38/46. In one embodiment, the first anti-EBOV antibody comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 2 and a LCVR comprising the amino acid sequence of SEQ ID NO: 10; the second anti-EBOV antibody comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 20 and an LCVR comprising the amino acid sequence of SEQ ID NO: 28; and the third anti-EBOV antibody comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 38 and a LCVR comprising the amino acid sequence of SEQ ID NO: 46. [00041] In certain embodiments, the formulation of any of the precedîng aspects has an attribute selected from the group consisting of: (i) the formulation is stable to long-term storage at 60°C, 55°C, 50°C, 45°C, 40°C, 35°C, 30°C, 25°C, 5°C, -20°C, -30^ûC and -80°C, as described herein; (ii) the formulation is stable to agitation stress as described herein; (iit) the formulation is stable to heat stress as described herein; (iv) the formulation is iow-viscosity (viscosity less than 20cPoise, preferably less than 15 cPoise); (v) the formulation is stable even with up to ± 50% variation in the formulation excipient concentrations, as described herein; (vi) the formulation is îso-osmolar to physiologie conditions; (vii) the formulation is stable to and compatible with intravenons delivery devices and procedures; and (viii) the formulation is stable to long-term storage in a glass vial or in a prefilled syringe.

[00042] In certain embodiments, the formulation of any of the preceding aspects has an attribute selected from the group consisting of: (i) the formulation has viscosity of less than 10 cP; (ii) the formulation has a viscosity of less than 5 cP; (îiî) the formulation has a viscosity of less than about 2.5; (iv) at least 90% of the antibody is the native species after 28 days at 45°C; (v) at least 18% of the antibody is the main charge variant of the antibody after 28 days at 45°C; (vî) ai least 96% of the antibody is the native species after three months at 25°C; (vii) at least 30% of the antibody is the main charge variant ofthe antibody after three months at 25°C; (viii) at least 96% ofthe antibody is the native species after 36 months at 5°C; (ix) at least 34% of the antibody is the main charge variant of the antibody after 36 months at 5°C; (x) at least 97% of the antibody is the native species after 120 minutes agitation; (xi) at least 35% ofthe antibody is the main charge variant ofthe antibody after 120 minutes agitation; (xii) at least 97% of the antibody is the native species after 8 freeze thaw cycles; and/or (xiii) at least 35% of the antibody is the main charge variant of the antibody after 8 freeze thaw cycles,

[00043] In certain embodiments, an antibody within the formulation of any of the preceding aspects has an attribute seiected from the group consisting of: (i) the antibody retains ADCC activity of at least about 90% after storage at -80°C for 12 months relative to the activity of the same antibody prior to storage; (ii) the antibody retains ADCC activity of at least about 80%, or at least about 90%, after storage at -30°C for 12 months relative to the activity of the same antibody prior to storage;

(iîî) the antibody retains ADCC activity of at least about 90%, or at least about 95%, after storage at -20°C for 3 months relative to the activity ofthe same antibody prior to storage; (iv) the antibody retaîns ADCC activity of at least about 90%, or at least about 95%, after storage at 5°C for 56 days relative to the activity ofthe same antibody prior to storage; (v) the antibody retains ADCC activity of at least about 90%, or at least about 95%, after storage at 25°C/60% relative humidity (RJH) for 28 days relative to the activity of the same antibody prior to storage; (vi) the antibody retains ADCC activity of at least about 90%, or at least about 95%, after storage at 40°C/75%RH for 28 days relative to the activity ofthe same antibody prior to storage; (vii) the antibody retains ADCC activity of at least about 90%, or at least about 95%, after agitation for 120 minutes, or 8 freeze/thaw cycles, relative to the activity of the same antibody prior to agitation or freeze/thaw, respectively, [00044] In certain embodiments, an antibody within the formulation of any of the preceding aspects has an attribute seiected from the group consisting of: (i) the antibody retains pseudovirus neutralization activity of at least about 90%, or at least about 95%, after storage at -80°C for 12 months relative to the activity of the same antibody prior to storage; (ii) the antibody retains pseudovirus neutralization activity of at least about 90%, or at least about 95%, after storage at 30°C for 12 months relative to the activity of the same antibody prior to storage; (iii) the antibody retains pseudovirus neutralization activity of at least about 90%, or at least about 95%, after storage at -20°C for 3 months relative to the activity of the same antibody prior to storage; (iv) the antibody retains pseudovirus neutralization activity of at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, after storage at 5°C for 56 days relative to the activity of the same antibody prier to storage; (v) the antibody retains pseudovirus neutralization activity of at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, after storage at 25°C/60% relative humidity (RH) for 28 days relative to the activity of the same antibody prior to storage; (vi) the antibody retains pseudovirus neutralization activity of at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, after storage at 40°C/75%RH for 28 days relative to the activity of the same antibody prior to storage; (vii) the antibody retains pseudovirus neutralization activity of at least about 90%, or at least about 95%, after agitation fbr 120 minutes, or 8 freeze/thaw cycles, relative to the activity of the same antibody prior to agitation or freeze/thaw, respectively.

[00045] In certain embodiments of this aspect, a stable lîquid formulation is provided, comprising: (a) at least one antibody that binds speciflcaliy to EBOV, wherein the at least one antibody comprises a heavy chain variable region/light chain variable région (HCVR/LCVR) amino acid sequence pair selected from the group consîstîng of (î) SEQ ID NOs: 2/10, (fl) SEQ ID NOs: 20/28, and (iii) SEQ ID NOs: 38/46, and wherein the total antibody comprises 50 mg/mL ± 7.5 mg/mL, (b) 10 mM ± 2 mM histidine buffer, pH 6.0 ± 0.3, (c) 0.1% ± 0.05% w/v polysorbate 80, and (d) 10% ± 2% w/v sucrose. In one embodiment according to this aspect, at least 96% of the antibody is the native species after 36 months at 5°C. In one embodiment according to this aspect, at least 97% of the antibody is the native species after 120 minutes agitation. In one embodiment according to this aspect, at least 97% of the antibody is the native species after 8 freeze thaw cycles. In some aspects, the pharmaceutical formulation consists of: (a) 50 mg/mL ±7.5 mg/mL total antibody, (b) 10 mM ± 2 mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate 80, and (d) 10% ± 2% w/v sucrose, in water at pH 6.0 ± 0.3.

[00046] In certain embodiments of this aspect, a stable liquid formulation is provided, comprising: (a) at least two antibodies that bind speciflcaliy to EBOV, wherein the at least two antibodies comprise a heavy chain variable region/light chain variable région (HCVR/LCVR) amino acid sequence pair selected from the group consisting of (ï) SEQ ID NOs: 2/10, (fl) SEQ ID NOs: 20/28, and (iii) SEQ ID NOs: 38/46, and wherein the total antibody comprises 50 mg/mL ± 7.5 mg/mL, (b) 10 mM ± 2 mM histidine buffer, pH 6.0 ± 0.3, (c) 0.1% ± 0.05% w/v polysorbate 80, and (d) 10% ± 2% w/v sucrose. In one embodiment according to this aspect, at least 96% of the antibody is the native species after 12 months at 5°C. In one embodiment according to this aspect, at least 97% of the antibody is the native species after 120 minutes agitation. In one embodiment according to this aspect, at least 97% of the antibody is the native species after 8 freeze thaw cycles. In some aspects, 15 the pharmaceutical formulation consists of: (a) 50 mg/mL ±7.5 mg/mL total antibody, (b) 10 mM ± 2 mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate 80, and (d) 10% ± 2% w/v sucrose, in water at pH 6.0 ± 0.3.

[00047] In certain embodiments of this aspect, a stable liquid formulation is provided, comprising: (a) a combination of three antîbodies that bind specifically to EBOV, wherein the three antîbodies comprise a heavy chain variable regîon/light chain variable région (HCVR/LCVR) amino acid sequence pair of (i) SEQ IDNOs: 2/10, (ii) SEQ ID NOs: 20/28, and (iii) SEQ ID NOs: 38/46, and wherein the total antibody comprises 50 mg/mL ± 7.5 mg/mL, (b) 10 mM ± 2 mM histidine buffer, pH 6.0 ± 0.3, (c) 0.1% ± 0.05% w/v polysorbate 80, and (d) 10% ± 2% w/v sucrose. In one embodiment according to this aspect, at least 96% ofthe antibody is the native species after 12 months at 5°C. In one embodiment according to this aspect, at least 97% of the antibody is the native species after 120 minutes agitation. In one embodiment according to this aspect, at least 97% ofthe antibody is the native species after 8 freeze thaw cycles. In some aspects, the pharmaceutical formulation consists of: (a) 50 mg/mL ± 7.5 mg/mL total antibody, (b) 10 mM ±2 mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate 80, and (d) 10% ± 2% w/v sucrose, in water at pH 6.0 ± 0.3.

[00048] In certain embodiments of this aspect, a stable liquid formulation is provided, comprising: (a) at least one antibody that binds specifically to EBOV, wherein the at least one antibody comprises a heavy chain variable regîon/light chain variable région (HCVR/LCVR) amino acid sequence pair selected from the group consistîng of (i) SEQ ID NOs: 2/10, (ii) SEQ ID NOs: 20/28, and (iii) SEQ ID NOs: 38/46, and wherein the total antibody comprises 100 mg/mL ± 15 mg/mL, (b) 10 mM ±2 mM histidine buffer, pH 6.0 ± 0.3, (c) 0.1% ± 0.05% w/v polysorbate 80, and (d) 10% ± 2% w/v sucrose. In one embodiment according to this aspect, at least 96% of the antibody is the native species after 12 months at 5°C. In one embodiment according to this aspect, at least 97% of the antibody is the native species after 120 minutes agitation. In one embodiment according to this aspect, at least 97% ofthe antibody is the native species after 8 freeze thaw cycles. In some aspects, the pharmaceutical formulation consists of: (a) 100 mg/mL ± 15 mg/mL total antibody, (b) 10 mM ± 2 mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate 80, and (d) 10% ± 2% w/v sucrose, in water at pH 6.0 ±0.3.

[00049] In certain embodiments of this aspect, a stable liquid formulation is provided, comprising: (a) at least two antîbodies that bind specifically to EBOV, wherein the at least two antîbodies comprise a heavy chain variable region/light chain variable région (HCVR/LCVR) amino acid sequence pair selected from the group consisting of (i) SEQ ID NOs: 2/10, (ii) SEQ ID NOs: 20/28, and (üi) SEQ ID NOs: 38/46, and wherein the total antibody comprises 100 mg/mL ± 15 mg/mL, (b) 10 mM ± 2 mM histidine buffer, pH 6.0 ± 0.3, (c) 0.1% ± 0.05% w/v polysorbate 80, and (d) 10% ± 2% w/v sucrose. In one embodiment according to this aspect, at least 96% of the antibody is the native species after 12 months at 5°C. In one embodiment according to this aspect, at least 97% of the antibody is the native species after 120 minutes agitation. In one embodiment according to this aspect, at least 97% of the antibody is the native species after 8 freeze thaw cycles. In some aspects, the pharmaceutical formulation consists of: (a) 100 mg/mL ± 15 mg/mL total antibody, (b) 10 mM ± 2 mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate 80, and (d) 10% ± 2% w/v sucrose, in water at pH 6.0 ±0.3.

[00050] In certain embodiments of this aspect, a stable liquid formulation is provided, comprising: (a) a combination of three antibodies that bind specifically to ESOV, wherein the three antibodies comprise a heavy chain variable region/light chain variable région (HCVR/LCVR) amino acid sequence pair of (i) SEQ ID NOs: 2/10, (ii) SEQ ID NOs: 20/28, and (üi) SEQ ID NOs: 38/46, and wherein the total antibody comprises 100 mg/mL ± 15 mg/mL, (b) 10 mM ± 2 mM histidine buffer, pH 6.0 ± 0.3, (c) 0.1% ± Û.05% w/v polysorbate 80, and (d) 10% ± 2% w/v sucrose. In one embodiment according to this aspect, at least 96% of the antibody is the native species after 12 months at 5°C. In one embodiment according to this aspect, at least 97% of the antibody is the native species after 120 minutes agitation. In one embodiment according to this aspect, at least 97% ofthe antibody is the native species after 8 freeze thaw cycles. In some aspects, the pharmaceutical formulation consists of: (a) 100 mg/mL ± 15 mg/mL total antibody, (b) 10 mM ± 2 mM histidine buffer, (c)0.1%±0.05% w/v polysorbate 80, and (d) 10% ± 2% w/v sucrose, in water at pH 6.0 ± 0.3.

[00051] In one embodiment, the stable liquid formulation comprises 50 mg/mL ± 7.5 mg/mL total antibody that specifically binds to EBOV and has a viscosity less than 3 cP at 25 °C. In one embodiment, > 90% of the antibodies hâve a molecular weight of 146 kDa ± 5 kDa, for example, 144,804 Da, 145,905 Da, or 143,689 Da. In one embodiment, the pharmaceutical formulation has a viscosity of less than 5 cP, less than 4 cP, or less than 3 cP at 25°C. In one embodiment, at least 90% of the antibody is the native species after 28 days at 45°C. In one embodiment, at least 18% of the antibody is the main charge variant ofthe antibody after 28 days at 45°C. In one embodiment, at

Ieast 96% of the antibody is the native species after three months at 25°C. In one embodiment, at Ieast 30% of the antibody is the main charge variant of the antibody after three months at 25°C. In one embodiment, at Ieast 96% of the antibody is the native species after 12 months at 5°C. In one embodiment, at Ieast 34% of the antibody is the main charge variant of the antibody after 12 months at 5°C. In one embodiment, at Ieast 97% of the antibody is the native species after 120 minutes agitation. In one embodiment, at Ieast 35% of the antibody is the main charge variant of the antibody after 120 minutes agitation. In one embodiment, at Ieast 97% of the antibody is the native species after S freeze thaw cycles. In one embodiment, at Ieast 35% of the antibody is the main charge variant of the antibody after 8 freeze thaw cycles.

[00052] In one embodiment, the stable liquid formulation comprises 100 mg/mL ± 15 mg/mL total antibody and has a vîscosity less than 5 cP at 20°C. In one embodiment, > 90% of the antibodies hâve a molecular weight of 145 kDa ± 2 kDa, for example, 144,804 Da, 145,905 Da, or 143,689 Da. In one embodiment, the pharmaceutical formulation has a viscosity of less than 6 cP or less than 5 cP at 20°C. In one embodiment, at Ieast 90% of the antibody is the native species after 28 days at 45°C. In one embodiment, at Ieast 18% of the antibody is the main charge variant of the antibody after 28 days at 45°C. In one embodiment, at Ieast 96% of the antibody is the native species after three months at 25°C. In one embodiment, at Ieast 30% of the antibody is the main charge variant of the antibody after three months at 25°C. In one embodiment, at Ieast 96% of the antibody is the native species after 12 months at 5°C. In one embodiment, at Ieast 34% of the antibody is the main charge variant of the antibody after 12 months at 5°C. In one embodiment, at Ieast 97% of the antibody is the native species after 120 minutes agitation. In one embodiment, at Ieast 35% of the antibody is the main charge variant of the antibody after 120 minutes agitation. In one embodiment, at Ieast 97% of the antibody is the native species after 8 freeze thaw cycles. In one embodiment, at Ieast 35% of the antibody is the main charge variant of the antibody after 8 freeze thaw cycles.

[00053] In certain embodiments of this aspect, a stable liquid formulation is provided, comprisîng: (a) a combination of three antibodies that bind specifically to EBOV, wherein the three antibodies comprise a heavy chain variable region/light chain variable région (HCVR/LCVR.) amino acid sequence pair of (i) SEQ ID NOs: 2/10, (ii) SEQ ID NOs: 20/28, and (iii) SEQ ID NOs: 38/46, and wherein the total antibody comprises 50 mg/mL ± 7.5 mg/mL, (b) 10 mM ± 2 mM histidine buffer, pH 6.0 ± 0.3, (c) 0.1% ± 0.05% w/v polysorbate 80, and (d) 10% + 2% w/v sucrose. In one embodiment of this particular formulation, the viscosity is less than 3 cPoise.

[00054] In certain embodiments of this aspect, a stable liquid formulation is provided, comprisîng: 18 (a) a combination of three antibodies that bind specificaliy to EBOV, wherein the three antibodies comprise a heavy chain variable region/light chaîn variable région (HCVR/LCVR) amino acid sequence pair of (i) SEQ ID NOs: 2/10, (ii) SEQ ID NOs: 20/28, and (iii) SEQ IDNOs: 38/46, and wherein the total antibody comprises 100 mg/mL ± 15 mg/mL, (b) 10 mM ± 2 mM histidine buffer, pH 6.0 ± 0,3, (c) 0.1% ± 0.05% w/v polysorbate 80, and (d) 10% ± 2% w/v sucrose. In one embodiment of this particular formulation, the viscosity is less than 5 cPoise.

[00055] In one aspect, the présent disclosure provides a stable liquid pharmaceutical formulation, comprising: (a) from 5% ± 1% to 15% ± 3% w/v sucrose, (b) from 5 mM ± 1 mM to 20 mM ± 4 mM histidine buffer, (c) from 0.01% ± 0.005% to 0.5% ± 0.25% w/v polysorbate, and (d) up to 100 mg/mL ± 15 mg/mL total anti-EBOV antibody, at pH 6.0 ± 0.3. In another aspect, a stable liquid pharmaceutical formulation Îs provided, comprising: (a) 10% ±2% w/v sucrose, (b) iOmM ±2mM histidine buffer, (c) 0.1% ±0.05% w/v polysorbate, and (d) 50 mg/mL ±7.5 mg/mL total antiEBOV antibody, at pH 6.0 ± 0.3. The anti-EBOV antibody, according to this aspect, comprises a combination of three antibodies that bind specifically to EBOV, wherein the three antibodies comprise a heavy chain variable region/light chain variable région (HCVR/LCVR) amino acid sequence pair of (i) SEQ ID NOs: 2/10, (ii) SEQ ID NOs: 20/28, and (iii) SEQ ID NOs: 38/46.

[00056] In one aspect, a stable liquid pharmaceutical formulation is provided, comprising: (a) from 5% ± 1% to 15% ± 3% w/v sucrose, (b) from 5 mM ± 1 mM to 20 mM ± 4 mM histidine buffer, (c) from 0.01% ± 0.005% to 0.5% ± 0.25% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total antiEBOV antibody, at pH 6.0 ± 0.3. In another aspect, a stable liquid pharmaceutical formulation is provided, comprising: (a) 10% ±2% w/v sucrose, (b) IOmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total antibody, at pH 6.0 ± 0.3. The antiEBOV antibody, according to this aspect, comprises a combination of three antibodies that bind specifically to EBOV, wherein the three antibodies comprise a heavy chain variable region/light chain variable région (HCVR/LCVR) amino acid sequence pair of (i) SEQ ID NOs: 2/10, (ii) SEQ ID NOs: 20/28, and (iii) SEQ ID NOs: 38/46.

[00057] In one embodiment, the stable liquid formulation comprises 150 mg/mL total anti-EBOV antibody. In one embodiment, the stable liquid formulation comprises 100 mg/mL total anti-EBOV antibody. In one embodiment, the stable liquid formulation comprises 50 mg/mL total anti-EBOV antibody. In one embodiment, the stable liquid formulation comprises 10 mM ± 2 mM histidine buffer. In one embodiment, the stable liquid formulation comprises 10% sucrose. In one embodiment, the stable liquid formulation comprises 9% sucrose. In one embodiment, the stable liquid formulation comprises 8% sucrose. In one embodiment, the stable liquid formulation comprises 5% sucrose. In one embodiment, the stable liquid formulation comprises 0.1% polysorbate. In one embodiment, the stable liquid formulation comprises 0.2% polysorbate. In one embodiment, the polysorbate is polysorbate 80 or polysorbate 20.

[00058] In one embodiment, the stable liquid formulation comprises 33.3 mg/mL antibody comprising a heavy chain variable region/light chain variable région (HCVR/LCVR) amino acid sequence pair of SEQ ID NOs: 2/10, 33.3 mg/mL antibody comprising an HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 20/28, and 33.3 mg/mL antibody comprising an HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 38/46, in an aqueous buffered solution, pH 6.0, containing 10 mM L-histidine, 10% (w/v) sucrose, and 0.1% (w/v) polysorbate 80. In one embodiment, the stable liquid formulation maintains ADCC potency of at least about 90%, or at least about 95%, in an ADCC bioassay after storage at 5°C for 6 months, relative to the same liquid formulation prior to storage at 5°C for 6 months. In one embodiment, the stable liquid formulation maintains pseudovirus neutralization activity of at least about 95% after storage at 5°C for 6 months, relative to the same liquid formulation prior to storage at 5°C for 6 months. In one embodiment, the stable liquid formulation maintains ADCC potency of at least about 80%, or at least about 85%, in an ADCC bioassay after storage at 25°C/60% RH for 6 months, relative to the same liquid formulation prior to storage at 25°C/60% RH for 6 months. In one embodiment, the stable liquid formulation maintains pseudovirus neutralization activity of at least about 95% after storage at 25°C/60% RH for 6 months, relative to the same liquid formulation prior to storage at 25°C/60% RH for 6 months. In one embodiment, the stable liquid formulation maintains pseudovirus neutralization activity of at least about 95% after storage at 40°C/75% RH for 6 months, relative to the same liquid formulation prior to storage at 40°C/75% RLI for 6 months. In one embodiment, the stable liquid formulation maintains ADCC potency of at least about 95% in an ADCC bioassay after agitation for 120 minutes, relative to the same liquid formulation prior to agitation for 120 minutes. In one embodiment, the stable liquid formulation maintains ADCC potency of at least about 85% in an ADCC bioassay after 8 freeze/thaw cycles, relative to the same liquid formulation prior to 8 freeze/thaw cycles. In one embodiment, the stable liquid formulation maintains pseudovirus neutralization activity of at least about 95% after agitation for 120 minutes, relative to the same liquid formulation prior to agitation for 120 minutes. In one embodiment, the stable liquid formulation maintains pseudovirus neutralization activity of at least about 95% after 8 freeze/thaw cycles, relative to the same liquid formulation prior 8 freeze thaw cycles.

[00059] In one aspect, a stable liquid pharmaceutical formulation of any of the precedîng aspects is provided in a container. In one embodiment, the container îs a vial. In one embodiment, the container is a polycarbonate vial. In one embodiment, the container is a glass vial. In one embodiment, the glass vial is a type 1 clear glass vial. In one embodiment, the glass vial îs a type 1 borosilicate glass vial with a fluorocarbon-coated butyl rubber stopper. In one embodiment, the container îs a microinfuser. In one embodiment, the container is a syringe. In one embodiment, the container îs a prefilled syringe. In one embodiment, the syringe comprises low-tungsten glass. In one embodiment, the syringe comprises an autoinjector. In one embodiment, the syringe comprises a fluorocarbon-coated plunger. In certain embodiments, the syringe is a 1 mL or 2.25 mL long glass syringe containîng less than about 500 parts per billion of tungsten equipped with a 27-G needle, a fluorocarbon-coated butyl rubber stopper, and a latex-free, non-cytotoxic rubber tip cap. In one embodiment, the syringe is a 1 mL long glass syringe equipped with a 27-G thin wall needle, a FLUROTEC-coated 4023/50 rubber stopper, and a FM 27 rubber tip cap. In one embodiment, the syringe is a 1 mL, 2 mL, 3 mL, 5 mL or 10 mL plastic syringe fitted with a needle.

[00060] In one aspect, a kit comprising a stable pharmaceutical composition of any one of the precedîng aspects, a container, and instructions is provided. In one embodiment, the container is a glass vial. In one embodiment, the container is a prefilled syringe. In one embodiment, the container is an autoinjector. In one embodiment, the syringe is a 1 mL or 2.25mL long glass syringe equipped with a 27-G thin wall needle, a FLUROTEC-coated 4023/50 rubber stopper, and a FM 27 rubber tip cap. In one embodiment, the syringe is a 1 mL, 2 mL, 3 mL, 5 mL or 10 mL plastic syringe fitted with a needle.

[00061] In certain embodiments, the présent disclosure provides a prefilled syringe comprising a stable liquid pharmaceutical formulation comprising: (i) from 5 ± 0.75 mg/ml to 250 ± 37.5 mg/ml of at least one human antibody that specifically binds to EBOV; (ii) from 5 mM ± 1 mM to 20 ± 4 mM histidine buffer; (iîî) from 0.05% ± 0.025% to 0.3% ± 0.15% (w/v) polysorbate 80; and (iv) from 1% ± 0.2% to 10% ± 2% (w/v) sucrose, atapHof6.0±0.3, wherein the at least one human anti-EBOV antibody is selected from the group consisting of a first antibody comprising three heavy chain CDRs (HCDRl, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10, a second antibody comprising three heavy chain CDRs (HCDRl, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28, and a third antibody comprising three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDRl, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46. In some aspects, the formulation has an attribute selected from the group consisting of: at least 90% of the antibody is the native species after 28 days at 45°C; at least 18% of the antibody is the main charge variant of the antibody after 28 days at 45°C; at least 96% of the antibody is the native species after three months at 25°C; at least 30% of the antibody is the main charge variant of the antibody after three months at 25°C; at least 96% of the antibody is the native species after 12 months at 5°C; at least 34% ofthe antibody is the main charge variant ofthe antibody after 12 months at 5°C; at least 97% ofthe antibody is the native species after 120 minutes agitation; at least 35% ofthe antibody is the main charge variant ofthe antibody after 120 minutes agitation; at least 97% ofthe antibody is the native species after 8 freeze thaw cycles; at least 35% of the antibody is the main charge variant of the antibody after 8 freeze thaw cycles; over 90% of the antibodies hâve a molecular weight of 145 kDa± 2 kDa, for example for example, 144,804 Da, 145,905 Da, or 143,689 Da; and the pharmaceuticaî formulation has a viscosity of less than 20 cP, less than 15 cP, less than 10 cP, less than 5 cP, or less than 3 cP.

[00062] In certain embodiments the présent discîosure provides a glass vial comprising a stable liquid pharmaceuticaî formulation comprising: (a) 10% + 2% w/v sucrose, (b) lOmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) from 5 mg/mL + 0.75 mg/mL to 250 mg/mL + 37.5 total anti-EBOV antibody, at pH 6.0 + 0.3; wherein the at least one anti-EBOV antibody is selected from the group consisting of: a first antibody comprising three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDRl, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10, a second antibody comprising three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDRl, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28, and a third antibody comprising three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDRl, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46. In some aspects, the formulation has an attribute selected from the group consisting of: the formulation is stable to storage and stress in a glass vial; the formulation is stable to and compatible for use in IV delivery devices; the formulation is chemically and physically stable to dilution with standard diluents known in the art (e.g., 0.9% sodium chloride or 5% dextrose or Lactated Ringer’s); the formulation is stable to IV bags made of giass or polymer plastics (e.g., polyvînyl chioride, phthaiates, polyolefins or polypropylene); the formulation is compatible with standard infusion pumps (e.g., peristaltic pump, fluid displacement pump); at least 90% of the antibody is the native species after 28 days at 45°C; at least 18% of the antibody is the main charge variant of the antibody after 28 days at 45°C; at least 96% of the antibody is the native species after three months at 25 °C; at least 30% of the antibody is the main charge variant of the antibody after three months at 25°C; at least 96% of the antibody is the native species after 12 months at 5°C; at least 34% of the antibody is the main charge variant of the antibody after 12 months at 5°C; at least 97% of the antibody is the native species after 120 minutes agitation; at least 35% ofthe antibody is the main charge variant ofthe antibody after 120 minutes agitation; at least 97% ofthe antibody is the native species after 8 freeze thaw cycles; at least 35% of the antibody is the main charge variant of the antibody after 8 freeze thaw cycles; over 90% ofthe antibodies hâve a molecular weight of 145 kDa± 2 kDa, for example, 144,804 Da, 145,905 Da, or 143,689 Da; and the pharmaceutical formulation has a viscosity of less than 20 cP, less than 15 cP, less than 10 cP, less than 5 cP, or less than 3 cP. In some aspects, the formulation is stable for shîpping at températures of about 2°C to about 8°C. In some aspects, the formulation is stable when stored at about 2°C to about 8°C. Stability studies hâve been performed to support potential excursions from storage conditions. In some aspects, the formulation is stable at room température for at least about 6 months. In some aspects, the formulation is physically and chemically stable against agitation and freeze/thaw cycles. In some aspects, the antibodies within the formulation maintain bîological activity, e.g. ADCC activity or pseudovirus neutralization activity, after exposure to températures up to 25°C, or up to 30°C, or after agitation or freeze/thaw cycles. [00063] Other embodiments will become apparent from a review of the ensuing detailed description.

| BRIEF DESCRIPTION OF FIGURES

[00064] Figure 1 shows an overlay of RP-UPLC chromatograms from HIHI7203P, HIH17139P, | and H1H17161P.

[00065] Figure 2 shows an overlay ofHlH17203P, HIH17139P, and H1H17I61P SE-UPLC | Chromatograms.

DETAILED DESCRIPTION

[00066] Therapeutic drugs such as biologics are typically formulated as individual drugs in

I

I formulations providing stability of the therapeutic for long-term storage at cool températures. Packaged biologics are treated with care, often maintaîned in lyophîiized form just until prîor to use in order to minimize aggregation and damage to the large molécules. Lyophîiized formulations are typically more stable than liquid formulations. In addition, packaged biologics are kept cool, if not frozen, during transport and storage.

[00067] Provided herein are stable pharmaceutical formulations comprising antibodies for the treatment of Ebola virus (EBOV) infection or prophylactic treatment for EBOV exposure. These formulations are stable liquid antibody formulations prepared to withstand rigorous transport and storage while maintaining stability. The therapeutics are prepared in a manner to facilitate use in remote areas where Ebola outbreaks occur such as Congo and Sudan. As such, the formulations are in liquid form to avoîd reconstitution steps required prier to using a drug in lyophîiized form, avoiding possible contamination of the drug product. The liquid pharmaceutical formulations are stable even when transported long distances and subjected to stress, for example, température cycles, extreme températures, agitation during transport, etc., conditions a therapeutic would be exposed to in transit from a manufacturing facility to remote field clinics where Ebola exposure has occurred and/or Ebola patients exist.

[00068] In some aspects, the stable liquid formulation comprises more than one antibody, e.g. is a cocktail comprising, for example, two or three anti-EBOV antibodies. Stable antibody cocktails formulations are diffîcult. Exposure of protein therapeutics in IV bags to ambient température and visible light are short term, so those mild conditions typically do not induce product dégradation. However, during long terni storage îndividual proteins typically undergo some dégradation processes includîng enhanced attractive intermolecular protein-proteîn interactions, increased viscosîty, and compromised structural integrity. Stress conditions présent during coformulation manufacturing, transport, storage, handling and patient administration can affect what becomes a critical product liability: aggregation, deamidation, oxidation, etc. In addition, coformulât!on conditions can lead to formation of heterogeneous aggregates. See Svitel et al., BioProcess International, 2019; Patel et al, Journal of Pharmaceutical Sciences, 107: 3032-3046, 2018; and Mueller et al., Journal of Pharmacy and Pharmacology, 70: 666-674, 2018.

[00069] Before the présent methods are described, it is to be understood that this invention îs not limited to particular methods, and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terniinology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the présent disciosure will be jimited only by the appended daims.

[00070] Unless defined otherwise, ail technical and scientific ternis used herein hâve the same meaning as commonly understood by one of ordînary skil! in the art to which this invention belongs. As used herein, the terni about”, when used in reference to a particular recited numerical value or range of values, means that the value may vary from the recited value by no more than 1%. For example, as used herein, the expression about 100 includes 99 and 101 and ail values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.). Although any methods and materîals similar or équivalent to those described herein can be used in the practice or testing of the présent disciosure, preferred methods and materîals are now described. Ail publications mentioned herein are incorporated herein by reference in theîr entirety.

[00071] As used herein, the expression pharmaceutical formulation means a combination of at least one active ingrédient (e.g., a small molécule, macromolecule, compound, etc. which is capable of exerting a biological effect in a human or non-human animal), and at least one inactive ingrédient which, when combined wîth the active ingrédient or one or more additional inactive ingrédients, is suitable for therapeutic administration to a human or non-human animal. The terni formulation”, as used herein, means pharmaceutical formulation unless speciflcaliy îndîcated otherwise. The présent disciosure provides pharmaceutical formulations comprising at least one therapeutic polypeptide. According to certain embodiments of the présent disciosure, the therapeutic polypeptide is an antibody, or an antigen-binding fragment thereof, which binds speciflcaliy to Ebola Virus (EBOV). More speciflcaliy, the présent disciosure includes stable pharmaceutical formulations that comprise: (i) one or more human antibodies that specifîcally bind to EBOV (ii) a histidine buffer; (iii) an organic cosolvent that is a non-ionie surfactant; and (iv) a stabilizer that is a carbohydrate. In one particular embodiment, the stable pharmaceutical formulation comprises: (i) three human antibodies that speciflcaliy bind to EBOV (ii) a histidine buffer; (îü) an organic cosolvent that is a non-ionic surfactant; and (iv) a stabilizer that is a carbohydrate. Spécifie exemplary components and formulations included within the présent disciosure are described in detail below.

ANTIBODIES THAT BIND SPECIFICALLY TO EBOV

[00072] The pharmaceutical formulations of the présent disciosure may comprise a human antibody, or an antigen-binding fragment thereof, that binds speciflcaliy to EBOV. As used herein, the terni EBOV” means Ebola Virus. Antibodies to EBOV are described in, for example, US

Patent/Publication Nos. 10,501,526 10,081,670, 9,771,414, 6,630,144, 6,875,433,7,335,356, and 8,513,391, and in WO 2016/123019, EP1539238, EP2350270, and EP8513391

[00073] The term antibody, as used herein, is generally intended to refer to immunoglobulin molécules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains înterconnected by disulfïde bonds, as well as multimers thereof (e.g., IgM); however, immunoglobulin molécules consisting of only heavy chains (i.e., lacking light chains) are also encompassed wîthin the définition of the term antibody”. Each heavy chain comprises a heavy chain variable région (abbreviated herein as HCVR or Vh) and a heavy chain constant région. The heavy chain constant région comprises three domains, CH1, CH2 and CH3. Each light chain comprises a light chain variable région (abbreviated herein as LCVR or Vl) and a light chain constant région. The light chain constant région comprises one domain (CL1). The Vu and Vl régions can be further subdivided into régions of hypervariability, termed complementarity determining régions (CDRs), interspersed with régions that are more conserved, termed Framework régions (FR). Each Vh and Vi. is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FRI, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[00074] Unless specifically indîcated otherwise, the term antibody”, as used herein, shah be understood to encompass complété antibody molécules as well as antigen-binding fragments thereof. The term antigen-binding portion or antigen-binding fragment of an antibody (or simply antibody portion or antibody fragment), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to EBOV or an epitope thereof.

[00075] An isolated antibody, as used herein, is intended to refer to an antibody that is substantially free of other antîbodies having different antigénie specificities (e.g., an isolated antibody that specifically binds EBOV is substantially free of antîbodies that specifically bind antigens other than EBOV).

[00076] The term specifically binds”, or the lîke, means that an antibody or antigen-binding fragment thereof forms a complex wîth an antigen that is relatively stable under physiologie conditions. Spécifie binding can be characterized by a dissociation constant of at least about IxiO'⁸ M or greater. Methods for determining whether two molécules specifically bind are well known in the art and include, for example, equilibrium dialysis, surface plasmon résonance, and the like. In the context of the présent disclosure, muItispécifie (e.g., bispecific) antîbodies that bind to EBOV as well as one or more additional antigens are deemed to specifically bind EBOV. Moreover, an isolated antibody may be substantially free of other cellular material or Chemicals.

[00077] Exemplary anti-EBOV antibodies that may be included in the pharmaceutical formulations of the présent disclosure are set forth in patent application publications US 2016/0215040, and WO 2016/123019, the disclosures of which are incorporated by reference in their entirety. Of particular interest are the three antibodies H1H17203P, H1H17139P, and ΡΠΗ17161Ρ disclosed therein and formulated independently or in any combination in a stable pharmaceutical formulation.

[00078] According to certain embodiments of the présent disclosure, the anti-EBOV antibody, or antigen-binding fragment thereof, comprises a heavy chain complementarity determining région (HCDR) 1 ofSEQ IDNO: 4, an HCDR2 ofSEQ IDNO: 6, and an HCDR3 ofSEQ IDNO: 8. in certain embodiments, the anti-EBOV antibody, or antigen-binding fragment thereof, comprises an HCVR ofSEQ ID NO: 2.

[00079] According to certain embodiments of the présent disclosure, the anti-EBOV antibody, or antigen-binding fragment thereof, comprises a light chain complementarity determining région (LCDR) 1 ofSEQ IDNO: 12, an LCDR2 ofSEQ ID NO: 14, and an LCDR3 ofSEQ IDNO: 16. In certain embodiments, the anti-EBOV antibody, or antigen-binding fragment thereof, comprises an LCVR ofSEQ IDNO: 10.

[00080] According to certain embodiments of the présent disclosure, the anti-EBOV antibody, or antigen-binding fragment thereof, comprises a HCVR having 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 2.

[00081] According to certain embodiments of the présent disclosure, the anti-EBOV antibody, or antigen-binding fragment thereof, comprises a LCVR having 90%, 95%, 98% or 99% sequence identity to SEQ IDNO: 10.

[00082] According to certain embodiments of the présent disclosure, the anti-EBOV antibody, or antigen-binding fragment thereof, comprises a HCVR comprising an amino acid sequence ofSEQ ID NO: 2 having no more than 5 amino acid substitutions.

[00083] According to certain embodiments of the présent disclosure, the anti-EBOV antibody, or antigen-binding fragment thereof, comprises a LCVR comprising an amino acid sequence of SEQ ID NO: 10 having no more than 2 amino acid substitutions.

[00084] According to certain embodiments of the présent disclosure, the anti-EBOV antibody, or antigen-binding fragment thereof, comprises a heavy chain complementarity determining région (HCDR) 1 ofSEQ ID NO: 22, an HCDR2 ofSEQ IDNO: 24, and an HCDR3 ofSEQ ID NO: 26.

In certain embodiments, the anti-EBOV antibody, or antigen-binding fragment thereof, comprises an HCVR ofSEQ ID NO: 20.

[00085) According to certain embodiments of the présent disclosure, the anti-EBOV antibody, or antigen-binding fragment thereof, comprises a light chain complementarity determining région (LCDR)l ofSEQ IDNO: 30, an LCDR2 ofSEQ ID NO: 32, and an LCDR3 ofSEQ IDNO: 34. In certain embodiments, the anti-EBOV antibody, or antigen-binding fragment thereof, comprises an LCVR ofSEQ ID NO: 28.

[00086] According to certain embodiments of the présent disclosure, the anti-EBOV antibody, or antigen-binding fragment thereof, comprises a I-ICVR having 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 20.

|00087] According to certain embodiments of the présent disclosure, the anti-EBOV antibody, or antigen-binding fragment thereof, comprises a LCVR having 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 28.

[00088] According to certain embodiments of the présent disclosure, the anti-EBOV antibody, or antigen-binding fragment thereof, comprises a HCVR comprising an amino acid sequence ofSEQ ID NO: 20 having no more than 5 amino acid substitutions.

[000891 According to certain embodiments of the présent disclosure, the anti-EBOV antibody, or antigen-binding fragment thereof, comprises a LCVR comprising an amino acid sequence of SEQ ID NO: 28 having no more than 2 amino acid substitutions.

[00090] According to certain embodiments of the présent disclosure, the anti-EBOV antibody, or antigen-binding fragment thereof, comprises a heavy chain complementarity determining région (HCDR) 1 ofSEQ ID NO: 40, an HCDR2 of SEQ IDNO: 42, and an HCDR3 ofSEQ IDNO: 44.

In certain embodiments, the anti-EBOV antibody, or antigen-binding fragment thereof, comprises an HCVR ofSEQ ID NO: 38.

[00091] According to certain embodiments of the présent disclosure, the anti-EBOV antibody, or antigen-binding fragment thereof, comprises a light chain complementarity determining région (LCDR)l ofSEQ IDNO: 48, an LCDR2 ofSEQ IDNO: 50, and an LCDR3 ofSEQ IDNO: 52. In certain embodiments, the anti-EBOV antibody, or antigen-binding fragment thereof, comprises an LCVR ofSEQ IDNO: 46.

[00092] According to certain embodiments of the présent disclosure, the anti-EBOV antibody, or antigen-binding fragment thereof, comprises a HCVR having 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 38.

[00093] According to certain embodiments of the présent disclosure, the anti-EBOV antibody, or antigen-binding fragment thereof, comprises a LCVR having 90%, 95%, 98% or 99% sequence identîty to SEQ ID NO: 46.

[00094] According to certain embodiments of the présent disclosure, the anti-EBOV antibody, or antigen-binding fragment thereof, comprises a HCVR comprising an amino acid sequence of SEQ ID NO: 38 havîng no more than 5 amino acid substitutions.

[00095] According to certain embodiments of the présent disclosure, the anti-EBOV antibody, or antigen-binding fragment thereof, comprises a LCVR comprising an amino acid sequence of SEQ ID NO: 46 havîng no more than 2 amino acid substitutions.

[00096] According to certain embodiments of the présent disclosure, a stable liquid pharmaceutical formulation comprises one or more of the anti-EBOV antibodies, or antigen-binding fragments thereof, as described above.

[00097] Sequence identity may be measured by any method known in the art (e.g., GAP, BESTFIT, and BLAST).

[00098] The présent disclosure also includes stable liquid formulations comprising anti-EBOV antibodies, wherein the anti-EBOV antibodies comprise variants of any of the HCVR, LCVR and/or CDR amino acid sequences disclosed herein havîng one or more amino acid substitutions, for example, conservative amino acid substitutions. Illustratively, the présent disclosure includes formulations comprising anti-EBOV antibodies havîng HCVR, LCVR and/or CDR amino acid sequences with, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc. amino acid substitutions, e.g. conservative amino acid substitutions, relative to any of the HCVR, LCVR and/or CDR amino acid sequences disclosed herein.

[00099] In certain embodiments, the anti-EBOV antibody comprises a Fc région elected from the group consisting of human IgGl, IgG2, IgG3, and IgG4 isotypes.

[000100] According to certain embodiments of the présent disclosure, the anti-EBOV, or antigenbinding fragment thereof, comprises a heavy chain of SEQ ID NO: 17 and a light chain of SEQ ID NO: 18.

[000101] According to certain embodiments of the présent disclosure, the anti-EBOV, or antigenbinding fragment thereof, comprises a heavy chain of SEQ IDNO: 35 and a light chain of SEQ ID NO: 36.

[000102] According to certain embodiments of the présent disclosure, the anti-EBOV, or antigenbinding fragment thereof, comprises a heavy chain of SEQ ID NO: 53 and a light chain of SEQ ID NO: 54.

[000103] It is well known in the art that terminal cleavage of amino acids can occur during production of antibodies (see, for example, Wang et al 2007, J. Pharma. Sci. 96: 1-26). Accordingly, în certain embodiments, the anti-EBOV antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 17, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 35, or wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 53. In some aspects, the heavy chain is missing the C-terminal lysine from the amino acid sequence of SEQ ID NO: 17. In some aspects, the heavy chain is missing the C-terminal lysine from the amino acid sequence of SEQ ID NO: 35. In some aspects, the heavy chain amino is missing the C-terminal lysine from the amino acid sequence of SEQ ID NO: 53. In certain embodiments, formulations of the présent disclosure contaîn about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98% or more of the anti-EBOV antibody wherein the C-terminal lysine is absent.

[000104] The amount of antibody, antibody combination, or antigen-binding fragment(s) thereof, contained within the stable liquid pharmaceutical formulations of the présent disclosure may vary depending on the spécifie properties desired of the formulations, as well as the particular circumstances and purposes for which the formulations are intended to be used. For example, it may be necessary to ship formulations comprising one or more anti-EBOV antibodies from the site of manufacture to remote areas of the world, e.g. Congo or other parts of Africa, where the formulations may be exposed to agitation during transit and/or high températures during transit or at point-of-care.

[000105] In certain embodiments, the pharmaceutical formulations are stable liquid formulations that may contain 5 ± 0.75 mg/mL to 250 ± 37.5 mg/mL total antibody; 10 ± 1.5 mg/mL to 240 ± 36 mg/mL total antibody; 20 ± 3.0 mg/mL to 230 ± 34.5 mg/mL total antibody; 25 ± 3.75 mg/mL to 240 ± 36 mg/mL total antibody; 50 ± 7.5 mg/mL to 230 ± 34.5 mg/mL total antibody; 60 ± 9 mg/mL to 240 ±36 mg/mL total antibody; 70 ± 10.5 mg/mL to 230 ± 34.5 mg/mL total antibody; 80 ± 12 mg/mL to 220 ± 33 mg/mL total antibody; 90 ± 13.5 mg/mL to 210 ± 31.5 mg/mL total antibody; 100 ± 15 mg/mL to 200 ± 30 mg/mL total antibody; 110 ± 16.5 mg/mL to 190 ± 28.5 mg/mL total antibody; 120 ± 18 mg/mL to 180 ±27 mg/mL total antibody; 130 ± 19.5 mg/mL to 170+25.5 mg/mL total antibody; 140 ± 21 mg/mL to 160 ± 24 mg/mL total antibody; 150 ± 22.5 mg/mL total antibody; or 175 ± 26.25 mg/mL For example, the formulations ofthe présent disclosure may comprise about 5 mg/mL; about 10 mg/mL; about 15 mg/mL; about 20 mg/mL; about 25 mg/mL; about 30 mg/mL; about 35 mg/mL; about 40 mg/mL; about 45 mg/mL; about 50 mg/mL; about 55 mg/mL; about 60 mg/mL; about 65 mg/mL; about 70 mg/mL; about 75 mg/mL; about 80 mg/mL;

about 85 mg/mL; about 90 mg/mL; about 95 mg/mL; about 100 mg/mL; about 105 mg/mL; about 110 mg/mL; about 115 mg/mL; about 120 mg/mL; about 125 mg/mL; about 130 mg/mL; about 135 mg/mL; about 140 mg/mL; about 145 mg/mL; about 150 mg/mL; about 155 mg/mL; about 160 mg/mL; about 165 mg/mL; about 170 mg/mL; about 175 mg/mL; about 180 mg/mL; about185 mg/mL; about 190 mg/mL; about 195 mg/mL; about 200 mg/mL; about 205 mg/mL; about210 mg/mL; about 215 mg/mL; about 220 mg/mL; about 225 mg/mL; about 230 mg/mL; about235 mg/mL; about 240 mg/mL; about 245 mg/mL; or about 250 mg/mL total antibody or antigenbinding fragment(s) thereof, that bind specifically to EBOV.

EXCIPIENTS AND pH

[000106] The pharmaceutical formulations of the present disclosure comprise one or more excipients. The term excipient”, as used herein, means any non-therapeutic agent added to the formulation to provide a desired consistency, viscosity or stabilizing effect.

[000107] In certain embodiments, the pharmaceutical formulation dîsclosed herein comprises at Ieast one organic cosolvent in a type and in an amount that stabilizes the EBOV antibody under conditions of rough handling or agitation, such as, e.g., vortexing, orbital shaking and shocking. In some embodiments, what is meant by “stabilizes” is the prévention of the formation of aggregated antibody, for example, prévention of the formation of more than 0% aggregated antibody, or more than 1% aggregated antibody, or more than 3% aggregated antibody of the total amount of antibody (on a molar basis) over the course of rough handling. In some embodiments, the cosolvent stabilizes the formulation to prevent the formation of 0% to 3% aggregated antibody. In some embodiments, the cosolvent stabilizes the formulation to prevent the formation of more than 0% aggregated antibody. In some embodiments, rough handling is vortexing a solution containing the antibody and the organic cosolvent for about 60 minutes or about 120 minutes.

[000108] In certain embodiments, the organic cosolvent is a non-ionic surfactant, such as an alkyl poly(ethylene oxide). Spécifie non-ionic surfactants that can be included in the formulations of the present disclosure include, e.g._t polysorbates such as polysorbate 20, polysorbate 28, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 81, and polysorbate 85; poloxamers such as poloxamer 181, poloxamer 188, poloxamer 407; or polyethylene glyco! (PEG). Polysorbate 20 îs also known as TWEEN 20, sorbitan monolaurate and polyoxyethylenesorbitan monolaurate. Poloxamer 188 is also known as PLURONIC F68.

[000109] The amount of non-ionic surfactant contained within the pharmaceutical formulations of the présent disclosure may vary depending on the spécifie properties desired of the formulations, as well as the particular circumstances and purposes for which the formulations are intended to be used. In certain embodiments, the formulations may contain 0.01% + 0.005% to 0.5% ± 0.25% surfactant. For example, the formulations of the présent disclosure may comprise about 0.005%; about 0.01%; about 0.02%; about 0.03%; about 0.04%; about 0.05%; about 0.06%; about 0.07%; about 0.08%; about 0.09%; about 0.1%; about 0.11%; about 0.12%; about 0.13%; about 0.14%; about 0.15%; about 0.16%; about 0.17%; about 0.18%; about 0.19%; about 0.20%; about 0.21%;

about 0.22%; about 0.23%; about 0.24%; about 0.25%; about 0.26%; about 0.27%; about 0.28%;

about 0.29%; about 0.30%; about 0.35%; about 0.40%; about 0.45%; about 0.46%; about 0.47%;

about 0.48%; about 0.49%; about 0.50%; about 0.55%; or about 0.575% polysorbate 20 or polysorbate 80.

[000110] The pharmaceutical formulations ofthe présent disclosure may also comprise one or more stabilizers in a type and in an amount that stabilizes the EBOV antibody under conditions of thermal stress. In some embodiments, what is meant by “stabilizes” is maintaining greater than about 91% of the antibody în a native conformation when the solution containing the antibody and the thermal stabilizer is kept at about 45°C for at least about 28 days. In some embodiments, what is meant by “stabilizes” is wherein less than about 6% of the antibody îs aggregated when the solution containing the antibody and the thermal stabilizer is kept at about 45°C for at least about 28 days. As used herein, “native” means the major form of the antibody by size exclusion, which is generally an intact monomer ofthe antibody. The term “native” also refers to non-aggregated and non-degraded form of the antibody.

[000111] In some embodiments, the thermal stabilizer is a polyol. In some embodiments, the thermal stabilizer is an amino acid. In some aspects, the thermal stabilizer is a sugar such as sucrose. The amount of stabilizer contained within the formulation can vary depending on the spécifie circumstances and intended purposes for which the formulation is used. In certain embodiments, the formulations may contain about 1% to about 15% sugar; about 2% to about 14% sugar; about 3% to about 13% sugar; about 4% to about 12% sugar; about 5% to about 12% sugar; about 6% to about 11% sugar; about 7% to about 10% sugar; about 8% to about 11% sugar; or about 9% to about 11% sugar. For example, the pharmaceutical formulations of the présent disclosure may comprise 4%± 0.8%; 5% ±1%; 6% ± 1.2%; 7% ± 1.4%; 8% ± 1.6%; 9% ± 1.8%; 10% ± 2%; 11% ± 2.2%; 12% ± 2.4%; 13% ± 2.6%; or about 14% ± 2.8% sugar (e.g., sucrose).

[000112] The pharmaceutical formulations of the présent disclosure may also comprise a buffer or 32 buffer System, which serves to maintain a stable pH and to help stabilize the EBOV antibody. The term “buffer” as used herein dénotés a pharmaceutically acceptable buffer which maintains a stable pH or resists changes în pH of the solution. In preferred embodiments, the buffer comprises histidine. In the context of this disclosure, “histidine buffer” or “buffer comprising histidine” is a buffer comprising the amino acid histidine. Examples of histidine buffers include histidine chloride, histidine acetate, histidine phosphate, and histidine sulfate. In one embodiment, the histidine buffer is prepared by dissolving L-histidine and L-histidine hydrochloride (e.g. as monohydrate) in a defmed amount and ratio. In one embodiment, the histidine buffer is prepared by titrating Lhistidîne (free base, solîd) with diluted hydrochloric acid. The term “histidine” is used interchangeably with “histidine buffer” throughout this disclosure. In some embodiments, what is meant by “stabilizes” is wherein less than 10% ± 0.5% of the antibody is aggregated when the solution containing the antibody and the buffer is kept at about 45°C for at least about 28 days. In some embodiments, what is meant by “stabilizes” is wherein less than 5% + 0.5% or less than 4% ± 0.5% of the antibody is aggregated when the solution containing the antibody and the buffer is kept at about 25 °C for up to about three months. In some embodiments, what is meant by “stabilizes” is wherein less than 5% ± 0.5% or less than 4% ± 0.5% of the antibody is aggregated when the solution containing the antibody and the buffer is kept at about 5°C for up to about 36 months. In some embodiments, what is meant by “stabilizes” is wherein at least 90% ± 0.5% or at least 94% ± 0.5% of the antibody is in its native conformation as determined by size exclusion chromatography when the solution containing the antibody and the buffer is kept at about 45°C for at least about 28 days. In some embodiments, what is meant by “stabilizes” is wherein at least 95% ± 0.5% or at least 96% ± 0.5% of the antibody is in its native conformation as determined by size exclusion chromatography when the solution containing the antibody and the buffer is kept at about 25°C for up to about 3 months. In some embodiments, what is meant by “stabilizes” is wherein at least 95% ± 0.5% or at least 96% + 0.5% of the antibody is in its native conformation as determined by size exclusion chromatography when the solution containing the antibody and the buffer is kept at about 5°C for up to about 12 months. By “native” or “native conformation”, what is meant is the antibody fraction that is not aggregated or degraded. This is generalîy determined by an assay that measures the relative size ofthe antibody entity, such as a size exclusion chromatographie assay. The nonaggregated and ηοπ-degraded antibody elutes at a fraction that equates to the native antibody, and is generalîy the main elutîon fraction. Aggregated antibody elutes at a fraction that indicates a size greater than the native antibody. Degraded antibody elutes at a fraction that indicates a size less than 33 the native antibody.

[000113] In some embodiments, what is meant by “stabilizes” is wherein at least 18% ± 0.5% of the antibody is in îts main charge form as determined by cation exchange chromatography when the solution containing the antibody and the buffer îs kept at about 45°C for at least about 28 days, or at least about a month. In some embodiments, what is meant by “stabilizes” is wherein at least 30% + 0.5% or at least 35% + 0.5% ofthe antibody is in its main charge form as determined by cation exchange chromatography when the solution containing the antibody and the buffer is kept at about 25°C for up to about 3 months. In some embodiments, what is meant by “stabilizes” is wherein at least 30% ± 0.5% or at least 34% ± 0.5% of the antibody is in its main charge form as determined by cation exchange chromatography when the solution containing the antibody and the buffer is kept at about 5°C for up to about 12 months. By “main charge” or “main charge form”, what is meant is the fraction of antibody that elutes from an ion exchange resin in the main peak, which is generally flanked by more “basic” peaks on one side and more “acidic” peaks on the other side.

[000114] The pharmaceuticaî formulations of the présent discîosure may hâve a pH of from about 5.2 to about 6.4. For example, the formulations ofthe présent discîosure may hâve a pH of about 5.5; about 5.6; about 5.7; about 5.8; about 5.9; about 6.0; about 6.1; about 6.2; about 6.3; about 6.4; or about 6.5. In some embodiments, the pH is 6.0 ± 0.4; 6.0 ± 0.3; 6.0 +0.2; 6.0± 0.1; about 6.0; or 6.0.

[000115] In some embodiments, the buffer or buffer System comprises at least one buffer that has a buffering range that overlaps fuily or in part the range ofpH 5.5-7.4. In certain embodiments, the buffer comprises a histidine buffer. In certain embodiments, the histidine buffer is présent at a concentration of 5 mM ± 1 mM to 15 mM ± 3 mM; 6 mM + 1.2 mM to 14 mM ± 2.8 mM; 7 mM ± 1.4 mM to 13 mM ± 2.6 mM; 8 mM ± 1.6 mM to 12 mM ± 2.4 mM; 9 mM ± 1.8 mM to 11 mM + 2.2 mM; 10 mM + 2 mM; or about 10 mM. In certain embodiments, the buffer System comprises histidine at 10 mM ± 2 mM, at a pH of 6.0 ±0.3. In certain embodiments, the histidine buffer comprises L-histidîne and L-histidine monohydrochloride monohydrate. In one embodiment, the histidine buffer comprises L-histidine at a concentration of 4.8 mM ± 0.96 mM. In one embodiment, the histidine buffer comprises L-histidine monohydrochloride monohydrate at a concentration of 5.2 mM + 1.04 mM. In one embodiment, the histidine buffer comprises L-histidine at a concentration of 4.8 mM ± 0.96 mM and L-hîstidîne monohydrochloride monohydrate at a concentration of 5.2 mM + 1.04 mM.

[000116] The pharmaceutical formulations of the présent disclosure may also comprise one or more excipients that serve to maîntain a reduced viscosity or to lower the viscosity of formulations containing a high concentration of anti-EBOV antibody drug substance (e.g., generally > 150 mg/ml of antibody). In certain embodiments, the viscosity modifier is an amino acid such as proline or histidine.

[000117] During the antibody purification process it may be desired or necessary to exchange one buffer for another to achieve appropriate excipient concentrations, antibody concentration, pH, etc. Buffer exchange can be accomplished, e.g., by ultrafiltration/diafiltration (UF/DF) using, e.g., a semi-permeable tangential flow filtration membrane. Use of such techniques, however, has the potential to cause the Gibbs-Donnan effect [Bolton et al., 2011, Biotechnol. Prog. 27(1):140-152]. The buildup of positive charge on the product side of the membrane during protein concentration is counterbalanced electrically by the preferential movement of positive ions to the opposite side of the membrane. The potential conséquence of this phenomenon is that the final concentrations of certain components (e.g., histidine, etc.) may be lower than the intended target concentrations of these components due to the electrostatic repulsion of positîvely charged diafiStration buffer excipients to the positîvely charged antibody protein during the UF/DF step. Thus, the présent disclosure includes formulations in which the concentration of, e.g., histidine vary from the recited amounts or ranges herein due to the Gibbs-Donnan effect.

[000118] Volume exclusion describes the behavior of highly concentrated samples in which a significant portion of the total volume of the solution is taken up by the soluté, especially large molécules such as proteins, excluding the cosolvent from this space. This then decreases the total volume of cosolvent available for other solutés to be dissolved in, which may resuit in unequal partition across the ultrafiltration membrane. Thus, the présent disclosure includes formulations in which the concentration of, e.g., histidine may vary from the recited amounts or ranges herein due to the volume exclusion effect.

[000119] During the manufacture of the formulations of the présent disclosure, variations in the composition of the formulation may occur. These variations may include the concentration of the active ingrédient, the concentration of the excipients, and/or the pH of the formulation. Because changes in any of these parameters could potentîally impact the stability or potency of the drug product, formulation robustness studies were conducted to assess whether variations in the composition, within the defined ranges, would impact the stability or potency of the antibody. Accordingly, the présent disclosure includes formulations comprising anti-EBOV antibodies which are stable and retain potency with up to 50% variation in the excipient concentration. For example, included herein are anti-EBOV antibody formulations, wherein stability and potency of said formulations is unaffected by ± 10%, ± 20%, ±30%, ± 40% or ± 50% variation in the concentration of antibody, sucrose, histidine buffer and/or polysorbate.

STABILITY AND VISCOSITY OF THE PHARMACEUTICAL FORMULATIONS

[000120] As illustrated in the examples below, the présent inventors hâve made the surprising discovery that stable liquid formulations comprising high concentrations of one or more anti-EBOV antibody (e.g., about 50 mg/mL or about 100 mg/mL) can be obtained by formulating the antibody with about 0.1 % polysorbate 80, about 10% sucrose, and about 10 mM histidine buffer. In some aspects, the stable liquid formulations comprise three anti-EBOV antibodies at total antibody concentrations of 50 mg/mL or 100 mg/mL, 0.1% polysorbate 80, 10% sucrose, and about 10 nM histidine buffer at a pH of about 6. Such formulations, even those containing three different antibodies, are stable to stress during rough handling and to storage at températures ranging from 80°C to 45°C, such as -30°C, -20°C, 5°C, 25°C, (shown herein) and hâve low viscosity (hâve viscosity below 5cP).

[000121] The pharmaceutical formulations of the présent disclosure typically exhibit high levels of stability. The term stable”, as used herein in reference to the pharmaceutical formulations, means that the antibodies within the pharmaceutical formulations retain an acceptable degree of Chemical structure or biological function after storage under defined conditions. A formulation may be stable even though the antibody contained therein does not maintain 100% of its Chemical structure or biological function after storage for a defined amount of time. Under certain cireumstances, maintenance of about 90%, about 95%, about 96%, about 97%, about 98% or about 99% of an antibody's structure or function after storage for a defined amount of time may be regarded as stable”.

[000122| Stability can be measured, inter alia, by determîning the percentage of native antibody that remains in the formulation after storage for a defined amount of time at a defïned température. The percentage of native antibody can be determined by, inter alia, size exclusion chromatography (e.g., size exclusion ultra performance liquid chromatography [SE-UPLC]), such that native means non-aggregated and non-degraded. An acceptable degree of stability”, as that phrase is used herein, means that at least 90% of the native form of the antibody can be detected in the formulation after storage for a defined amount of time at a given température. In certain embodiments, at least about

90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the native form of the antibody can be detected in the formulation after storage for a defmed amount of time at a defined température. The defined amount of time after which stability is measured can be at least 14 days, at least 28 days, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, or more. The defined température at which the pharmaceutical formulation may be stored when assessing stability can be any température from about -80°C to about 60°C, e.g., storage at about -80°C, about -30°C, about 20°C, about 0°C, about 4°-8°C, about 5°C, about 25°C, about 35°C, about 37°C, about 40°C, or about 45°C. For example, a pharmaceutical formulation may be deemed stable if after 28 days of storage at 40°C/75% humîdity (RH), greater than about 95%, 96%, 97% or 98% of native antibody is detected by SE-UPLC. A pharmaceutical formulation may be deemed stable if after 12 months of storage at 5°C, greater than about 95%, 96%, 97% or 98% of native antibody is detected by SE-UPLC. A pharmaceutical formulation may also be deemed stable if after 3 months of storage at 25°C, greater than about 95%, 96%, 97% or 98% of native antibody is detected by SE-UPLC. A pharmaceutical formulation may also be deemed stable if after 28 days of storage at 45°C, greater than about 89%, 90%, 91%, 92%, 93%, 94%, 95% or 96% of native antibody is detected by SE-UPLC. A pharmaceutical formulation may also be deemed stable if after 12 months of storage at -20°C, greater than about 96%, 97%, or 98% of native antibody is detected by SE-UPLC. A pharmaceutical formulation may also be deemed stable if after 12 months of storage at -30°C, greater than about 96%, 97% or 98% of native antibody is detected by SE-UPLC. A pharmaceutical formulation may also be deemed stable if after 12 months of storage at -80°C_f greater than about 96%, 97% or 98% of native antibody is detected by SE-UPLC.

[000123] Stability can be measured, inter alia, by determining the percentage of antibody that forms in an aggregate wîthin the formulation after storage for a defmed amount of time at a defined température, wherein stability is inversely proportîonal to the percent aggregate that is formed. The percentage of aggregated antibody can be determined by, inter alia, size exclusion chromatography (e.g., size exclusion ultra performance liquid chromatography [SE-UPLC]). An acceptable degree of stability”, as that phrase is used herein, means that at most 5% of the antibody is in an aggregated form (also denoted as the high molecular weight - HMW - form) detected in the formulation after storage for a defined amount of time at a given température. In certain embodiments an acceptable degree of stability means that at most about 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of the antibody can be detected in an aggregate in the formulation after storage for a defîned amount of time at a given température, The defîned amount of time after which stability is measured can be at least 2 weeks, at least 28 days, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, or more. The température at which the pharmaceutical formulation may be stored when assessîng stability can be any température from about -80°C to about 45°C, e.g., storage at about -80°C, about -30°C, about 20°C, about 0°C, about 4°-8°C, about 5°C, about 25°C, about 35°C, about 37°C, about 40°C, or about 45°C. For example, a pharmaceutical formulation may be deemed stable if after 12 months of storage at 5°C, less than about 2%, 1%, 0.5%, or 0.1% of the antibody is detected in an aggregated form. A pharmaceutical formulation may also be deemed stable if after three months of storage at 25°C, less than about 4%, 3%, 2%, 1%, 0,5%, or 0.1% ofthe antibody is detected in an aggregated form. A pharmaceutical formulation may also be deemed stable if after 28 days of storage at 40°C/75%RH, less than about 4%, 3%, 2%, 1%, 0,5%, or 0.1% of the antibody is detected in an aggregated form. A pharmaceutical formulation may also be deemed stable if after 28 days of storage at 45°C, less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5%, ofthe antibody is detected in an aggregated form. A pharmaceutical formulation may also be deemed stable if after three months of storage at -20°C, -30°C, or -80°C less than about 3%, 2%, 1%, 0.5%, or 0.1% of the antibody is detected in an aggregated form.

[000124] Stability can be measured, inter alia, by determining the percentage of antibody that migrâtes in a more acidic fraction during ion exchange (“acidic form”) than in the main fraction of antibody (“main charge form”), wherein stability is inversely proportional to the fraction of antibody in the acidic form. While not wishing to be bound by theory, deamidation of the antibody may cause the antibody to become more negatively charged and thus more acidic relative to the nondeamîdated antibody (see, e.g., Robinson, N., Protein Deamidation, PNAS, April 16, 2002, 99(8):5283-5288). The percentage of “acidified” antibody can be determined by, inter alia, ion exchange chromatography (e.g., cation exchange ultra performance liquid chromatography [CEXUPLC]). An acceptable degree of stability”, as that phrase is used herein, means that at most 45% ofthe antibody is in a more acidic form detected in the formulation after storage for a defîned amount of time at a defîned température. In certain embodiments an acceptable degree of stability means that at most about 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of the antibody can be detected in an acidic form in the formulation after storage for a defîned amount of time at a given température. In one embodiment, an acceptable degree of stability means that less than 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% ofthe antibody can be detected in an acidic form in the formulation after storage for a defined amount of time at a given température. The defined amount of time after which stability is measured can be at least 2 weeks, at least 28 days, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, or more. Thé température at which the pharmaceutical formulation may be stored when assessing stability can be any température from about -80°C to about 45°C, e.g., storage at about -80°C, about -30°C, about 20°C, about 0°C, about 4°-8°C, about 5°C, about 25°C, or about 45°C. For example, a pharmaceutical formulation may be deemed stable if after three months of storage at -80°C, -30°C, or -20°C less than about 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1% ofthe antibody is in a more acidic form. A pharmaceutical formulation may also be deemed stable if after 12 months of storage at 5°C, less than about 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0,1% of the antibody is in a more acidic form. A pharmaceutical formulation may also be deemed stable if after 3 months of storage at 25°C, less than about 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1% of the antibody is in a more acidic form. A pharmaceutical formulation may also be deemed stable if after 28 days of storage at 45°C, less than about 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 10%,9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0. i% ofthe antibody can be detected in a more acidic form.

[000125] Other methods may be used to assess the stability of the formulations of the présent disciosure such as, e.g., dîfferentîal scanning calorimetry (DSC) to détermine thermal stability, controlled agitation to détermine mechanical stability, and absorbance at about 350 nm or about 405 nm to détermine solution turbidities. For example, a formulation of the présent disciosure may be considered stable if, after 6 or more months of storage at about 5°C to about 25°C, the change in OD405 of the formulation is less than about 0.05 (e.g., 0.04, 0.03, 0.02, 0.01, or less) from the OD405 of the formulation at tîme zéro.

[000126] Measuring the biological activity or binding affinity of the antibody to its target may also be used to assess stability. For example, a formulation of the present disclosure may be regarded as stable if, after storage at e.g., 5°C, 25°C, 45°C, etc. for a defined amount of tîme (e.g., 1 to 36 months), the anti-EBOV antibody contained within the formulation binds to EBOV with an affinity that is at Ieast 90%, 95%, or more of the binding affinity of the antibody prior to said storage. Binding affinity may be determined by e.g., EL ISA or surface plasmon résonance.

Biological actîvity may be determined by a EBOV activity assay, such as e.g., contactîng a cell infected with EBOV with the formulation comprisîng the anti-EBOV antibody. The binding of the antibody to such a cell may be measured directly, such as e.g., via FACS analysis. Alternatively, activity of antibody can be determined by a decrease in viral load in vitro or in vivo, or by an increase in survival of a mammal infected with EBOV.

[000127] Additionally, measuring the relative potency of the antibody in an antîbody-dependent cellular cytotoxicity assay (ADCC assay) can be used to assess stability. For example, a formulation ofthe present disclosure may be regarded as stable if, after storage at e.g., - 80°C, -30°C, -20°C, 5°C, 25°C, 40°C, 45°C, etc. for a defined amount of time (e.g., 1 to 36 months), the anti-EBOV antibody contained within the formulation retains 90%, 95%, or more relative ADCC potency compared to the antibody prior to storage.

[000128] Simîlarly, measuring the relative potency ofthe antibody in pseudovirus neutralization assay can be used to assess stability. For example, a formulation of the present disclosure may be regarded as stable if, after storage at e.g., - 80°C, -30°C, -20°C, 5°C, 25°C, 40°C, 45°C, etc. for a defined amount of tîme (e.g, 1 to 36 months), the anti-EBOV antibody contained within the formulation retains 90%, 95%, or more relative pseudovirus neutralization compared to the antibody prior to storage.

[000129] Additional methods for assessing the stability of an antibody in formulation are demonstrated in the Examples presented below.

[000130] The liquid pharmaceutical formulations of the present disclosure may, in certain embodiments, exhibit low to moderate levels of viscosity. Viscosity as used herein may be kinematic viscosity or absolute viscosity”. Kinematic viscosity is a measure of the résistive flow of a fluid under the influence of gravity. When two fluids of equal volume are placed in identical capillary viscometers and allowed to flow by gravity, a viscous fluid takes longer than a less viscous fluid to flow through the capillary. For example, if one fluid takes 200 seconds to complété its flow and another fluid takes 400 seconds, the second fluid is twice as viscous as the first on a kinematic viscosity scale. Absolute viscosity, sometimes called dynamic or simple viscosity, is the product of kinematic viscosity and fluid density (Absolute Viscosity = Kinematic Viscosity x Density). The dimension of kinematic viscosity is L²/T where L is a length and T is a time. Commonly, kinematic viscosity is expressed în centistokes (cSt). The SI unît of kinematic viscosity is mm²/s, which is 1 cSt. Absolute viscosity is expressed in units of centipoise (cP). The SI unit of absolute viscosity is the milliPascal-second (mPa-s), where 1 cP = 1 mPa-s.

[000131] As used herein, a low level of viscosity, in reference to a fluid formulation of the présent disclosure, will exhibit an absolute viscosity of less than about 20 cPoise (cP). For example, a fluid formulation disclosed herein will be deemed to hâve low viscosity”, if, when measured using standard viscosity measurement techniques, the formulation exhibits an absolute viscosity of about 20 cP, about 19 cP, about 18 cP, about 15 cP, about 12 cP, about 10 cP, about 9 cP, about 8 cP, or less. As used herein, a moderate level of viscosity, în reference to a fluid formulation of the présent disclosure, will exhibit an absolute viscosity of between about 35 cP and about 20 cP. For example, a fluid formulation disclosed herein will be deemed to hâve moderate viscosity”, if when measured using standard viscosity measurement techniques, the formulation exhibits an absolute viscosity of about 34 cP, about 33 cP, about 32 cP, about 31 cP, about 30 cP, about 29 cP, about 28 cP, about 27 cP, about 26 cP, about 25 cP, about 24 cP, about 23 cP, about 22 cP, about 21 cP, about 20 cP, about 19 cP, 18 cP, about 17 cP, about 16 cP, or about 15 cP. Formulations provided herein can hâve a low viscosity, for example, a viscosity of about 2 cP.

EXEMPLARY FORMULATIONS

[000132] According to one aspect of the présent disclosure, the pharmaceutical formulation is a stable, low viscosity, generally physiologically isotonie liquid formulation, which comprises: (i) a human antibody that specifically binds to EBOV (e.g., HIHI7203P, H1H17139P, and/or H1H17161P), at a concentration of up to 250 mg/mL ± 45 mg/mL; (ii) a histidine buffer System that provides sufficient buffering at about pH 6.0 ± 0.3; (iii) an organic cosolvent, which protects the structural integrity of the antibody; and (iv) a stabilizer that is a sugar.

[000133] According to one embodiment, the stable, liquid pharmaceutical formulation comprises: (a) 10% ± 2% w/v sucrose, (b) lOmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ± 7.5 mg/mL total anti-EBOV antibody, at pH 6.0 ± 0.3; wherein the antibody is a human IgGl antibody that comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) 41 and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10. In one embodiment, the anti-EBOV antibody comprises anHCDRl ofSEQ ID NO: 4, an HCDR2 ofSEQIDNO: 6, an HCDR3 ofSEQ ID NO: 8, an LCDRI ofSEQ ID NO: 12, an LCDR2 ofSEQ ID NO: 14, and an LCDR3 ofSEQ ID NO: 16.

[000134] According to one embodiment, the stable, liquid pharmaceutical formulation comprises: (a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ±7.5 mg/mL total anti-EBOV antibody, at pH 6.0 ± 0.3; wherein the antibody is a human IgGl antibody that comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs; 20/28. In one embodiment, the anti-EBOV antibody comprises an HCDR1 ofSEQ ID NO: 22, an HCDR2 ofSEQ ID NO: 24, an HCDR3 ofSEQ ID NO: 26, an LCDRI ofSEQ ID NO: 30, an LCDR2 ofSEQ ID NO: 32, and an LCDR3 ofSEQ ID NO: 34.

[000135] According to one embodiment, the stable, liquid pharmaceutical formulation comprises: (a) 10% ± 2% w/v sucrose, (b) lOmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ±7.5 mg/mL total anti-EBOV antibody, at pH 6.0 ± 0.3; wherein the antibody is a human IgGl antibody that comprises three heavy chaîn CDRs (HCDR1,I-ICDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (îii) SEQ ID NOs: 38/46. In one embodiment, the anti-EBOV antibody comprises an HCDR1 ofSEQ ID NO: 40, an HCDR2 ofSEQ ID NO: 42, an HCDR3 ofSEQ ID NO: 44, an LCDRI ofSEQ ID NO: 48, an LCDR2 ofSEQ ID NO: 50, and an LCDR3 ofSEQ ID NO: 52.

[000136] According to one embodiment, the stable, liquid pharmaceutical formulation comprises: (a) 10% ± 2% w/v sucrose, (b) lOmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ±7.5 mg/mL total anti-EBOV antibody, at pH 6.0 ± 0.3; wherein a first antibody îs a human IgGl antibody that comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10, and a second antibody is a human IgGl antibody that comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained în the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28. In one embodiment, the first anti-EBOV antibody comprises an HCDR1 ofSEQ ID NO: 4, an HCDR2 ofSEQ ID NO: 6, an HCDR3 ofSEQ ID NO: 8, an LCDRI ofSEQ ID NO: 12, 42 an LCDR2 of SEQ ID NO: 14, and an LCDR3 of SEQ ID NO: 16; and the second anti-EBOV antibody comprises an HCDRl of SEQ ID NO: 22, an HCDR2 of SEQ ID NO: 24, an HCDR3 of SEQ ID NO: 26, an LCDR1 of SEQ ID NO: 30, an LCDR2 of SEQ ID NO: 32, and an LCDR3 of SEQ ID NO: 34.

[000137] According to one embodiment, the stable, liquid pharmaceutical formulation comprises: (a) 10% ± 2% w/v sucrose, (b) lOmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ± 7.5 mg/mL total anti-EBOV antibody, at pH 6.0 ± 0.3; wherein a first antibody is a human IgGl antibody that comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10, and a second antibody is a human IgGI antibody that comprises three heavy chain CDRs (HCDRl, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46. In one embodiment, the first anti-EBOV antibody comprises an HCDR1 of SEQ ID NO: 4, an HCDR2 of SEQ ID NO: 6, an HCDR3 of SEQ ID NO: 8, an LCDR1 of SEQ ID NO: 12, an LCDR2 of SEQ ID NO: 14, and an LCDR3 of SEQ ID NO: 16; and the second antiEBOV antibody comprises an HCDR1 of SEQ ID NO: 40, an HCDR2 of SEQ ID NO: 42, an HCDR3 ofSEQIDNO: 44, an LCDR1 ofSEQ ID NO: 48, an LCDR2 ofSEQIDNO: 50, and an LCDR3 ofSEQ ID NO: 52.

[000138] According to one embodiment, the stable, liquid pharmaceutical formulation comprises: (a) 10% ± 2% w/v sucrose, (b) 10mM + 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ± 7.5 mg/mL total anti-EBOV antibody, at pH 6.0 ± 0.3; wherein a first antibody is a human IgGl antibody that comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28, and a second antibody is a human IgGl antibody that comprises three heavy chain CDRs (HCDRl, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46. In one embodiment, the first anti-EBOV antibody comprises an HCDRl of SEQ IDNO: 22, an HCDR2 ofSEQ ID NO: 24, an HCDR3 ofSEQ IDNO: 26, an LCDR1 ofSEQ ID NO: 30, an LCDR2 ofSEQ ID NO: 32, and an LCDR3 ofSEQ ID NO: 34; and the second antiEBOV antibody comprises an HCDRl ofSEQ ID NO: 40, an HCDR2 ofSEQ ID NO: 42, an HCDR3 ofSEQ IDNO: 44, an LCDR1 ofSEQ IDNO: 48, an LCDR2 ofSEQ IDNO: 50, and an LCDR3 ofSEQ ID NO: 52.

[000139] According to one embodiment, the stable, liquid pharmaceutical formulation comprises; (a) 10% ± 2% w/v sucrose, (b) I0mM ± 2mM histidine buffer, (c) 0.1% ± 0,05% w/v polysorbate, and (d) 50 mg/mL ±7.5 mg/mL total anti-EBOV antibody, at pH 6.0 ± 0.3; wherein a first antibody is a human IgGl antibody that comprises three heavy chain CDRs (HCDRI, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10, a second antibody is a human IgG 1 antibody that comprises three heavy chain CDRs (HCDRI, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28, and a third antibody is a human IgGl antibody that comprises three heavy chain CDRs (HCDRI, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46. In one embodiment, the first anti-EBOV antibody comprises an HCDRI of SEQ ID NO: 4, an HCDR2 of SEQ ID NO: 6, an HCDR3 of SEQ ID NO; 8, an LCDRI of SEQ ID NO: 12, an LCDR2 of SEQ ID NO: 14, and an LCDR3 of SEQ ID NO: 16; the second anti-EBOV antibody comprises an HCDRI of SEQ ID NO: 22, an HCDR2 of SEQ ID NO: 24, an HCDR3 of SEQ ID NO; 26, an LCDRI of SEQ ID NO: 30, an LCDR2 of SEQ ID NO: 32, and an LCDR3 of SEQ ID NO: 34; and the third anti-EBOV antibody comprises an HCDRI of SEQ ID NO: 40, an HCDR2 of SEQ ID NO: 42, an HCDR3 of SEQ ID NO: 44, an LCDRI of SEQ ID NO: 48, an LCDR2 of SEQ TD NO: 50, and an LCDR3 ofSEQ ID NO: 52.

[000140] According to one embodiment, the stable, liquid pharmaceutical formulation comprises: (a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total anti-EBOV antibody, at pH 6.0 ± 0.3; wherein the antibody is a human IgGl antibody that comprises three heavy chain CDRs (HCDRI, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10. In one embodiment, the anti-EBOV antibody comprises an HCDRI ofSEQ ID NO: 4, an HCDR2 ofSEQ ID NO: 6, an HCDR3 ofSEQ ID NO: 8, an LCDRI ofSEQ ID NO: 12, an LCDR2 ofSEQ ID NO: 14, and an LCDR3 ofSEQ ID NO: 16.

[000141] According to one embodiment, the stable, liquid pharmaceutical formulation comprises: (a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total anti-EBOV antibody, at pH 6.0 ± 0.3; wherein the antibody is a human IgGl antibody that comprises three heavy chain CDRs (HCDRI, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino 44 acid sequence pair of (ii) SEQ ID NOs; 20/28. In one embodiment, the anti-EBOV antibody comprises an HCDRl of SEQ ID NO; 22, an HCDR2 of SEQ ID NO: 24, an HCDR3 of SEQ ID NO: 26, an LCDR1 of SEQ ID NO: 30, an LCDR2 of SEQ ID NO: 32, and an LCDR3 of SEQ ID NO: 34.

[000142] According to one embodiment, the stable, liquid pharmaceutical formulation comprises: (a) 10% ± 2% w/v sucrose, (b) lOmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ±15 mg/mL total anti-EBOV antibody, at pH 6.0 ± 0.3; wherein the antibody is a human IgGl antibody that comprises three heavy chain CDRs (HCDRl, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs; 38/46. In one embodiment, the anti-EBOV antibody comprises an HCDR1 of SEQ ID NO: 40, an HCDR2 of SEQ ID NO: 42, an HCDR3 of SEQ ID NO: 44, an LCDR1 of SEQ ID NO: 48, an LCDR2 ofSEQ ID NO; 50, and an LCDR3 ofSEQ ID NO: 52.

[000143] According to one embodiment, the stable, liquid pharmaceutical formulation comprises: (a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total anti-EBOV antibody, at pH 6.0 ±0.3; wherein a first antibody is a human IgGl antibody that comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs; 2/10, and a second antibody is a human IgGl antibody that comprises three heavy chain CDRs (HCDRl, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28. In one embodiment, the first anti-EBOV antibody comprises an HCDRl ofSEQ ID NO: 4, an HCDR2 ofSEQ ID NO: 6, an HCDR3 ofSEQ ID NO: 8, an LCDR1 ofSEQ ID NO: 12, an LCDR2 ofSEQ IDNO: 14, and an LCDR3 ofSEQ IDNO: 16; and the second anti-EBOV antibody comprises an HCDRl ofSEQ ID NO: 22, an HCDR2 ofSEQ ID NO: 24, an HCDR3 of SEQ ID NO: 26, an LCDR1 ofSEQ IDNO: 30, an LCDR2 ofSEQ ID NO: 32, and an LCDR3 of SEQ ID NO: 34.

[000144] According to one embodiment, the stable, liquid pharmaceutical formulation comprises: (a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total anti-EBOV antibody, at pH 6.0 ± 0.3; wherein a first antibody is a human IgGl antibody that comprises three heavy chain CDRs (HCDRl, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino 45 acid sequence pair of (i) SEQ ID NOs: 2/10, and a second antibody is a human IgGl antibody that comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contaîned in the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46. In one embodiment, the first anti-EBOV antibody comprises an HCDR1 of SEQ ID NO: 4, an HCDR2 of SEQ ID NO: 6, an HCDR3 of SEQ ID NO: 8, an LCDR1 of SEQ ID NO: 12, an LCDR2 of SEQ ID NO: 14, and an LCDR3 of SEQ ID NO: 16; and the second antiEBOV antibody comprises an HCDR1 of SEQ ID NO: 40, an HCDR2 of SEQ ID NO: 42, an HCDR3 of SEQ ID NO: 44, an LCDR1 ofSEQ ID NO: 48, an LCDR2 of SEQ ID NO: 50, and an LCDR3 ofSEQ ID NO: 52.

[000145] According to one embodiment, the stable, liquid pharmaceutical formulation comprises: (a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total anti-EBOV antibody, at pH 6.0 ± 0.3; wherein a first antibody is a human IgGI antibody that comprises three heavy chain CDRs (HCDRl, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28, and a second antibody is a human IgGl antibody that comprises three heavy chain CDRs (HCDRl, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46. In one embodiment, the first anti-EBOV antibody comprises an HCDRl of SEQ ID NO: 22, an HCDR2 ofSEQ ID NO: 24, an HCDR3 ofSEQ ID NO: 26, an LCDR1 ofSEQ ID NO: 30, an LCDR2 ofSEQ ID NO: 32, and an LCDR3 ofSEQ ID NO: 34; and the second antiEBOV antibody comprises an HCDR1 ofSEQ ID NO: 40, an HCDR2 ofSEQ ID NO: 42, an HCDR3 ofSEQ IDNO: 44, an LCDR1 ofSEQ ID NO: 48, an LCDR2 ofSEQ ID NO: 50, and an LCDR3 ofSEQ ID NO: 52.

[000146] According to one embodiment, the stable, liquid pharmaceutical formulation comprises: (a) 10% ± 2% w/v sucrose, (b) 10mM + 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total anti-EBOV antibody, at pH 6.0 ± 0.3; wherein a first antibody is a human IgGl antibody that comprises three heavy chain CDRs (HCDRl, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10, a second antibody is a human IgGl antibody that comprises three heavy chain CDRs (HCDRl, HCDR2 and HCDR3) and three light chaîn CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28, and a third antibody is a human IgGl antibody that comprises three heavy chain 46

CDRs (HCDR1, HCDR2 and HCDR3) and three lightchain CDRs (LCDRl, LCDR2 and LCDR3) contained in the HCVR/LCVR. amino acid sequence pair of (iii) SEQ ID NOs: 38/46. In one embodiment, the first anti-EBOV antibody comprises an HCDR1 of SEQ ID NO: 4, an HCDR2 of SEQ ID NO: 6, an HCDR3 of SEQ ID NO: 8, an LCDRl of SEQ ID NO: 12, an LCDR2 of SEQ ID NO: 14, and an LCDR3 of SEQ ID NO: 16; the second anti-EBOV antibody comprises an HCDR1 ofSEQ ID NO: 22, an HCDR2 of SEQ ID NO: 24, an HCDR3 ofSEQ ID NO: 26, an LCDRl of SEQ ID NO: 30, an LCDR2 ofSEQ ID NO: 32, and an LCDR3 ofSEQ ID NO: 34; and the third anti-EBOV antibody comprises an HCDRl ofSEQ ID NO: 40, an HCDR2 ofSEQ ID NO: 42, an HCDR3 of SEQ ID NO: 44, an LCDRI of SEQ ID NO: 48, an LCDR2 of SEQ ID NO: 50, and an LCDR3 ofSEQ ID NO: 52.

[000147] Additional non-limiting examples of pharmaceuticaî formulations encompassed by the présent discîosure are set forth elsewhere herein, including the working Examples presented below.

CONTAINERS AND METHODS OF ADMINISTRATION

[000148] The pharmaceuticaî formulations of the présent discîosure may be contained within any container suitable for storage of medicines and other therapeutic compositions. For example, the pharmaceuticaî formulations may be contained within a sealed and sterilized plastic or glass container having a defined volume such as a vial, ampule, syringe, cartrîdge, or bottle. Different types ofvials can be used to contain the formulations ofthe présent discîosure including, e.g., clear and opaque (e.g., amber) glass or plastic vials. Likewise, any type of syringe can be used to contain or administer the pharmaceuticaî formulations ofthe présent discîosure.

[000149] The pharmaceuticaî formulations of the présent discîosure may be contained within normal tungsten syringes or low tungsten syringes. As will be appreciated by persons of ordinary skill in the art, the process of making glass syringes generally invoives the use of a hot tungsten rod which functions to pierce the glass thereby creating a ho le from which liquid s can be drawn and expelled from the syringe. This process results in the déposition of trace amounts of tungsten on the înterior surface of the syringe. Subséquent washing and other processing steps can be used to reduce the amount of tungsten in the syringe. As used herein, the term normal tungsten means that the syringe contains greater than or equal to 500 parts per billion (ppb) of tungsten. The term low tungsten means that the syringe contains less than 500 ppb of tungsten. For example, a low tungsten syringe, according to the présent discîosure, can contain less than about 490, 480, 470, 460, 450, 440, 430, 420, 410, 390, 350, 300, 250, 200, 150, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10 or fewer ppb of tungsten.

[000150] The rubber plungers used in syringes, and the rubber stoppers used to close the openings of vials, may be coated to prevent contamination of the médicinal contents of the syringe or vial, or to preserve their stability. Thus, pharmaceutical formulations of the présent disclosure, according to certain embodiments, may be contained within a syringe that comprises a coated plunger, or within a vial that is sealed with a coated rubber stopper. For example, the plunger or stopper may be coated with a fluorocarbon film. Examples of coated stoppers or plungers suitable for use with vials and syringes containing the pharmaceutical formulations of the présent disclosure are mentioned in, e.g., U.S. Patent Nos. 4,997,423; 5,908,686; 6,286,699; 6,645,635; and 7,226,554, the contents of which are incorporated by reference herein in their entireties. Particular exemplary coated rubber stoppers and plungers that can be used in the context of the présent disclosure are commercially available under the tradename FluroTec®”, available from West Pharmaceutical Services, Inc. (Lionville, PA). FluroTec® is an example of a flurocarbon coating used to mînimize or prevent drug product from adhering to the rubber surfaces.

[000151] According to certain embodiments of the présent disclosure, the pharmaceutical formulations may be contained within a low tungsten syringe that comprises a fluorocarbon-coated plunger.

[000152] The pharmaceutical formulations can be administered to a patient by parentéral routes such as injection (e.g., subcutaneous, intravenous, intramuscular, intraperitoneal, etc.) or percutaneous, mucosal, nasal, pulmonary or oral administration. Numerous reusable pen or autoinjector delivery devices can be used to subcutaneously deliver the pharmaceutical formulations of the présent disclosure. Examples include, but are not limited to AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25™ pen, HUMALOG™ pen, HUMALIN 70/30™ pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™, and OPTICLIK™ (sanofi-aventis, Frankfurt, Germany). Examples of disposable pen or autoinjector delivery devices having applications in subcutaneous delivery of a pharmaceutical composition of the présent disclosure include, but are not limited to the SOLOSTAR™ pen (sanofi-aventis), the FLEXPEN™ (Novo Nordisk), and the KWIKPEN™ (Eli Lilly), the SURECLICK™ Autoinjector (Amgen, Thousand Oaks, CA), the PENLET™ (Haselmeier, Stuttgart, Germany), the EP1PEN (Dey, L.P.), and the

HUMIRA™ Pen (Abbott Labs, Abbott Park, IL).

[000153] The use of a microinfosor to deliver the pharmaceutical formulations ofthe présent disclosure is also contemplated herein. As used herein, the term microinfusor means a subcutaneous delivery device designed to slowly adminîster large volumes (e.g., up to about 2.5 mL or more) of a therapeutic formulation over a prolonged period of time (e.g., about 10, 15, 20, 25, 30 or more minutes). See, e.g., U.S. 6,629,949; US 6,659,982; and Meehan et al., J. ControlledRelease 46:107-116 (1996). Microinfusors are particularly useful for the delivery of large doses of therapeutic proteins contained within high concentration (e.g., about 100, 125, 150, 175, 200 or more mg/mL) or viscous solutions.

[000154] In certain embodiments, the stable liquid pharmaceutical formulation of any of the preceding aspects is contained in a stérile glass vial and is administered as an IV infusion. Exemplary dosages include 30,000 mg, 25,000 mg, 20,000 mg, 15,000 mg, 13,500 mg, 12,500 mg, 10,000 mg, 7,500 mg, 5000 mg, 2500 mg, 1450 mg, 1000 mg, 725 mg, 600 mg, 500 mg, 250 mg, 200 mg, 150 mg, 100 mg, 75 mg, 50 mg, or 25 mg.

[000155] In one embodiment, the container is a 20 mL type I clear borosilicate glass vial. In certain embodiments, the container is a 2 mL, 5mL or 10 mL type 1 borosilicate glass vial with a chlorobutyl stopper, with a FluroTec® coating.

[000156] In one embodiment, the liquid pharmaceutical formulation of the présent disclosure comprising about 25 mg/mL, 50 mg/mL, 100 mg/mL, or 150 mg/mL anti-EBOV antibody is administered intravenously and may be contained in a glass vial. In some embodiments, the présent disclosure provides a glass vial comprising a stable liquid formulation comprising 50 mg/mL, 100 mg/mL, or 150 mg/mL total anti-EBOV antibody, 10mM of histidine, at pH of about 6.0, 10% sucrose, and 0.1% polysorbate 80.

[000157] In some embodiments, each antibody is administered at 50 mg/kg of body weight. In one embodiment, two antibodies are co-formulated such that the final formulation provides for each antibody to be administered at 50 mg/kg of body weight. Accordingly, the final dose to be administered to the patient is 100 mg/kg of body weight, with the two antibodies in the formulation at a 1:1 ratio. In one embodiment, the co-formulated antibodies are delivered intravenously over a time period of about 2 hours.

[000158] In some embodiments, three antibodies are co-formulated such that the final formulation provides for each antibody to be administered at 50 mg/kg of body weight. Accordingly, the final dose to be administered to the patient is 150 mg/kg of body weight, with the three antibodies in the formulation at a 1:1:1 ratio. In one embodiment, the co-formulated antibodies are delivered intravenously over a tîme period of about 2 hours.

[000159] In some aspects, a patient weighing about 90 kg receiving 150 mg/kg dose would get dose of about 13,500 mg dose. In some aspects, a patient weighing about 45 kg person receiving 150 mg/kg would get dose of about 6,750 mg. In some aspects, a patient might receive as much as 30,000 mg.

[000160] In certain embodiments, the three antibodies are prepared in a glass vial. In certain embodiments, each vial may contain 725 mg of total antibody, i.e. three antibodies at a 1:1:1 ratio in a volume of 14.5 mL, giving a final antibody concentration of 50 mg/mL. This may be administered intravenously to a patient in a time period of two hours.

[000161] In certain embodiments, the three antibodies are prepared in a glass vial. In certain embodiments, each vial may contain 1450 mg of total antibody, i.e. three antibodies at a 1 ;1:1 ratio in a volume of 14.5 mL, giving a final antibody concentration of 100 mg/mL. This may be administered intravenously to a patient in a time period of two hours.

[000162] In certain embodiments, the présent disclosure provides an autoinjector comprising any of the liquid formulations described herein. In some embodiments, the présent disclosure provides an autoinjector comprising a stable liquid formulation comprising about 50 mg/mL, about 100 mg/mL, about 150 mg/mL or about 175 mg/mL total anti-EBOV antibody, about lOmM of histidine, at pH of about 6.0, about 10% sucrose, and about 0.1% polysorbate 80.

[000163] In certain embodiments, the présent disclosure provides an autoinjector comprising any of the liquid formulations described herein. In some embodiments, the présent disclosure provides an autoinjector comprising a stable liquid formulation comprising 50 mg/mL or 100 mg/mL total anti-EBOV antibody, lOmM of histidine, at pH of about 6.0, 10% sucrose, and 0.1% polysorbate 80. [000164] In certain embodiments, the présent disclosure provides a prefilled syringe comprising any of the liquid formulations described herein. In some embodiments, the présent disclosure provides a prefilled syringe comprising a stable liquid formulation comprising about 50 mg/mL, about 100 mg/mL, about 1 50 mg/mL or about 175 mg/mL anti-EBOV antibody, about I0mM of histidine, at pH of about 6.0, about 10% sucrose, and about 0.1% polysorbate 80. In certain embodiments, the syringe is a 1 mL or 2.25 mL long glass syringe filled with a 27-gauge thin wall needle, a fluorocarbon coated rubber plunger and a rubber needle shield.

[000165] In one embodiment, the liquid pharmaceutical formulation containing about 100 mg/mL ± 15 mg/mL total anti-EBOV antibody is administered in a volume of approximately up to 2 mL in a prefilled syringe. In certain embodiments, the syringe is a l mL or 2.25 mL long glass syringe filled with a 27-gauge thin wall needle, a fluorocarbon coated rubber plunger and a rubber needle shield. In one embodiment. the syringe is an OMPI 1 mL long glass syringe fitted with a 27-gauge needle, a FM27 rubber needle shield, and a FLUROTEC® coated 4023/50 rubber plunger.

[000166] In one embodiment, the liquid pharmaceutical formulation containing about 50 mg/mL ± 7.5 mg/mL anti-EBOV antibody is administered in a volume of approximately up to 2 mL in a prefilled syringe. In one embodiment, the syringe is a 1 mL or 2.25 mL long glass syringe filled with a 27-gauge thin wall needle, a fluorocarbon coated rubber plunger and a rubber needle shield. In one embodiment, the syringe is an OMPI 1 mL long glass syringe fitted with a 27-gauge needle, a FM27 rubber needle shield, and a FLUROTEC® coated 4023/50 rubber plunger.

Compati bility

[000167] In one embodiment, the stable formulation îs a liquid solution containing 50 mg/mL total anti-EBOV antibody (e.g. 16.7 mg/mL each of H1H17203P, I-11H17139P, and/or H1H1716 IP; or about 25 mg/mL each of any two of H1H17203P, H1H17139P, and H1H17161 P) for IV administration. In some aspects, the IV admixture solution has compatibility (including în-use stability) with diluents and materîals used in the dosing System (IV bags, sets, and filters), including 0.9% Sodium Chloride, 5% Dextrose or Lactate Ringer’s solution, PVC (polyvinyl chloride) and polyethylene.

[000168] Exemplary dosages include 10 mg/kg, 30 mg/kg, 50 mg/kg, and 150 mg/kg. In-use stability of the anti-EBOV formulation during IV delivery supports administration of the clinical doses. The 0.9% Sodium Chloride PVC IV bags, containing the diluted antibodies, in some embodiments, can be înitially held for 24 hours at 5 °C, then incubated for at least 8 hours at 25 °C. After these incubations, each of the infusion sets can be connected to IV bags, primed with the diluted DP and held for 1 hour at ambient room température. The diluted DP solutions can be then pumped through the respective infusion sets at 25 mL/hr and 500 mL/hr. These infusion sets contain the basîc materîals (PVC with DEHP, PVC with TOTM and polyethylene) that comprise infusion sets used for IV delivery of the antibody combination în clinical uses. The infusion sets can contain a 0.2 pm polyethersulfone înlîne filter.

[000169] In some aspects, a 50 mg/mL anti-EBOV formulation comprising at least one antiEBOV antibody, diluted in 0.9% Sodium Chloride Injection to concentrations of either 2.2 mg/mL or 23.7 mg/mL, is physically and chemically stable when tested under these conditions within the proposed dose ranges and administration conditions. The anti-EBOV formulation can, în some

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I aspects, exhibit no meaningful change in quaiity attributes after dilution in IV bags, storage in IV bag for 24 hours at 2 - 8°C and at least 8 hours at 25°C, infusion set hold for one hour, or delivery with pumpîng rates between 25 mL/hour to 500 mL/hour.

[000170] In some aspects, the additional flexibiIity of using different diluents for dose préparation of a co-formulated antibody formulation and to support température excursion (higher than 25 °C) which may occur during IV administration is provided. When the anti-EBOV antibodies are diluted with 0.9% Sodium Chloride, 5% Dextrose or Lactated Ringer's at 40 °C the formulation continued to exhibit stability. The IV bags containing diluted antibodies can be held initially for 24 hours at 5 °C; then incubated for at least 6 hours at 40 °C. After incubations, each of the infusion sets can be connected to the IV bags, primed with the diluted antibodies and held for 1 hour at ambient room température. The diluted antibody solutions can then be pumped through the respective infusion sets.

[000171] In some aspects, a 50 mg/mL anti-EBOV antibody formulation comprising at least one anti-EBOV antibody, diluted in 0.9% Sodium Chloride Injection, 5% Dextrose or lactated ringer's to concentrations of either 1.6 mg/mL or 27.9 mg/mL can be physically and chemically stable under the conditions tested within the proposed dose ranges and administration conditions. The anti-EBOV formulation can, in some aspects, exhibit no meaningful change in quaiity attributes after dilution in IV bags, storage in IV bag for 24 hours at 2 - 8 °C and at least 6 hours at 40 °C, infusion set hold for one hour.

[000172] The IV compatibility characteristics (încluding in-use stability) of the stable liquid pharmaceutical formulations support the foliowing conclusions pertaining to dose préparation and IV administration (50 mg/mL):

• 0.9% Sodium Chloride Injection, 5% Dextrose Injection and Lactate Ringer’s IV bags made of PVC are compatible with IV administration of the formulation containing at least one anti-EBOV antibody;

• The anti-EBOV antibody formulation can be diluted to antibody concentrations as low as 2.2 mg/mL and as high as 23.7 mg/mL in the PVC IV bags containing IV diluent of 0.9% Sodium Chloride, 5% Dextrose or Lactated Ringer's for IV administration;

• Diluted co-formulated antibodies prepared with 0.9% Sodium Chloride Injection can be stored at room température up to 25°C for at least about 8 hours from the time of préparation to the end of the infusion or at 2°C to 8°C for at least about 24 hours from the time of préparation to the end of infusion;

Diluted co-formulated antibodies prepared with 5% Dextrose or Lactate Rînger’s can be stored at room température up to 25°C for at least about 4 hours from the time of préparation to the end of the infusion or at 2°C to 8°C for at least about 24 hours from the time of préparation to the end of infusion;

Diluted co-formulated antibodies (2.2 mg/mL to 23.7 mg/mL) prepared with 0.9% Sodium Chloride, 5% Dextrose or Lactate Rînger’s solution is stable for 6 hours at 40 °C;

Diluted co-formulated antibodies can be administered with an infusion set composed of either PVC containing DEHP, PVC containing TOTM, or polyethylene lined PVC;

Diluted co-formulated antibodies are compatible with the use of an inlîne 0.2 pm polyethersulfone fîlter.

THERAPEUTIC USES OF THE PHARMACEUTICAL FORMULATIONS

[000173] The pharmaceutical formulations ofthe présent disclosure are useful, inter alla, for the treatment, prévention or amelioration of EBOV or any symptom related thereto.

EXAMPLES

[000174] The following examples are presented so as to provide those of ordinary ski 11 in the art with a complété disclosure and description of how to make and use the methods and compositions disclosed herein, and are not intended to limit the scope of what the inventors regard as their invention. Efforts hâve been made to ensure accuracy with respect to numbers used (e.g., amounts, température, etc.) but some experimental errors and déviations should be accounted for. Unless indicated otherwise, parts are parts by mole, molecular weight is average molecular weight, température is in degrees Centigrade, and pressure is at or near atmospheric pressure.

Example 1: Development of an Anti-EBOV Antibody Formulation

[000175] The goals of the formulation activities were to develop a formulation with the following attri butes:

A liquid formulation that is stable after being subjected to stress, for example température cycles, extreme températures, agitation during transport, etc., conditions a therapeutic would be exposed to in transit from a manufacturing facîlity to remote field clinics where 53

Ebola exposure has occurred and/or Ebola patients exist;

• A liquîd formulation with a concentration of the anti-EBOV antibody sufficient to delîver a dose of 25 mg to 30,000 mg, for example about 7500 mg, about 5000 mg, about 3000 mg, about 2000 mg, about 1500 mg, 1000 mg, about 800 mg, about 750 mg, about 500 mg, about 250 mg, about 200 mg, about 150 mg, about 100 mg, about 75 mg, about 50 mg, or about 25 mg, by intravenous infusion;

• A near iso-osmolar formulation that is stable upon dilution with commonly used diluents, e.g., 0.9% sodium chloride injection or 5% dextrose injection or Lactated Ringer’s injection, for intravenous infusion;

♦ A formulation that is compatible with and stable in Type 1 clear glass vial and standard sérum stopper as packaging; and * A stérile drug product (DP) solution that supports long-term stability;

o A formulation that minimizes antibody hîgh molecular weight (HMW) species when subjected to handling and thermal stresses;

o A formulation that minimizes changes in the relative distribution of antibody charged species when subjected to thermal stress; and o A formulation that maintams biological activity when subjected to rough transit and thermal stress in extreme envîronments.

[000176] Throughout formulation development, three primary protein stress conditions (representing extreme handling conditions which the antibody drug product could be subjected to during handling, manufacturing, shipping, storing, and labeling) were employed to develop and optimize the antibody formulations and to evaluate the effects of potential real-world stresses on the stability of the drug product used in remote régions of the wortd. These stress conditions included:

• Agitation (vortexing) of the protein solution at room température. Vortexing in glass vials exceeds the agitation that occurs during the handling and manufacturing of the protein.

• Incubating the protein solution at elevated température (37°C, 40°C or 45°C) relative to the proposed DP storage condition (2°C-8°C).

• Subjecting the protein to multiple freeze thaw cycles. Since the protein will undergo at least one freeze thaw cycle during the manufacture of DP, multiple freeze thaw cycles simulate and exceed the actual stress the protein is expected to expérience.

[000177] There were several main goals of the initial formulation development work:

1, Sélection of buffer and pH for each of three anti-EBOV antibodies: The choice of buffer and pH can hâve a large effect on the stabilîty of proteins, hence deciding on the optimal buffer species and pH is an important process. Studies are presented in these sections that demonstrate the rationaie for choice of the optimal buffer and pH for each antibody.

2. Sélection of surfactant or organic cosolvent for each of three anti-EBOV antibodies: A surfactant or organic cosolvent, such as polysorbate, is typically required to prevent précipitation or aggregation of proteins when agitated. Soluble protein may be subjected to agitation when handled, filtered, mixed, manufactured, shipped, and administered. The antibody drug substance in a simple buffered solution can become visibly cloudy with excess agitation. Therefore, it was determined that stabilizing each of the proteins to handling and agitation was important.

3. Identification/selection of stabilizing/tonicifying excipients: The addition of sugars, salts, and amino acids were examined for their abiIity to improve the stabilîty of each of the three antibodies to thermal stress and to increase the shelf life of the drug product (DP). The rationaie for inclusion of these thermal stabilizers, as well as studies identifying the optimal concentrations in the final formulation are presented herein.

4, Sélection of antibody concentration: The effect of antibody concentration on the stabilîty of the drug product with the selected excipients was examined.

5. Co-formulating three anti-EBOV antibodies: The three anti-EBOV antibodies were coformulated into a liquid formulation at two concentrations, and buffer and pH were selected for the combination, surfactant or organic cosolvent were selected, additional excipients tested, and stabilizers were identified and selected.

[000178] Initial formulation development activities were conducted using 100 mg/mL of each anti-EBOV antibody separately formulated, and involved screening organic cosolvents, thermal stabilizers, and buffers in liquid formulations of each of the anti-EBOV antibodies to identify excipients that are compatible with the protein and enhance its stabilîty, while maintaining near physiologie osmolaîity and low viscosity for intravenous and subeutaneous injection. Buffer conditions were also examined to détermine the optimal pH for maximum protein stabilîty (described in Example 6 herein).

[000179] Results from this initial formulation development work were used to develop an initial formulation that was suitable for clinical studies.

[000180] With the knowledge gained from the initial formulation development, the late stage formulation development activities involved co-formulating the three antibodies at two concentrations, confirming pH, surfactant concentration, and stabilizers to identify excipients that enhance protein stability at both low and high protein concentrations and when exposed to stress such as high températures and agitation (described in Examples 4-9).

[000181] Throughout formulation development, the formulations were assessed for stress and storage stability. The methods used to assess stability in the formulation development studies are described in Example 3 herein. Examples 4 through 9 describe the storage and stress stability of the formulations.

[000182] Results generated from these studies were used to develop stable liquid formulations suitable for clinical use, for intravenous (IV) administration. Such formulations exhibited stability when exposed to thermal or agitational stress.

[000183] Other attributes of the formulations will be apparent from the description herein.

Anti-EBOV antibodies:

[000184] Anti-EBOV antibodies are described in US 2016/0215040, incorporated herein in its entirety. The exemplary antibodies used in the Examples below are fully human anti-EBOV antibodies H1H17203P (REGN3470; having an HCVR amino acid sequence ofSEQ ID NO: 2 and an LCVR amino acid sequence ofSEQ IDNO: 10), HIH17139P (REGN3471; having an HCVR amino acid sequence ofSEQ ID NO: 20 and an LCVR amino acid sequence ofSEQ ID NO: 28), and H1HI7161P (REGN3479; having an HCVR amino acid sequence ofSEQ ID NO: 38 and an LCVR amino acid sequence ofSEQ IDNO: 46) comprising the sequences described in detail above.

Example 2: Exemplary Formulations

[000185] In certain embodiments, the anti-EBOV antibodies are individually formulated or coformulated as an aqueous buffered formulation comprising: (a) from 5% ± 1% to 15% ± 3% w/v sucrose, (b) from 5 mM ± 1 mM to 20 mM ± 4 mM histidine buffer, (c) from 0.01% ± 0.005% to 0.5% ± 0.25% w/v polysorbate, and (d) 50 mg/mL ±7.5 mg/mL total anti-EBOV antibody, at pH 6.0 ±0.3. In certain embodiments, the anti-EBOV antibodies are individually formulated or coformulated as an aqueous buffered formulation comprising: (a) 10% ± 2% w/v sucrose, (b) lOmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ±7.5 mg/mL total antibody, at pH 6.0 ± 0.3. When co-formulated, the anti-EBOV antibodies are present in a 1:1:1 ratio.

[000186] In certain embodiments, the anti-EBOV antibodies are individually formulated or co56

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I formulated as an aqueous buffered formulation comprising: (a) from 5% ± 1% to 15% ± 3% w/v sucrose, (b) from 5 mM ± 1 mM to 20 mM ± 4 mM histidine buffer, (c) from 0.01% ± 0.005% to 0.5% ± 0.25% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total antibody, at pH 6.0 ± 0.3. In certain embodiments, the anti-EBOV antibodies are individually formulated or co-formulated as an aqueous buffered formulation comprising: (a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total antibody, at pH 6.0 ± 0.3. When co-formuSated, the anti-EBOV antibodies are présent in a 1:1:1 ratio.

[000187] Exemplary formulations include:

• A stable liquid pharmaceutical formulation comprising: (a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ± 7.5 mg/mL H1H17203P anti-EBOV antibody, at pH 6.0 ± 0.3.

• A stable liquid pharmaceutical formulation comprising: (a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ± 7.5 mg/mL, H1H17139P anti-EBOV antibody, at pH 6.0 ± 0.3.

• A stable liquid pharmaceutical formulation comprising; (a) 10% ± 2% w/v sucrose, (b) 1 OmM ± 2mM histidine buffer, (c) 0.1 % ± 0.05% w/v polysorbate, and (d) 50 mg/mL ± 7.5 mg/mL H1H1716 IP anti-EBOV antibody, at pH 6.0 + 0.3.

• A stable liquid pharmaceutical formulation comprising: (a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ± 7.5 mg/mL total H1H17203P and H1HI7139P anti-EBOV antibody, at pH 6.0 ± 0.3.

• A stable liquid pharmaceutical formulation comprising: (a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ± 7.5 mg/mL total H1H17203P and H1H1716IP anti-EBOV antibody, atpH 6.0 ± 0.3.

• A stable liquid pharmaceutical formulation comprising: (a) 10% ± 2% w/v sucrose, (b) lOmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ± 7.5 mg/mL total H1H17139P and H1H17161P anti-EBOV antibody, at pH 6.0 ± 0.3.

• A stable liquid pharmaceutical formulation comprising: (a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% + 0.05% w/v polysorbate, and (d) 50 mg/mL ± 7.5 mg/mL total H1H17203P, H1H17139P, and H1H17161P anti-EBOV antibody, at pH 6.0 ± 0.3.

• A stable liquid pharmaceutical formulation comprisîng: (a) 10% ± 2% w/v sucrose, (b) lOmM ±2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 10 mg/mL H1H17203P anti-EBOV antibody, at pH 6.0 ± 0.3.

• A stable liquid pharmaceutical formulation comprisîng: (a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL, H1I-I17139P anti-EBOV antibody, at pI T 6.0 ± 0.3.

• A stable liquid pharmaceutical formulation comprisîng: (a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL H1H17161P anti-EBOV antibody, at pH 6.0 ± 0.3.

• A stable liquid pharmaceutical formulation comprisîng: (a) 10% ± 2% w/v sucrose, (b) 1 OmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total H11-117203P and Η1H17139P anti-EBOV antibody, at pH 6.0 ± 0.3.

• A stable liquid pharmaceutical formulation comprisîng: (a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total HIH17203P and H1H17161P anti-EBOV antibody, at pH 6.0 ±0.3.

• A stable liquid pharmaceutical formulation comprisîng: (a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total H1H17139P and H1 PI 17161P anti-EBOV antibody, at pH 6.0 ± 0.3.

• A stable liquid pharmaceutical formulation comprisîng: (a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total H1H17203P, H1HI7139P, and H1H17161P anti-EBOV antibody, at pH 6.0 ±0.3.

Example 3: Methods Used to Assess Formulation Stability

[000188] The following assays were applied to assess formulation stability:

• Color and appearance by Visual inspection • pH • Turbidity measured by increase in OD at 405nm, or by nephelometry • Particulate matter analysis performed by microflow imaging (MFI) (reported as particle counts obtained as is), and light obscuration (HIAC) • Protein concentration by reverse phase-ultra performance liquid chromatography (RP-UPLC) 58 • Purity by sîze exclusion- ultra performance liquid chromatography (SE-UPLC), or by reduced and non-reduced microchip capillary electrophoresis sodium dodecyl sulfate (MCE-SDS) PAGE • Charge variant analysis by cation exchange chromatography-ultra performance liquid chromatography (CEX-UPLC), or by imaged capillary isoelectric focusing (iCIEF) • Potency by bioassay: The relative potency of each sample is determined using a bioassay and is defîned as: (IC50 reference sample/ICjo sample)* 100%. The measured potency of storage stability samples must be within 50% to 150% of the measured potency ofthe reference standard.

[000189] The physical stability of a formulation refers to properties such as color, appearance, pH, turbidity, and protein concentration. The presence of visible particulates in solution can be detected by Visual inspection. A solution passes visual inspection if it is clear to slightly opalescent, essentially free from visible particulates, and colorless to pale yellow. In addition, turbidity, measured by OD at 405 nm, can also be used to detect particulates in solution. An increase in OD at 405 nm may indicate the presence of particulates, an increase in opalescence, or color change ofthe test articles. MFI is used to measure subvisible particulates that are > 2 pm in size. The anti-EBOV antibody protein concentration is measured by a RP-UPLC assay and reported as percent protein recovery relative to the starting material. In the RP-UPLC assay, anti-EBOV antibody is eluted from the RP column as a single peak. The protein concentration is determined from the antibody total peak area by comparing it with a calibration curve generated using antibody standards. Percent of recovery is calculated based on the measured protein concentration relative to the starting protein concentration.

[000190| Chemical stability refers to the formation of covalently modified forms (e.g. covalent aggregates, cleavage products, or charge variant forms) and non-covalently modified forms (e.g. non-covalent aggregates) of protein. Higher and lower molecular weight dégradation products can be separated from native antibody by SE-UPLC and MCE-SDS methods. The percentage of degraded anti-EBOV antibody in the SE-UPLC and MCE-SDS methods is calculated from the ratio ofthe area of ail non-native peaks to the total area of ail anti-EBOV antibody peaks. Charge variant forms of anti-EBOV antîbodies are resolved using CEX-UPLC and iCIEF. In the CEX-UPLC method, peaks with rétention times earlier than that of the main peak are labeled as “acidic” peaks; the peaks with rétention times later than that of the main peak are labeled as “basic” peaks. In the iCIEF method, peaks that are focused to a pi lower than that of the main peak are labeled “acidic”

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I peaks, whereas those focused to a pi higher than that of the main peak are labeled “basic” peaks.

Example 4: Stability Studies for Aqueous Formulations of Anti-EBOV Antibodies

[000191] Ail studies outlined in this section in this Example refer to research stability studies performed on H1H17203P Drug Product (DP), H1H17139P DP, and H1H17161P DP. Each DP was formulated and filled separately to provide stability data under real time, accelerated, and stress stability conditions. The Drug Substance (DS) lots used for these studies are représentative of the DS manufactured for clinical use.

Formulation Development

[000192] H1H17203P, H1H17139P and H1H17161P antibodies are formulated for delivery by intravenous (IV) injection for a first-in-human study. The stability of individually formulated and filled H1H17203P, H1H17139P, and H1H1716IP drug products were assessed in the clîmcal formulation; the analytical characterization results indicated that this formulation provided adéquate stability for H1H17203P, H1H17139P, and H1H17161P antibodies under ail conditions examined. The H1H17203P, H1H17139P, andH1HÎ7l6lP antibody formulation contains 10 mM histidine, pH 6.0, 0.1% (w/v) polysorbate S0, and 10% (w/v) sucrose.

Research Stability

[000193] Ail FDS (Formulated Drug Substance) and DP (Drug Product) studies outlined in this section refer to research stability studies performed on individually formulated and filled H1H17203P, H1H17139P, and H1H17161P antibodies, manufactured for developmentai use. Formai stability studies examining H1H17203P, H1H17139P, and H1H17161P antibodies manufactured for clinica! use are discussed below.

[000194] Stability studies hâve been initiated to détermine the storage, accelerated, and stress stability of individually formulated and filled research lots of 50 mg/mL HIHI7203P DP, 50 mg/mL H1H17139P DP and 50 mg/mL H1H17161P DP. The DS lots used for these studies are représentative ofthe DS manufactured for clinical use. The DP was incubated under several elevated température conditions, relative to storage température conditions. These accelerated conditions were selected to simulate the conditions beyond which the DP may not be subjected during manufacturing and handling and to elucidate the dégradation pathways for H1H17203P DP, H1H17139P DP and FI1H17I61P DP. An outline ofthe storage, accelerated and stress stability conditions for the H1H17203P DP, H1H17139P DP, and H1H17161P DP are presented in Table 1 and the analysis plans are presented in Table 2.

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Table 1: Research Stability Studies for H1H17203P DP, H1H17139P DP, and II1H17161P DP

Storage Stability	Container/Closure
Storage Température	Length of Storage (months)	Type 1 borosilicate glass with FluroTec® coated 4432/50 butyl rubber stopper
5°C	0, 1,3, 6, 9, 12
Accélérated Stability
Incubation Condition	Length of Incubation
25°C	0, 0.5, 1, and 3 months
45°C	0, 7, 14, and 28 days
Stress Stability
Stress	Duration of Stress
Agitation (vortex)	0, 60, and 120 minutes
Freeze/Thawa	0, 4, and 8 cycles

^aFrozen at -80°C and thawed at room température.

Table 2:Research Stability Studies Analysis Plan for H1H17203P DP, H1H17139P DP, and

H1HI7161P DP

Assay	Samples to be Analyzed
Color and Appearance	AU Samples
pH	AU Samples
Turbidity (Increase in OD at 405 nm)	Ail Samples
% Protein Recovered by RP-UPLC	Ail Samples
% Purîty by Non-Reduced and Reduced MCE-SDS	t = 0, 6, 12, 24 and 36 months at 5°C; 3 months at 25°C; 28 days at 45°C 120 min Agitation, 8X Freeze/Thaw
% Purity by SE-UPLC	Ail Samples
Charge Variant Analysis by CEX-UPLC	AU Samples
Charge Variant Analysis by iCIEF	t = 0, 6,12at5°C; 3 months at 25°C; 28 days at 45°C 120 min Agitation, 8X Freeze/Thaw
Partîculate Matter Analysis by MFI	t = 0, 6, 12, 24 and 36 months at 5°C; 3 months at 25°C; 28 days at 45°C 120 min Agitation, 8X Freeze/Thaw

Research Stability for 50 mg/mL Η1Π17203Ρ DP Research Storage Stability for 50 mg/mL H1H17203P DP

[000195] Three months of research stability data are shown for the 50 mg/mL H1H17203P DP. The 50 mg/mL H1H17203P DP was physically and Chemically stable when stored at 5°C for 3 months (Table 3). No appréciable change in the physical or Chemical stability was detected in any of the monitored attributes.

Research Accelerated Stability for 50 mg/mL H1H17203P DP

[000196] Results from the analysis of the 50 mg/mL H1H17203P DP following incubation under accelerated conditions are provided in Table 6. After H1H17203P DP was incubated for 28 days at 45°C, 2.1% and 1.6% increases in the relative amount of HMW and LMW species (SE-UPLC), and 15.1% and 13.5% increases in the percentage of acîdic charge variant species, determined by CEXUPLC and iCIEF, respectively, were observed. After H1H17203P DP was incubated for 3 months at 25°C, a 0.3% increase in the amount of both HMW and LMW species (SE-UPLC) and 2.9% and 3.0% increases in the percentage of acidic charge variant species, determined by CEX-UPLC and iCIEF, respectively, were observed. The results from accelerated stability testing demonstrated that an increase in the relative amount of HMW and LMW species and the formation of acidic charge variants were the main dégradation pathways for 50 mg/mL H1H17203P DP.

Research Stress Stability for 50 mg/mL H1H17203P DP

[000197] Results from the research stress stability studies are presented in Table 9. HIH17203P DP was physically and chemically stable when agitated (vortexed at ambient température) for 120 minutes. No appréciable change in the physical or Chemical stability was detected in any of the monitored attributes. HIH17203P DP was physically and chemically stable when subjected to 8 freeze/thaw cycles (freezing at -80°C and thawing at room température). No appréciable change in the physical or Chemical stability was detected in any of the monitored attributes.

Research Stability for 50 mg/mL H1H17139P DP

Research Storage Stability for 50 mg/mL H1H17139P DP

[000198] Three months of research stability data are shown for the 50 mg/mL H1H17139P DP. The 50 mg/mL H1HI7139P DP was physically and chemically stable when stored at 5°C for 3 months (Table 4). No appréciable change in the physical or Chemical stability was detected in any of the monitored attributes. The 50 mg/mL H1H17139P DP maintained potency over the three-month assessment interval as determined by bioassay analysis.

Research Accelerated Stability for 50 mg/mL H1H17I39P DP

[000199] Results from the analysis ofthe 50 mg/mL H1H17139P DP following incubation under accelerated conditions are provided in Table 7. After H1HI7139P DP was incubated for 28 days at 45°C, 0.8% and 1.8% increases in the relative amount of HMW and LMW species (SE-UPLC), and 13.8% and 12.9% increases in the percentage of acidic charge variant species, determined by CEXUPLC and iCIEF, respectively, were observed. After H1H17139P DP was incubated for 3 months at 25°C, 0.4% and 0.5% increases in the amount of HMW and LMW species (SE-UPLC) and 2.6% and 3.1% increases in the percentage of acidic charge variant species, determined by CEX-UPLC and iCIEF, respectively, were observed. H1H17139P maintained potency, as determined by bioassay analysis, after incubation under each of the accelerated conditions. The results from accelerated stability testing demonstrated that an increase in the relative amount of HMW and LMW species and the formation of acidic charge variants were the main dégradation pathways for 50 mg/mL H1HI7139P DP.

Research Stress Stability for 50 mg/mL H1H17139P DP

[000200] Results from the research stress stability studies are presented in Table 10. H1H17139P DP was physically and chemically stable when agitated (vortexed at ambient température) for 120 minutes. No appréciable change in the physical or Chemical stability was detected in any of the monîtored attributes. H1H17139P DP was physically and chemically stable when subjected to 8 freeze/thaw cycles (freezing ai -80°C and thawing at room température). No appréciable change in the physical or Chemical stability was detected in any of the monitored attributes.

Research Stability for 50 mg/mL H1H17161P DP

Research Storage Stability for 50 mg/mL H1H17161P DP

[000201] Three months of research stability data are shown for 50 mg/mL H1H17161P DP, The 50 mg/mL H1H17161P DP was physically and chemically stable when stored at 5°C for 3 months (Table 5). No appréciable change in the physical or Chemical stability was detected in any of the monitored attributes. The 50 mg/mL H1H17161P DP maintained potency over the three-month assessment interval as determined by bioassay analysis.

Research Accelerated Stability for 50 mg/mL H1H17161P DP

[000202] Results from the analysis of 50 mg/mL H1H17161P DP following incubation under accelerated conditions are provided in Table 8. After H1H17161P DP was incubated for 28 days at 45°C, 1.0% and 1.8% increases in the relative amount of HMW and LMW species (SE-UPLC), and 15.6% and 13.2% increases in the percentage of acidic charge variant species, determined by CEXUPLC and iCIEF, respectively, were observed. After H1H17161P DP was incubated for 3 months at

25°C, 0.7% and 0.5% increases in the amount of HMW and LMW species (SE-UPLC) and 4.2% and 3.4% increases in the percentage of acidic charge variant species, determined by CEX-UPLC and iCIEF, respectîvely, were observed. H1H17161P maintained potency, as determined by bioassay analysis, after incubation under each of the accelerated conditions. The results from accelerated stability testing demonstrated that an increase in the relative amount of HMW and LMW species and the formation of acidic charge variants were the main dégradation pathways for 50 mg/mL HIH17161P DP.

Research Stress Stability for 50 mg/mL H1H17161P DP

[000203] Results from the research stress stability studies are presented in Table 11. H1H17161P DP was physically and chemically stable when agitated (vortexed at ambîent température) for 120 minutes. No appréciable change in the physical or Chemical stability was detected in any of the monitored attributes. H1H17161P DP was physically and chemically stable when subjected to 8 freeze/thaw cycles (freezing at -80°C and thawing at room température). No appréciable change in the physical or Chemical stability was detected în any of the monitored attributes.

Research Stability Conclusions for HÏH17203P DP, H1H17139P DP, and H1H17161P DP [000204] The results from the DP storage, accelerated, and stress stability studies indicate that H1H17203P DP, H1H17139P DP, and HIH17161P DP formulations can withstand limited exposures to room température without compromising physical or Chemical stability. In addition, the results from HIH17203P, H1H17139P, and H1H17161P formulation studies indicate H1H17203P DP, H1H17139P DP, and H1H17161P DP are stable when stored at 5°C for at least 3 months.

HIH17203P DP, H1H17139P DP, and H1H17161P DP should be stored at 2°C to 8°C and exposure to températures greater than 8°C should be limited.

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Table 3: Research Stability of 50 mg/mL H1H17203P Drug Product Stored at 5°C

Stability Study Number	H1H17203-SS004
Source DS Lot Number	9018800002
Formulation Lot Number	L15-0397
Formulation	50 mg/mL H1H17203P, 10 mM histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Fill Volume	0.4 mL
Container/Closure	2 mL Type I borosilicate glass vial with West S2-F451 4432/50 GRY B2-40 stopper
Assay	Length of Storage (months)
0	1	3	6	9	12
Color and Appearance	Pass	Pass	Pass	Pass	Pass	Pass
Turbidity (Increase in OD at 405 nm)	0.00	0.00	0.00	0.00	0.00	0.00
pH	6.1	6.1	6.1	6.1	6.1	6.1
% Total H1H17203P Recovered by RP-UPLC	100	101	102	109	100	99
Purity by MCE-S DS	Non-reduced; % main peak	100	NR	NR	NA	NR	NA
Reduced; % heavy + light chain	99.6	NR	NR	NA	NR	NA
Purity by SE-UPLC	% HMW	0.6	0.6	0.7	0.8	0.8	0.9
% Native	98.3	98.5	98.4	98.2	97.9	97.7
% LMW	1.2	0.9	0.9	LO	1.3	1.5
Charge Variant Analysis by CEX-UPLC	% Acidic	42.2	42.2	41.2	41.5	41.8	41.9
% Main	46.5	46.9	47.9	48.3	48.1	47.9
% Basic	11.3	10.9	10.9	10.2	10.1	10.2
Charge Variant Analysis by iCIEF	% Acidic	57.1	NR	NR	NA	NR	NA
% Main	40.5	NR	NR	NA	NR	NA
% Basic	2.4	NR	NR	NA	NR	NA
Particulate Analysis by	2-10 pm	25573	NR	NR	9370	NR	1212
> 10 pm	1267	NR	NR	436	NR	24

Stability Study Number	H1H17203-SS004
Source DS Lot Number	9018800002
Formulation Lot Number	L15-0397
Formulation	50 mg/mL H1HI7203P, 10 mM histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Fill Volume	0.4 mL
Container/Closure	2 mL Type 1 borosilicate glass vial with West S2-F451 4432/50 GRY B2-40 stopper
		Length of Storage (months)
Assay		0	1	3	6	9	12
MF1 (particles/mL)	> 25 pm	150	NR	NR	28	NR	3

Table 4: Research Stability of 50 mg/mL H1H17139P Drug Product Stored at 5°C

Stability Study Number	HIH17139-SS004
Source DS Lot Number	9019300002
Formulation Lot Number	L15-0396
Formulation	50 mg/mL H1H17139P, 10 mM histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Fill Volume	0.4 mL
Container/Closure	2 mL Type 1 borosiiicate glass vial with West S2-F451 4432/50 GRY B2-40 stopper
Assay	Length of Storage (months)
0	1	3	6	9	12
Color and Appearance	Pass	Pass	Pass	Pass	Pass	Pass
Turbidity (Increase in OD at 405 nm)	0.00	0.00	0.00	0.00	0.00	0.00
pH	6.0	6.1	6.1	6.1	6.1	6.1
% Total H1H17139P Recovered by RP-UPLC	100	100	103	94	101	100
Purity by MCE-SDS	Non-reduced; % main peak	100	NR	NR	NA	NR	NA
Reduced; % heavy + light chain	98.7	NR	NR	NA	NR	NA

Stability Study Number	H1H17139-SS004
Source DS Lot Number	9019300002
Formulation Lot Number	L15-0396
Formulation	50 mg/mL H1H17139P, 1Û mM histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Fill Volume	0.4 mL
Container/Closure	2 mL Type 1 borosilicate glass vial with West S2-F451 4432/50 GRY B2-40 stopper
Assay	Length of Storage (months)
0	1	3	6	9	12
Purity by SE-UPLC	% HMW	0.6	0.6	0.7	0.8	0.9	0.9
% Native	98.4	98.4	98.3	98.2	97.8	97.5
% LMW	1.1	1.0	1.0	1.1	1.4	1.6
Charge Variant Analysis by CEX-UPLC	% Acidic	42.9	42.8	42.8	43.6	42.9	43.5
% Main	53.2	53.2	52.9	52.1	52.8	51.6
% Basic	4.0	4.0	4.3	4.3	4.4	4.9
Charge Variant Analysis by iCIEF	% Acidic	49.4	NR	NR	NA	NR	NA
% Main	46.8	NR	NR	NA	NR	NA
% Basic	3.2	NR	NR	NA	NR	NA
Parti eu late Analysis by MFI (particles/mL)	2-10 pm	7332	NR	NR	654	NR	1153
> 10 pm	37	NR	NR	15	NR	24
> 25 pm	3	NR	NR	3	NR	3

Table 5:Research Stability of 50 mg/mL H1H17161P Drug Product Stored at 5°C

Stability Study Number	H1H17161-SS004
Source DS Lot Number	9019800002
Formulation Lot Number	L15-0400
Formulation	50 mg/mL H1H17161P, 10 mM histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Fill Volume	0.4 mL
Container/Closure	2 mL Type I borosilicate glass vial with West S2-F451 4432/50 GRY B 2-40 stopper
Assay	Length of Storage (months)
0	1	3	6	9	12
Color and Appearance	Pass	Pass	Pass	Pass	Pass	Pass
Turbidity (Increase in OD at 405 nm)	0.00	0.00	0.00	0.00	0.00	0.00
pH	6.1	6.1	6.1	6.1	6.1	6.1
% Total H1H17161P Recovered by RP- UPLC	100	99	106	106	104	106
Purity by MCE-SDS	Non-reduced; % main peak	100	NR	NR	NA	NR	NA
Reduced; % heavy + light chain	98.4	NR	NR	NA	NR	NA
Purity by SE-UPLC	% HMW	1.1	1.3	1.4	1.5	1.6	1.7
% Native	97.4	97.3	97.2	97.1	96.6	96.2
% LMW	1.5	1.5	1.4	1.4	1.8	2.0
Charge Variant Analysis by CEX-UPLC	% Acidic	60.5	60.3	59.8	59.2	61.0	59.8
% Main	35.7	35.7	35.1	36.4	35.6	34.8
% Basic	3.9	4.0	5.1	4.4	3.5	5.4
Charge Variant Analysis by iCIEF	% Acidîc	54.1	NR	NR	NA	NR	NA
% Main	42.7	NR	NR	NA	NR	NA
% Basic	3.2	NR	NR	NA	NR	NA
Particulate Analysis by	2-10 gm	7526	NR	NR	1274	NR	3066
> 10 gm	39	NR	NR	99	NR	148

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Stability Study Number	H1H17161-SS004
Source DS Lot Number	9019800002
Formulation Lot Number	L15-0400
Formulation	50 mg/mL H1HI7161P, 10 mM histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Fill Volume	0.4 mL
Contaiuer/Closure	2 mL Type I borosilicate glass vial with West S2-F451 4432/50 GRY B2-40 stopper
Àssav	Length of Storage (months)
		0	1	3	6	9	12
MF1 (particles/mL)	> 25 pm	7	NR	NR	8	NR	22

Table 6: Research Stability of 50 mg/mL H1H17203P Drug Product - Effect of Accelerated Conditions

Stability Study Number	H1H172O3-SS004
Source DS Lot Number	9018800002
Formulation Lot Number	L15-0397
Formulation	50 mg/mL H1H17203P, 10 mM histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Fill Volume	0.4 mL
Container/Closure	2 mL Type ï borosilicate glass via! with West S2-F451 4432/50 GRY
Assay	Storage Condition/Length of Storage
No Storage	25°C (months)	45°C (days)
0	0.5	1	3	7	14	28
Color and Appearance	Pass	Pass	Pass	Pass	Pass	Pass	Pass
Turbidity (Increase in OD at 405 nm)	0.00	0.00	0.00	0.00	0.00	0.01	0.01
pH	6.1	6.0	6.1	6.1	6.1	6.1	6.1
% Total H1H17203P Recovered by	100	100	101	102	99	99	101
Purity by MCE-SDS	Non-reduced; % main peak	100	NR	NR	100	NR	NR	98.2
Reduced; % heavy + light chain	99.6	NR	NR	99,1	NR	NR	98.4
Purity by SE-UPLC	% HMW	0.6	0.7	0.8	0.9	1.4	1.8	2.7
% Native	98.3	98.3	98.1	97.6	97.1	96.2	94.4
% LMW	1.2	1.0	1.1	1.5	1,5	2.0	2.8
Charge Variant	% Acidic	42.2	42.3	43.0	45.1	46.2	50.3	57.3
% Main	46.5	47.2	47.0	45.9	43.7	40,3	33.4

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Stability Study Number	H1H17203-SS004
Source DS Lot Number	9018800002
Formulation Lot Number	L15-0397
Formulation	50 mg/mL H1H17203P, 10 mM histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Fill Volume	0.4 mL
Container/Closure	2 mL Type 1 borosilicate glass vial with West S2-F451 4432/50 GRY
Assay		Storage Condition/Length of Storage
No Storage	25°C (months)	45°C (days)
0	0.5	1	3	7	14	28
Analysis by CEX-UPLC	% Basic	11.3	10.5	10.0	9.0	10.1	9.4	9.3
Charge Variant Analysis by iCIEF	% Acidic	57.1	NR	NR	60.1	NR	NR	70.6
% Main	40.5	NR	NR	37.0	NR	NR	26.3
% Basic	2.4	NR	NR	3.0	NR	NR	3.1
Particulate Analysis by MFI (particles/m L)	2-10 pm	25573	NR	NR	10568	NR	NR	2677
> 10 pm	1267	NR	NR	989	NR	NR	149
> 25 pm	150	NR	NR	187	NR	NR	25

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Table 7: Research Stability of50 mg/mL HIH17139P Drug Product - Effect of Accélérated Conditions

Stability Study Number	H1H17I39-SS004
Source DS Lot Number	9019300002
Formulation Lot Number	L15-0396
Formulation	50 mg/mL H1H17139P, 10 mM histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Fil] Volume	0.4 mL
Container/Closure	2 mL Type 1 borosilicate glass vial with West S2-F451 4432/50 GRY
Assay	Storage Condition/Length of Storage
No Stora ge	25°C (montbs)	45°C(days)
0	0.5	1	3	7	14	28
Color and Appearance	Pass	Pass	Pass	Pass	Pass	Pass	Pass
Turbidîty (Increase in OD at 405 nm)	0.00	0.00	0.00	0.00	0.00	0.00	0.01
pH	6.0	6.0	6.1	6.1	6.1	6.1	6.0
% Total H1H17139P Recovered by RP-	100	100	100	104	100	100	99
Purîty by MCE-SDS	Non-reduced; % main peak	100	NR	NR	99.5	NR	NR	98.8
Reduced; % heavy + light chain	98.7	NR	NR	99.1	NR	NR	98.4
Purîty by SE-UPLC	% HMW	0.6	0.7	0.8	1.0	0.9	1.1	1.4
% Native	98.4	98.1	98.0	97.4	97.6	96.8	95.7
% LMW	l.l	1.2	1.2	1.6	1.5	2.1	2.9
Charge Variant Analysis by CEX-UPLC	% Acidic	42.9	43.0	43.2	45.5	45.4	49.5	56.7
% Main	53.2	52.8	52.4	49.6	49.9	45.6	38.5
% Basic	4.0	4.3	4.4	4.9	4.8	5.0	4.8
Charge Variant Analysis by ÎCIEF	% Acidic	49.4	NR	NR	52.5	NR	NR	62.3
% Main	46.8	NR	NR	43.0	NR	NR	32.2
% Basic	3.2	NR	NR	3.9	NR	NR	4.8
Parti eu late	2-10 pm	7332	NR	NR	1279	NR	NR	4628
> 10 pm	37	NR	NR	65	NR	NR	170

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Stabilîty Study Number	H1H17139-SS004
Source DS Lot Number	9019300002
Formulation Lot Number	L15-0396
Formulation	50 mg/mL H1H17139P, 10 mM histidine, 10% (w/v) sucrose,0.1% (w/v) polysorbate 80, pH 6.0
Fill Volume	0.4 mL
Container/Closure	2 mL Type I borosilicate glass vial with West S2-F451 4432/50 GRY
	Storage Condition/Length of Storage
No Stora ge	25°C (months)	45° C (days)
Assay		0	0.5	1	3	7	14	28
Analysis by MFI (particles/mL)	> 25 pm	3	NR	NR	6	NR	NR	23

Table 8: Research Stabilîty ofSO mg/mL HlH17I61PDrug Product - Effect of Accéléra tet

Conditions

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Stabilîty Study Number	H1H17161-SS004
Source DS Lot Number	9019800002
Formulation Lot Number	LJ 5-0400
Formulation	50 mg/mL H1HI7161P, 10 mM histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Fill Volume	0.4 mL
Container/Closure	2 mL Type I borosilicate glass vial with West S2-F451 4432/50 GRY
Assay	Storage Condition/Length of Storage
No Stora ge	25°C (months)	45°C (days)
0	0.5	1	3	7	14	28
Color and Appearance	Pass	Pass	Pass	Pass	Pass	Pass	Pass
Turbidîty (Increase in OD at 405 nm)	0.00	0.00	0.00	0.00	0.00	0.00	0.00
pH	6.1	6.1	6.1	6.1	6.1	6.1	6.1
% Total H1H17161P Recovered by RPUPLC	100	105	98	107	99	96	99
Purity by MCE-SDS	Non-reduced; % main peak	100	NR	NR	98.4	NR	NR	96.1
Reduced; % heavy + light chain	98.4	NR	NR	97.6	NR	NR	97.8

Stability Study Number	H1H17161-SS004
Source DS Lot Number	9019800002
Formulation Lot Number	L15-0400
Formulation	50 mg/mL H1H17161P, 10 mM histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Fill Volume	0.4 mL
Container/Closure	2 mL Type I borosilicate glass vial with West S2-F451 4432/50 GRY
Assay	Storage Condition/Length of Storage
No Stora ge	25°C (months)	45°C (days)
0	0.5	1	3	7	14	28
Purity by SE-UPLC	% HMW	L1	1.4	1.6	1.8	1.5	1.7	2.1
% Native	97.4	97.0	96.8	96.2	96.5	95.6	94.6
% LMW	1.5	1.7	1.7	2.0	2.0	2.6	3.3
Charge Variant Analysis by CEX-UPLC	% Acidic	60.5	61.0	61.7	64.7	64.7	69.1	76.1
% Main	35.7	34.6	34.2	30.0	30.8	26.6	19.4
% Basic	3.9	4.4	4.2	5.4	4.4	4.2	4.5
Charge Variant Analysis by iCIEF	% Acidic	54.1	NR	NR	57.5	NR	NR	67.3
% Main	42.7	NR	NR	38.0	NR	NR	26.9
% Basic	3.2	NR	NR	4.4	NR	NR	5.8
Parti culate Analysis by MFI (partie les/mL)	2-10 pm	7526	NR	NR	468	NR	NR	2204
> 10 pm	39	NR	NR	33	NR	NR	98
>25 pm	7	NR	NR	5	NR	NR	7

Table 9: Research Stability of50 mg/mL H1H17203P Drug Product - Effect of Stress Conditions

Stability Study Number	RG3470-SS004
Source DS Lot Number	9018800002
Formulation Lot Number	L15-0397
Formulation	50 mg/mL HJH17203P, 10 mM histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Fill Volume	0.4 mL
Container/Closu re	2 mL Type I borosilicate glass vial with West S2-F451 4432/50 GRY
Assay	Stress Condition/Length of Stress
No Stress	Agitation (minutes)	Freeze/Thaw (cycles)
0	60	120	4	8
Color and Appearance	Pass	Pass	Pass	Pass	Pass
Turbidity (Increase in OD at 405 nm)	0.00	0.00	0.00	0.00	0.00
pH	6.1	6.1	6.1	6.1	6.1
% Total H1H17203P Recovered by RPUPLC	100	100	100	99	100
Purity by MCE-SDS	Non-reduced; % main peak	100	NR	100	NR	100
Reduced; % heavy + light chain	99.6	NR	99.6	NR	99.2
Purity by SE-UPLC	% Total HMW	0.6	0.5	0.5	0.6	0.6
% Total Native	98.3	98.3	98.3	98.3	98.3
% Total LMW	1.2	1.2	1.2	1.1	1.1
Charge Variant Analysis by CEX-UPLC	% Acidic	42.2	42.3	42.3	42.3	42.4
% Main	46.5	46.8	46.8	46.7	46.6
% Basic	11.3	11.0	11.0	11.0	11.0
Charge Variant Analysis by iCIEF	% Acidîc	57.1	NR	57.5	NR	57.1
% Main	40.5	NR	39.8	NR	40.5
% Basic	2.4	NR	2.6	NR	2.3

Table 10: Research Stability of 50 mg/mL H1H17139P Drug Product - Effect of Stress Conditions

Stability Study Number	H1H17139-SS004
Source DS Lot Number	9019300002
Formulation Lot Number	L15-0396
Formulation	50 mg/mL H1H17139P, 10 mM histîdine, 10%(w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Fill Volume	0.4 mL
Container/Closure	2 mL Type I borosilicate glass vial with West S2-F45I 4432/50 GRY
Assay	Stress Condition/Length of Stress
No Stress	Agitation (minutes)	Freeze/Thaw (cycles)
0	60	120	4	8
Color and Appearance	Pass	Pass	Pass	Pass	Pass
Turbidity (Increase in OD at 405 nm)	0.00	0.00	0.00	0.00	0.00
pH	6.0	6.1	6.0	6.0	6.1
% Total H1H17I39P Recovered by RP- UPLC	100	100	100	100	100
Purîty by MCE-SDS	Non-reduced; % main peak	100	NR	100	NR	100
Reduced; % heavy + light chain	98.7	NR	99.1	NR	99.3
Purîty by SE-UPLC	% Total HMW	0.6	0.5	0.5	0.6	0.6
% Total Native	98.4	98.4	98.4	98.4	98.4
% Total LMW	1.1	1.1	1.1	l.l	1.1
Charge Variant Analysis by CEX-UPLC	% Acidic	42.9	42.9	42.9	43.1	42.9
% Main	53.2	53.2	53.2	53.0	53.2
% Basic	4.0	3.9	3.9	4.0	3.9
Charge Variant Analysis by iCIEF	% Acidic	49.4	NR	49.8	NR	49.5
% Main	46.8	NR	46.0	NR	46.5
% Basic	3.2	NR	3.7	NR	3.5

Table 11: Research Stability of 50mg/mL H1H17161P Drug Product - Effect of Stress Conditions

Stability Study Number	H1H17161-SS004
Source H1H17161P DS Lot	9019800002
Formulation Lot Number	L15-0400
Formulation	50 mg/mL H1H17161P, 10 mM histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Fill Volume	0.4 mL
Contaîner/Closure	2 mL Type I borosilicate giass vial with West S2-F451 4432/50 GRY
Assay	Stress Condition/Length of Stress
No Stress	Agitation (minutes)	Freeze/Thaw (cycles)
0	60	120	4	S
Col or and Appearance	Pass	Pass	Pass	Pass	Pass
Turbidity (Increase in OD at 405 nm)	0.00	0.00	0.00	0.00	0.00
pH	6.1	6.1	6.1	6.1	6.1
% Total H1H17161P Recovered by RPUPLC	100	100	101	99	98
Purity by MCE-SDS	Non-reduced; % main peak	100	NR	100	NR	100
Reduced; % heavy + light chain	98.4	NR	98.7	NR	97.9
Purity by SE-UPLC	% Total HMW	1.1	1.0	1.1	1.1	1.1
% Total Native	97.4	97.4	97.5	97.4	97.3
% Total LMW	1.5	1.5	1.5	1.5	1.5
Charge Variant Analysis by CEX-UPLC	% Acidic	60.5	60.3	60.3	60.5	60.9
% Main	35.7	35.9	35.8	35.6	35.2
% Basic	3.9	3.8	3.9	4.0	4.0
Charge Variant Analysis by iCIEF	% Acidic	54.1	NR	53.2	NR	54.4
% Main	42.7	NR	42.6	NR	42.3
% Basic	3.2	NR	4.3	NR	3.3

Conclusions

[000205] H1H17203P, H1H17139P, and H1H17161P antîbodies are manufactured as a liquid DP for IV administration. The ΗΙΗ17203Ρ DP contains 50 mg/mL HIH17203P antibody formulated in a solution containing 10 mM histidine, pH 6.0, 0.1% (w/v) polysorbate 80, and 10% (w/v) sucrose. The H1H17139P DP contains 50 mg/mL H1H17139P antibody formulated in a solution containing 10 mM histidine, pH 6.0, 0.1% (w/v) polysorbate 80, and 10% (w/v) sucrose. The H1H17161P DP contains 50 mg/mL H1H1716IP antibody formulated in a solution containing 10 mM histidine, pH 6.0, 0.1% (w/v) polysorbate 80, and 10% (w/v) sucrose.

[000206] Based on the results of the studies in this Example, 50 mg/mL H1HI7203P DP, 50 mg/mL H1H17139P DP and 50 mg/mL H1H17161P DP are stable when stored at 2-8°C for at least 12 months. In addition, the main dégradation pathways îdentified under accelerated conditions were formation of HMW and LMW species and acidic charge variants.

Example 5: Stability Studies for Aqueous Formulation Containing 50 mg/mL Anti-EBOV Antibody Combination

[000207] Three anti-EBOV monoclonal antîbodies, H1HI7203P, H1H17139P, and H1H17161P were formulated using 50 mg/mL total protein (16.7 mg/mL H1H17203P, 16.7 mg/mL H1H17I39P, and 16.7 mg/mL H1H17161P), 10 mM histidine, pH 6.0, 0.1% (w/v) polysorbate 80, and 10% (w/v) sucrose. Three anti-EBOV monoclonal antîbodies were formulated and combined into a single glass vial. Methods used to assess stability were developed to provide, where possible information on each component antibody. However, many of the analytical methods are incapable of providing information on each individual antibody. When not able to individually provide results for each antibody, the analytical method provides stability data for the total drug product.

[000208] The physical stability of a formulation refers to properties such as color, appearance, pH, turbidity and protein concentration. The presence of visible particulates in solution can be detected by Visual inspection. A solution passes visual inspection îf it is clear to slightly opalescent, essentîally free from visible particulates, and colorless to pale yellow. Turbidity, measured by an increase in OD at 405 nm, can also be used to delect particulates in solution. An increase in OD at 405 nm may indicate the presence of particulates, an increase in opalescence, or color change of the test articles. MFI is used to measure subvisible particulates that are >2 pm in size. Total protein concentration is measured by a RP-UPLC assay and reported as percent protein recovery relative to the starting material.

[000209] In the RP-UPLC assay, H1H17203P, H1H17139P, and H1HI7161P peaks cannot be 77 resolved from each another following elution from the reversed-phase column (Figure 1). The total protein concentration (FI 1H17203P, H1H17139P, and H1H17I61P) is determined by comparing the peak area to a calibration curve generated using a H1HI7203P standard. Because the extinction coefficient of H1H17203P, H1H17139P, and H1H17161P is 1.50, 1.57 and 1.36, respectively, the extinction coefficient of co-formulated H1HI7203P, H1 FI17139P, and H1H17161P (1:1:1) would be approxîmately 1.48 (the average of the three extinction coefficients). Therefore, H1H17203P standard (extinction coefficient, 1.50) was chosen to generate the standard curve to détermine the total protein concentration in the co-formulated formulation. Percent recovery is calculated based on the measured total protein concentration relative to the starting concentration.

[000210] Chemical stability refers to the formation of covalentiy modîfied forms (e.g. covalent aggregates, cleavage products or charge variant forms) and non-covalently modified forms (e.g. non-covalent aggregates) of protein. Higher and lower molecular weight dégradation products can be separated from native molecular weight product using SE-UPLC and MCE-SDS methods. The three-way antibody formulations were characterized for total purity (native H1H17203P, H1H17139P, and H1H17161 P) by SE-UPLC (i.e. molecular weight purity of H1H17203P, H1H17139P, and H1H17161P were not determined individually) because H1H17203P, FTIFI17I39P, and H1H17161P native species cannot be resolved from each other (Figure 2).

Similarly, three-way antibody formulations will be characterized for total high molecular weight (HMW) species (H1H17203P HMW, H1H17139P HMW, and H1H17161P HMW) and total low molecular weight (LMW) species (HIH17203P LMW, H1H17139P LMW, and H1H17I61P LMW) because HMW or LMW species of H1H17203P, H1H17139P, and H1H17161P cannot be resolved from each other (Figure 2). The percentage of total HMW species or total LMW species in the 3way formulation, determined using the SE-UPLC method, is calculated from the ratio of the area of total HMW species or total LMW species to the total area of ail HIH17203P, H1H17139P, and H1H17161P peaks, respectively. Total purity, determined by non-reduced MCE-SDS is calculated from the ratio of the H1H17203P, H1H17139P, and H1H17I61P main band intensity to the total intensity of ail bands. Total purity, determined by reduced MCE-SDS is calculated from the ratio of the sum ofthe H1H17203P, H1H17139P, and H1H1716IP heavy chain and light chain band intensities relative to the total intensity of ail bands.

[000211] The iCIEF method did not hâve sufficient resolution to separate ail charge variant forms of ail three antibodies. Therefore, this analytical method was not used to assess changes in the charge variant profile for the three-way formulation samples. Charge variant forms of H1H17203P,

H1H17139P, and HIH17161P that are co-formulated were able to be resolved using the CEX-UPLC method. For H1H17203P, H1H17139P, and H1H17161P, peaks with rétention times earlier than that of the main peak are labeled as “acidic” peaks; peaks with rétention times later than that of the main peak are labeled as “basic” peaks. The percentages of acidic, main, and basic peaks are calculated by comparing the individual peak area to the total peak areas of each antibody.

[000212] The Drug Product (DP) used for the storage, accelerated, and stress stability studies was created by filling 0.4 mL of FDS in 2 mL Type 1 glass vials. The DP was incubated under several elevated température conditions, relative to storage température conditions. These accelerated conditions were selected to simulate the conditions to which the DP may be subjected during manufacturing and handling in order to elucidate the dégradation pathways for co-formulated H1HI7203P, H1H17139P, and H1H17161P DP. An outline ofthe storage, accelerated, and stress stability conditions for the co-formulated DP are presented in Table 12 and the analysis plans are presented in Table 13.

Table 12: Research Stability Studies for H1H17203P, H1H17139P, and H1H17161P

Combination DP

Storage Stability	Container/Closure
Storage Température	Length of Storage (months)	Type 1 borosilîcate glass with FluroTec® coated 4432/50 butyl rubber stopper
5°C	0, 1, 3,6,9, 12, 18,24, and 36
Accelerated Stability
Incubation Condition	Length of Incubation
25°C	0, 0.5, 1, and 3 months
45°C	0, 7, 14,and 28 days
Stress Stability
Stress	Duration of Stress
Agitation (vortex)	0, 60, and 120 minutes
Freeze/Thawa	0, 4, and 8 cycles

^aFrozen at -30°C and thawed at room température.

Table 13: Research Stability Studies, Analysis Plan for H1H17203P, H1H17139P, and

H1H17161P Combination DP

Assay	Samples to be Analyzed
Color and Appearance	Ail Samples
pH	Ail Samples
Turbidîty (Increase in OD at 405 nm)	Ail Samples
% Total I-11 PI 17203P, H1H17139P, H1H17161P Recovered by RP-UPLC	Ail Samples
Total Purity (H1HI7203P, H1H17139P, H1H17161 P) by Non-Reduced and Reduced MCE-SDS	t = 0, 6, 12, 24 and 36 months at 5°C; 6 months at 25°C; 28 days at 45°C 120 min Agitation, 8X Freeze/Thaw
Total (H1HI7203P, H1H17139P, H1H17161P) Purity by SE-UPLC	Ail Samples
Charge variant analysis by CEX-UPLC	Ail samples
Particulate Matter Analysis by MF1	t = 0, 6, 12, 24 and 36 months at 5°C; 6 months at 25°C; 28 days at 45°C 120 min Agitation, 8X Freeze/Thaw
% H1H17203P, H1H17139P, and HIH17161P Relative Potency by Bioassay	t = 0, 6, 12, 24 and 36 months at 5°C; 6 months at 25°C; 28 days at 45°C 120 min Agitation, 8X Freeze/Thaw

Research Storage Stability for Co-formulated H1H17203P, H1H17139P, and H1H17161P DP (1:1:1, 50 mg/mL total protein)

[000213] Three months of research storage stability data are shown for the co-formulated H1H17203P, H1H17139P, and H1H17161P DP. Co-formulated H1H17203P, H1H17139P, and H1H17161P DP was physically stable when stored at 5°C for 3 months. An increase of 0.2% in total HMW species was observed by SE-UPLC when co-formulated H1H17203P, H1H17139P, and H1H17161P DP (1:1:1, 50 mg/mL total protein) was stored at 5°C for 3 months, and an increase of 0.6 in total HMW was observed by SE-UPLC after storage at 5°C for 18 months. No appréciable change in the physical or Chemical stability ofthe co-formulated H1H17203P, H1H17139P, and HlH17161PDP(l:l:l,50 mg/mL total protein) was detected in any of the other monitored attributes. HIH17203P, H1H17I39P, and H1HI7161P maintained potency over the 3 month assessment interval as determined by bioassay analysis. See Table 14.

Research Accelerated Stability for Co-formulated H1H17203P, H1H17139P, and H1H17161P DP (1:1:1, 50 mg/mL total protein)

[000214] Results from the analysis ofthe co-formulated H1H17203P, H1HI7139P, and H1H17161P DP following incubation under accelerated conditions are provided in 4. After incubation for 28 days at 45 °C, an increase of 1.3% in the relative amount of total HMW species (SE-UPLC) was observed. After incubation for 28 days at 45°C, an increase of 14.7%, 14.4% and 22.9% was observed in H1H17203P, H1HI7139P, and H1H17161P acidic charge variant species (CEX-UPLC), respectively. After incubation for 3 months at 25°C, an increase of 2.6%, 2.5% and 5.6% was observed in H1H17203P, EU H17139P, and H1H17161P acidic charge variant species (CEX-UPLC), respectively. H1H17203P, H1H17139P, and H1H17161P maintained potency, as determined by bioassay analysis, after incubation under the accelerated conditions. The results from accelerated stability testing démonstrated that an increase in the relative amounts of total HMW species, total LMW species, and the formation of acidic charge variants for HIH17203P, H1H17139P, and HIH17161P were the main dégradation pathways for the co-formulated H1H17203P, H1H17139P, and H1H17161P DP (1:1:1, 50 mg/mL total protein). See Table 15.

Research Stress Stability for Co-formulated H1H172Û3P, H1H17139P, and H1H17161P DP (1:1:1, 50 mg/mL total protein)

[000215] Results from the co-formulated HIH17203P, H1H17139P, and H1H17161P DP stress stability studies are provided in Table 16. Co-formulated H1H17203P, HIH17139P, and H1H17161P DP was physically and chemically stable when agitated (vortexed at ambient température) for 120 minutes or when subjected to 8 freeze/thaw cycles (freezing at -30°C and thawing at room température). No appréciable change in the physical or Chemical stability was detected in any ofthe monitored attributes. H1HL7203P, H1H17139P, and H1H17161P maintained potency when the DP was agitated for 120 minutes or when subjected to 8 freeze/thaw cycles. See Table 16.

Research Stability Conclusions for Co-Formulated H1H17203-3471-3479 Drug Product [000216] The results from storage, accelerated, and stress stability studies îndicate that coformulated H1H17203 P, H1H17139P, and H1H17161P DP will be stable during manufacture (fi 11/finish and labeling operations). The HIH17203P, H1H17139P, and H1HI7161P Combination DP formulation can withstand short exposures to room température without compromising physical 81 or Chemical stability. H1H17203P, H1H17I39P, and H1H17161P Combination DP will be stored at 2°C to 8°C and exposure to températures greater than 8°C will be limited.

[000217] The long-term storage of co-formulated HIH17203P, H1H17139P, and H1H17161P DP at 2-8 °C was determined over 36 months (Table 14). Increases of 0.7% each in total HMW species and total LMW species were observed following storage at 5°C for 36 months. Changes of 1.1%, 1.2% and 7.3% in acidic species were observed for HIH17203P, H1H17139P and HIH17161P, respectively. No significant change in potency was observed over the 36-month duration ofthe study, îndicating that the anti-EBOV formulation provided acceptable long term storage stability under refrigerated conditions.

Table 14: Research Stability of H1H17203P, H1H17139P, and H1H17161P Combination DP (1:1:1, 50 mg/mL total protein) Stored at 5°C

Stability Study Number	H1H17203P, H1H17139P, and H1H17161P-SS002
Lot Number	9018800002,9019300002, 9019800002
Formulation Lot Number	L15-401
Formulation	16.7 mg/mL Η1ΙΠ7203Ρ, 16.7 mg/mL ΗΠΓ17139Ρ, 16.7 mg/mL H1H17161P, 10 mM histidine, pH 6.0, 0.1% (w/v) polysorbate 80,10% (w/v) sucrose
Fill Volume	0.4 mL
Container/Closure	2 mL Type 1 borosîlieate glass vial with West S2-F451 4432/50 GRY B2-40 stopper
Ass a y	Length of Storage (months)
0	1	3	6	9	12	18	24	36
Color and Appearance	Pass	Pass	Pass	Pass	Pass	Pass	Pass	Pass	Pass _
Turbîdity (Increase in OD at 405 nm)	0.00	0.00	0.00	0.00	0.00	0.00	0.00	0.01	0.01
pH	6.1	6.1	6.1	6.1	6.0	6.1	6.0	6.1	6.1
% Total Protein Recovered by RP-UPLC	H1H17203P, HIH17139P, and H1H17161P	100	101	104	104	103	103	101	103	102
Total Purity by MCE-SDS	Non-reduced; % (H1H17203P, HIH17I39P, and HIH17161P) main	100	NR	NR	99.6	NR	99.7	NR	99.7	100.0
Reduced; %(HlH17203P, H1H17139P, and H1HI7I61P) heavy chain + % (H1H17203P, H1H17I39P, and H1H17161P) light chain	99.3	NR	NR	99.2	NR	99.2	NR	99.1	98.9
Total Purity by SE-UPLC	% Total HMW	0.7	0.8	0.9	1.1	l.l	1.2	1.3	1.3	1.4
% Total Native	98.2	98.0	98.0	97.8	97.6	97.2	97.3	96.9	96.8
% Total LMW	1.1	l.l	l.l	1.1	1.3	1.7	1.5	1.8	1.8
Charge variants by CEX-UPLC	HIH17203P	% Acidic	37.3	37.2	36.6	36.0	36.9	37.1	37.9	38.2	38.4
% Main	41.3	41.3	41.8	42.8	42.1	42.1	41.3	41.1	42.6
% Basic	21.5	21.6	21.6	21.2	21.1	20.7	20.8	20.7	19.0

Stability Study Number	H1H17203P, H1H17139P, and H1H1716IP-SS002
Lot Number	9018800002,9019300002, 9019800002
Formulation Lot Number	L15-401
Formulation	16.7 mg/mL H1H17203P, 16.7 mg/mL HUII7139P, 16.7 mg/mL IIIHI7161 P, 10 mM histidine, pH 6.0,0.1% (w/v) polysorbate 80,10% (w/v) sucrose
Fill Volume	0.4 mL
Container/Closure	2 mL Type I borosilicate glass vial with West S2-F451 4432/50 GRY B2-40 stopper
Assay		Length of Storage (months)
0	1	3	6	9	12	18	24	36
	H1H17139P	% Acidic	43.2	43.1	42.9	40.7	41.9	42.5	44.2	44.5	42.0
% Main	53.5	53.7	53.8	56.0	54.7	53.9	52.4	52.0	54.4
% Basic	3.2	3.2	3.3	3.4	3.4	3.6	3.5	3.5	3.6
H1H17161P	% Acidic	50.3	50.5	48.3	50.5	52.4	50.9	54.3	55.2	57.6
% Main	44.6	44.4	45.0	46.0	43.8	43.7	41.9	40.2	38.1
% Basic	5.2	5,1	6.7	3.5	3.8	5.4	3.8	4.7	4.3
Particulate Analysis by MF J (part ici es/mL)	2-10 pm	16393	NR	NR	7081	NR	1472	4337	4506	8719
> 10 μηι	55	NR	NR	626	NR	35	359	951	1212
> 25 μιη	3	NR	NR	120	NR	5	26	129	210
% Relative Potency (Bioassay)	Virus Neutralization assay	107	NR	80	80	NR	69	NR	72	86
ADCC assay	112	NR	105	126	NR	125	NR	111	116

NR, Not Required.

[000218] Results from the accelerated studies are provided below in Table 15. After incubation for 3 months at 25°C, an increase of 0.6% in the relative amount of total HMW species and total LMW species was observed. Increases in acidic charge variants of 2.6%, 2.5% and 5.6% were observed for H1H17203P, H1H17139P, and H1H17161P, respectively. Co-formulated H1HI7203P, H1H17139P, and H] H17161P DP maintaîned potency after incubation under the accelerated conditions. After incubation for 28 days at 45°C, an increase of 1.3% in the relative amount of total HMW species was observed while the increase in total LMW species was 1.9%.

[000219] The results from stress and accelerated stability studies of co-formulated H1H17203P, H1H17139P, and H1H17161P DP demonstrated iimited increases in the relative amounts of total HMW species, total LMW species, and acidic charge variants for co-formulated H1HI7203P, H1H17139P, and H1H17161P DP similarly to those from the individual formulations.

Table 15: Research Stability of H1H17203P, H1H17139P, and H1H17161P Combination DP (1:1:1, 50 mg/mL total protein) - Effect of Accelerated Conditions

Stability Study Number	H1H17203P, H1H17139P, and H1H17161P-SS002
Lot Number	9018800002, 9019300002, 9019800002
Formulation Lot Number	L15-401
Fo rmulatîon	16.7ing/mL HIH17203P, 16.7 mg/mL HIH17139P, 16.7 mg/mL H1H1716IP, 10 mM histidine, pH 6.0,0.1% (w/v) polysorbate 80, 10% (w/v) sucrose
Fill Volume	0.4 mL
Container/Closure	2 mL Type 1 horosilicate glass vial with West S2-F451 4432/50 GRY B2-40 stopper
Assay	Storage Candi tion/Length of Storage
No Storage	25°C (months)	45°C (days)
0	0.5	1	3	7	14	28
Color and Appearance	Pass	Pass	Pass	Pass	Pass	Pass	Pass
Turbidity (Increase in OD at 405 nm)	0.00	0.00	0.01	0.00	0.00	0.01	0.01
pH	6.1	60	6.1	6.1	6.0	6.1	6 1
% Total Protein Recovered by RPUPLC	H1H17203P, HIH17139P, and H1H17161P	J 00	100	101	104	99	98	101
Total Purity by MCE-SDS	Non-reduce d; % (HIH17203P, H1H17139P, and HJH1716JP) main	100	NR	NR	100	NR	NR	98.5
Reduced; % (H1H17203P, H1H17139P, and H1H17161P heavy chain)+ % (I-11H17203P, H1H17139P, and H1H17J61P) light chain	99.3	NR	NR	98.8	NR	NR	98.0
Total Purity by SE-UPLC	% Total HMW	0.7	1.0	l.l	1.3	1.1	14	2.0
% Total Native	98.2	97.7	97.6	97.0	97.2	96.5	95 0
% Total LMW	1.1	1.3	1.3	1.7	1.7	2.2	3.0
Charge variants by CEX-UPLC	H1H17203P	% Acidic	37.3	37.5	38.0	39.9	40.2	43.7	52.0
% Main	41.3	41.6	41.5	40.4	39.2	36.4	317
% Basic	21.5	20.9	20.5	19.6	20.6	19.9	16.2
H1H17139P	% Acidic	43.2	43.1	43.5	45.7	46.0	49.8	576
% Main	53.5	53.4	53.0	50.3	49.9	45.6	38.1
% Basic	3.2	3.5	3.5	4.0	4.0	4.6	4.4
H1H17161P	% Acidic	50.3	51.7	53.2	55.9	56.2	61.5	73.2
% Main	44.6	43.1	42.3	37.0	38.9	33.2	22.1
% Basic	5.2	5.3	4.5	7.1	4.9	5.3	4.6
Particulate Analysis by MFI (parti cles/mL)	2-10 pm	16393	NR	NR	1785	NR	NR	1882
> 10 pm	55	NR	NR	200	NR	NR	144
> 25 pm	3	NR	NR	41	NR	NR	33
% Relative Potency by Bioassay	Virus Neutralization assay	107	NR	NR	86	NR	NR	75
ADCC assay	112	NR	NR	116	NR	NR	123

NR, Not Requircd.

[000220] Results from the stress stability studies showed that co-formulated H1H17203P,

H1HI7139P, and H1H17161P DP was physically and Chemically stable when agitated (vortexed at ambîent room température) for 120 minutes or when subjected to eight freeze/thaw cycles (Table 16). No appréciable change in the physical or Chemical stabilîty was detected in any of the monitored attributes, Potency was maintained when the co-formulated H1H17203P, H1H17139P, and H1H17161P DP was agitated or when subjected to freeze/thaw cycles.

Table 16: Research Stabilîty of H1H17203P, H1H17139P, and H1H17161P Combination DP (1:1:1, 50 mg/mL total protein) - Effect of Stress Conditions

Stabilîty Study Number	H1H17203P, H1H17139P, and ΗΠΙΙ7Ι6ΙΡ -SS002
Lot Number	9018800002,9019300002,9019800002
Formulation Lot Number	L15-401
Formulation	16.7 mg/mL H1H17203P, 16.7 mg/mL H1H17139P, 16.7 mg/mL H1H17161P, 10 mM histidine, pH 6.0, 0.1% (w/v) polysorbate 80, 10% (w/v) sucrose
Fill Volume	0.4 mL
Container/Closure	2 mL Type I borosilicate glass vial with West S2-F451 4432/50 GRY B2-40 stopper
Assay	Stress Condition/Length of Stress
No Stress	Agitation (minutes)	Freeze/Thaw (cycles)
0	60	120	4	8
Col or and Appearance	Pass	Pass	Pass	Pass	Pass
Turbidiiy (Increase in OD at 405 nm)	0.00	0.00	0.00	0.00	0.00
pH	6.1	6.0	6.0	6.1	6.1
% Total Protein Recovered by RPUPLC	H1H17203P, HIH17139P, and H1H17161P	100	100	100	101	101
Total Purity by MCE-SDS	Non-reduced, % Native (H1H17203P, H1H17139P, and H1H17161P)	100	NR	99.7	NR	100
Reduced; % (H1H17203P, H1HI7139P, and H1H17161P heavy chain) + % (H1H17203P, H1H17139P. and H1H17161P) light chain	99.3	NR	99 1	NR	98.8
Total Purity by SE-UPLC	% Total HMW	0.7	0.7	0.7	0.7	0.8
% Total Native	98.2	98.1	98.1	98.2	98.1
% Total LMW	1.1	1.2	1.2	1.1	1.1
Charge variants by CEX-UPLC	HIH17203P	% Acidic	37.3	37.1	37.3	37.2	37.4
% Main	41.3	41.3	41.2	41.2	41.0
% Basic	21.5	21.6	21.5	21.6	21.6

Stability Study Number	H1H17203P, H1H17139P, and H1II17161P -SS002
Lot Number	9018800002, 9019300002, 9019800002
Formulation Lot Number	L15-401
Formulation	16.7 mg/mL H1H17203P, 16.7 mg/mL HIH17139P, 16.7 mg/mL H1H17161P, 10 mM histidine, pH 6.0, 0.1% (w/v) polysorbate 80, 10% (w/v) sucrose
Fill Volume	0.4 mL
Containcr/Closure	2 mL Type I borosilicate glass vial with West S2-F451 4432/50 GRY B2-40 stopper
Assay		Stress Condition/Lengtli of Stress
No Stress	Agitation (minutes)	Freeze/Thaw (cycles)
0	60	120	4	8
	HIHI7I39P	% Acidic	43.2	43.1	43.4	43.3	43.5
% Main	53.5	53.6	53.5	53.4	53.3
% Basic	3.2	3.3	3.2	3.3	3.2
H1H17161P	% Acidic	50.3	50.4	50.5	50.3	50.6
% Main	44.6	44.6	443	44.5	44.2
% Basic	5.2	5.0	5.2	5.2	5.2
% Relative Potency (Bioassay)	Virus Neutralization assay	107	NR	116	NR	94
ADCC assay	112	NR	87	NR	127

NR, Not Required

Conclusions

[000221] Co-formulated H1H17203P, HIH17139P, and H1H17161P DP is manufactured as a liquid DP for IV administration. The H1H17203P, H1H17139P, and H1Hi716IP DP can contain 16.7 mg/mL H1H17203P, 16.7 mg/mL H1H17139P and 16.7 mg/mL H1H17161P formulated in a solution containing 10 mM histidine, pH 6.0, 0.1 % (w/v) polysorbate 80, and 10% (w/v) sucrose. Based on the results of the studîes herein:

[000222] Co-formulated HIH17203P, H1H17139P, and H1H17161P DP is stable when stored at 2-8°C for at Ieast 3 months.

[000223] The main dégradation pathways identified under accelerated conditions were formation of HMW and LMW species and acidic charge variants.

Example 6: Effect of Different Buffers and pH

[000224] The effect of buffer and pH on the thermal stability of the three anti-EBOV antibodies was examined in liquid formulations by incubating 100 mg/mL total antibody at 45°C for 28 days in a sériés of buffer Systems at varying pH ranges. The following pH and buffer Systems were studied:

citrate (pH 5.2, 6.0, 6.8) and histidine (pH 5.2, 6.0, 6.8). Based on resuIts from SE-UPLC analysis, maximum protein stability was observed when the antibodies were formulated at pH 6.0 in histidine buffer (Tables 17-20 and 22-25). Presence of sub-visible particles was determined in the three-way antibody formulation using micro fluid imaging (MFI) (Table 21).

Table 17: Effect of Buffer and pH on the Stability of 100 mg/mL H1H17203P Incubated at 45°C for 28 Days - Visual, OD, pH, SE-UPLC, and RP-UPLC ResuIts

Buffer/pH	Days	Visual	OD @ 405 nm	Δ OD	pH	% HMW	% Native	% LMW	Protein Conc. (mg/mL)	% Recovery
lOmM Histidine pH 5.2	t=0	pass	0.085	0.00	5.4	1.0	97.8	1.2	31.8	100.0
7	pass	0.084	0.00	5.4	2.2	96.0	1.8	32.3	101.7
14	pass	0.089	0.00	5.4	3.2	94.2	2.6	31.9	100.4
21	pass	0.089	0.00	5.4	4.9	92.2	2.9	32.3	101.7
28	pass	0.091	0.01	5.5	6.0	90.6	3.4	32.5	102.1
lûmM Histidine pH6.0	t=0	pass	0.088	0.00	6.1	1.3	97.6	1.1	33.3	100.0
7	pass	0.087	0.00	6.1	1.3	97.0	1.7	33.9	101.9
14	pass	0.090	0.00	6.1	1.6	96.0	2.3	33.3	100.2
21	pass	0.093	0.01	6.1	2.2	95.3	2.5	33.9	101.8
28	pass	0.094	0.01	6.1	2.7	94.4	3.0	34.0	102.1
10mM Histidine pH6.8	t=0	pass	0.087	0.00	7.0	1.7	97.1	1.2	33.0	100.0
7	pass	0.088	0.00	7.0	1.7	96.6	1.7	33,7	102.0
14	pass	0.089	0.00	7.0	2.2	95.5	2.4	33.0	100.0
21	pass	0.092	0.01	7.0	2.8	94.6	2.6	33.3	100.9
28	pass	0.095	0.01	7.1	3.4	93.4	3.1	33.6	101.8
10mM Citrate pH 5.2	t=0	pass	0.101	0.00	5.3	1.6	97.2	1.2	32.8	100.0
7	pass	0.154	0.05	5.3	16.2	82.1	1.8	33.4	101.6
14	pass	0.347	0.25	5.3	30.1	67.7	2.3	32.5	99.1
21	pass	1.320	1.22	5.3	32.2	64.7	3.1	23.3	71.0
28	pass	2.332	2.23	5.3	NP	NP	NP	NP	NP
10mM Citrate pH 6.0	t=0	pass	0.102	0.00	6.1	1.9	97.0	1.2	31.1	100.0
7	pass	0.103	0.00	6.1	3.0	95.3	1.7	31.2	100.4
14	pass	0.106	0.00	6.1	4.4	93.4	2.2	30.8	99.1
21	pass	0.118	0.02	6.1	6.3	91.3	2.4	31.6	101.6
28	pass	0.131	0.03	6.1	7.7	89.4	2.9	31.7	101.9
10mM Citrate pH 6.8	t=0	pass	0.103	0.00	6.8	2.6	96.3	1.2	32.1	100.0
7	pass	0.105	0.00	6.9	3.3	95.0	1.7	32.1	100.0
14	pass	0.109	0.01	6.8	4.4	93.3	2.3	31.9	99.5
21	pass	0.117	0.01	6.9	5.8	91.7	2.5	32.5	101.4
28	pass	0.123	0.02	6.9	7.1	90.0	3.0	32.7	102.1

mM citrate, pH 5.2, 28d samples were not run on UPLC instruments due to visual failures

Table 18: Effect of Buffer and pH on the Stability of 100 mg/mL H1H17139P Incubated at 45°C for 28 Days - Visual, OD, pH, SE-UPLC and RP-UPLC Results

Buffer/pH	Days	Visual	OD @ 405 nm	Δ OD	pH	% HMW	% Native	% LMW	Protein Conc. (mg/mL)	% Recovery
10mM Hîstîdine pH 5.2	t=O	pass	0.085	0.00	5.4	0.8	97.8	1.4	33.4	100.0
7	pass	0.083	0.00	5.4	0.6	97.3	2.1	33.7	100.9
14	pass	0.085	0.00	5.4	0.7	96.5	2.8	33.8	101.0
21	pass	0.085	0.00	5.4	0.8	96.1	3.1	33.8	101.1
28	pass	0.088	0.00	5.4	0.9	95.4	3.7	33.9	101.4
10mM Hîstîdine pH6.0	t=0	pass	0.087	0.00	6.1	1.1	97.5	1.4	33.9	100.0
7	pass	0.085	0.00	6.1	0.8	97.3	1.9	34.1	100.6
14	pass	0.088	0.00	6.1	0.9	96.7	2.5	34.3	101.0
21	pass	0.091	0.00	6.1	1.0	96.3	2.7	34.5	101.6
28	pass	0.091	0.00	6.2	1.1	95.8	3.2	34.5	101.6
lOmM Hîstîdine pH 6.8	t=0	pass	0.085	0.00	6.9	1.4	97.3	1.4	32.6	100.0
7	pass	0.085	0.00	6.9	1.1	96.9	2.0	32.9	100.8
14	pass	0.088	0.00	6.9	1.3	96.2	2.5	32.8	100.7
21	pass	0.090	0.01	7.0	1.4	95.8	2.8	32.9	101.0
28	pass	0.091	0.01	7.0	1.6	95.0	3.4	32.8	100.8
lOmM Citrate pH 5.2	t=0	pass	0.093	0.00	5.3	1.1	97.5	1.4	32.1	100.0
7	pass	0.093	0.00	5.3	1.2	96.7	2.2	32.5	101.2
14	pass	0.095	0.00	5.3	1.4	95.5	3.0	32.5	101.0
21	pass	0.097	0.00	5.2	1.8	94.8	3.4	32.4	100.7
28	pass	0.097	0.00	5.3	2.1	93.9	4.1	32.5	101.1
10mM Citrate pH 6.0	t=0	pass	0.096	0.00	6.1	1.6	97.1	1.4	31.2	100.0
7	pass	0.094	0.00	6.1	1.5	96.5	1.9	31.4	100.7
14	pass	0.096	0.00	6.0	1.8	95.7	2.5	31.1	99.9
21	pass	0.097	0.00	6.1	2.0	95.3	2.7	31.3	100.4
28	pass	0.098	0.00	6.1	2.2	94.6	3.2	31.6	101.3
10mM Citrate pH 6.8	t=0	pass	0.099	0.00	6.8	2.2	96.4	1.3	31.9	100.0
7	pass	0.097	0.00	6.8	2.1	95.9	2.0	32.2	100.7
14	pass	0.099	0.00	6.8	2.4	95.1	2.5	32.0	100.4
21	pass	0.102	0.00	6.8	2.6	94.7	2.8	31.9	100.0
28	pass	0.101	0.00	6.9	2.8	93.9	3.3	32.2	100.9

Table 19: Effect of Buffer and pH on the Stability of 100 mg/mL H1HI7161P Incubated at 45°C for 28 Days - Visual, OD, pH, SE-UPLC, and RP-UPLC Results

Buffer/pH	Days	Visual	OD @ 405 nm	Δ OD	pH	% HMW	% Native	% LMW	Protein Conc. (mg/mL)	% Recovery
lOmM	t=O	pass	0.104	0.00	5.3	1.9	96.6	1.5	31.1	100%
Hîstîdine	7	pass	0.100	0.00	5.4	1.4	96.4	2.3	31.3	101%
pH 5.2	14	pass	0.102	0.00	5.4	1.4	95.7	2.9	31.1	100%

	21	pass	0.103	0.00	5.4	1.5	95.3	3.2	31.2	100%
28	pass	0.108	0.00	5.5	1.5	94.7	3.8	31.3	101%
lOmM Histidine pH 6.0	t=0	pass	0.107	0.00	6.1	2.3	96.3	1.5	32.1	100%
7	pass	0.106	0.00	6.1	1.7	96.3	2.1	32.6	102%
14	pass	0.112	0.01	6.1	1.7	95.6	2.7	32.1	100%
21	pass	0.106	0.00	6.2	1.8	95.4	2.8	32.4	101%
28	pass	0.108	0.00	6.2	1.9	94.9	3.3	32.6	101%
10mM Histidine pH6.8	t=0	pass	0.106	0.00	7.0	2.8	95.8	1.5	31.1	100%
7	pass	0.108	0.00	7.0	2.2	95.7	2.1	31.4	101%
14	pass	0.109	0.00	7.0	2.4	94.8	2.7	31.0	100%
21	pass	0.109	0.00	7.0	2.6	94.5	2.9	31.4	101%
28	pass	0.108	0.00	7.1	2.8	93.7	3.5	31.4	101%
lOmM Citrate pH 5.2	t=0	pass	0.112	0.00	5.2	2.2	96.3	1.5	30.0	100%
7	pass	0.117	0.01	5.2	1.9	95.7	2.4	30.3	101%
14	pass	0.111	0.00	5.2	2.2	94.6	3.3	30.2	101%
21	pass	0.110	0.00	5.3	2.4	94.0	3.6	30.2	101%
28	pass	0.110	0.00	5.2	2.6	93.1	4.3	30.3	101%
10mM Citrate pH 6.0	t=0	pass	0.120	0.00	6.0	3.1	95.5	1.5	31.6	100%
7	pass	0.122	0.00	6.0	2.8	95.1	2.1	31.9	101%
14	pass	0.119	0.00	6.0	3.1	94.3	2.6	31.9	101%
21	pass	0.118	0.00	6.0	3.3	93.9	2.8	32.0	101%
28	pass	0.116	0.00	6.0	3.6	93.2	3.3	31.9	101%
lOmM Citrate pH 6.8	t=0	pass	0.123	0.00	6.8	4.0	94.6	1.5	31.9	100%
7	pass	0.123	0.00	6.9	3.8	94.1	2.1	32.3	102%
14	pass	0.125	0.00	6.8	4.3	93.1	2.7	31.9	100%
21	pass	0.123	0.00	6.9	4.6	92.5	2.9	32.2	101%
28	pass	0.121	0.00	6.9	4.9	91.6	3.4	32.1	101%

Table 20: Effect of Buffer and pH on the Stability of 100 mg/mL Total H1H17203P, H1H17I39P, and H1H17161P Combination Incubated at 45°C for 28 Days - Visual, OD, pH, SE-UPLC, and RP-UPLC Results

Buffer/pH	Days	Visual	OD @ 405 nm	Δ OD	pH	% HMW	% Native	% LMW	Protein Conc. (mg/mL)	% Recovery
lOmM Histidine pH 5.2	t=0	pass	0.168	0.00	5.5	1.3	97.3	1.4	95.2	100%
7	pass	0.168	0.00	5.5	2.3	95.7	2	94.1	99%
14	pass	0.175	0.01	5.5	3.2	94.0	2.8	93.2	98%
21	pass	0.176	0.01	5.5	4.2	92.9	2.9	94.7	99%
28	pass	0.181	0.01	5.6	4.8	91.9	3.4	94.9	100%
lOmM Histidine pH 6.0	t=0	pass	0.177	0.00	6.2	1.7	97.0	1.4	98.2	100%
7	pass	0.177	0.00	6.3	2.3	95.8	1.9	96.9	99%
14	pass	0.183	0.01	6.2	2.9	94.6	2.5	94.4	96%

	21	pass	0.190	0.01	6.3	3.4	94.	2.6	95.6	97%
28	pass	0.193	0.02	6.3	3.8	93.2	3	97.8	100%
lOmM Histidine pH 6.8	t=0	pass	0.180	0.00	7.1	2.1	96.4	1.6	95.9	100%
7	pass	0.186	0.01	7.2	3.3	94.8	1.9	95.2	99%
14	pass	0.194	0.01	7.1	4.1	93.3	2.6	92.6	97%
21	pass	0.196	0.02	7.1	4.8	92.4	2.7	92.9	97%
28	pass	0.199	0.02	7.1	5.4	91.3	3.3	95.7	100%
10mM Citrate pH 5.2	t=0	pass	0.189	0.00	5.4	1.7	96.9	1.3	94,7	100%
7	pass	0.219	0.03	5.4	7.6	90.4	2	94.2	99%
14	pass	0.362	0.17	5.4	14	83.3	2.7	91.1	96%
21	fait	0.737	0.55	5.4	17.7	79.3	2.9	92.9	98%
28	pass	1.267	1.08	5.4	NA	NA	NA	NA	NA
lOmM Citrate pH 6.0	t=0	pass	0.201	0.00	6.2	2.3	96.4	1.3	93.3	100%
7	pass	0.201	0.00	6,2	3.6	94.6	1.9	93.0	100%
14	pass	0.208	0.01	6.2	4.7	92.9	2.5	92.8	99%
21	pass	0.220	0.02	6.2	5.7	91.8	2.5	92.6	99%
28	pass	0.226	0.03	6.2	6.6	90.4	3	94.5	101%
10mM Citrate pH 6.8	t=0	pass	0.212	0.00	6.9	3	95.7	1.3	96.1	100%
7	pass	0.213	0.00	6.9	4.4	93,7	1.9	95.7	100%
14	pass	0.225	0.01	6.9	5.6	91.8	2.6	95.5	99%
21	pass	0.224	0.01	6.9	6.5	90.9	2.6	95,7	100%
28	pass	0.234	0.02	6.9	7.4	89.5	3.2	96.4	100%

Table 21: MFI Résulte for Total H1H17203P, H1H17139P, and H1H17161P Combination

Formulation

	2-10 pm	>2pm	>10pm	>25 pm
Sample	Conc.(#/ml)	Conc.(#/ml)	Conc.(#/nil)	Conc.(#/ml)
10 mM Histidine pH 5.2 t=0	468	507	40	2
10 mM Histidine pH 6.0 t=0	557	570	13	0
10 mM Histidine pH 6.8 t=0	607	641	33	6
10 mM Citrate pH 5,2 t=0	973	1017	44	6
10 mM Citrate pH 6.0 t=0	741	770	29	10
10 mM Citrate pH 6.8 t=0	710	802	92	21
10 mM Histidine pH 5.2 t=28d at 45 C	1380	1439	58	2

10 mM Histidine pH 6.0 t=28d at 45 C	1396	1463	67	8
10 mM Histidine pH 6.8 t=28d at 45 C	1959	2024	65	6
10 mM Citrate pH 5.2 t=28d at45C	50767	57378	6611	582
10 mM Citrate pH 6.0 t=28d at45C	1326	1359	33	0
10 mM Citrate pH 6.8 t=28d at 45 C	1508	1600	92	10

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[000225] Based on results from CEX-UPLC analysis, maximum protein stability was observed when the antibodies were formulated between pH 5.2 and 6.8 in histidine buffer or between pH 5.2 and 6.8 in acetate buffer. These analyses also revealed that aggregation (i.e. formation of HMW species), fragmentation (i.e. formation of LMW species), and formation ofcharge variants were the main dégradation pathways. Histidine buffer was selected as the formulation buffer because it provided the best overall level of protein stabilization with respect to formation of HMW and LMW species and formation of charge variants. A pH of 6.0 was chosen for the formulation because formation of HMW species and charge variants, which are the major dégradation pathways, were minimized at this pH. Based on these results, 10 mM histidine buffer at pH 6.0 was chosen for the anti-EBOV individual and combination formulations. See Tables 22-25.

Table 22: Effect of Buffer and pH on the Stability of 100 mg/mL H1H17203P Incubated at

45°C for 28 Days - CEX-UPLC Results

Formulation	Stress	Days	HIH17203P
lOmM Histidine pH5.2			% Acidic	%Main	% Basic
45°C	0	34.7	52.2	13.1
7	37.1	45.8	17.1
14	41.9	39.9	18.2
21	45.4	35.1	19.5
28	48.9	32.4	18.7
lOmM Histidine pH 6.0	45°C	0	35.2	51.9	12.9
7	39.2	49.3	11.6
14	45.0	44.4	10.6
21	49.9	39.9	10.1
28	54.0	36.3	9.8
10mM Histidine	45°C	0	35.6	51.5	13.0
7	44.2	47.1	8.8

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pH6.8		14	53.3	40.1	6.7
21	60.2	33.9	6.0
28	65.6	29.0	5.5
!0mM Citrate pH5.2	45 °C	0	34.5	52.4	13.2
7	37.3	40.7	22.0
14	33.4	25.6	41.1
21	47.7	27.3	25.1
28	NP	NP	NP
10mM Citrate pH 6.0	45°C	0	34.8	52.0	13.2
7	41.7	49.9	8.5
14	48.5	43.0	8.5
21	53.7	37.5	8.8
28	58.1	33.2	8.7
10mM Citrate pH 6.8	45°C	0	34.8	51.6	13.6
7	44.0	48.5	7.5
14	52.3	41.0	6.7
21	58.6	34.6	6.7
28	63.6	29.9	6.6

Citrate, pH 5.2, 28d samples were not run on LIPLC instruments due to visual failures

Table 23: Effect of Buffet and pH on the Stability of 100 mg/mL H1H17139P ïncubated at 45°C for 28 Days - CEX-UPLC Results

Formulation	Stress	Days	H1H17139P
lOmM Histidine pH5.2			% Acidic	%Main	% Basic
45°C	0	36.9	58.8	4.3
7	40.8	53.3	5.9
14	51.6	44.0	4.5
21	51.6	41.4	7.1
28	55.6	37.3	7.1
lOmM Histidine pH 6.0	45°C	0	37.3	58.5	4.3
7	40.9	54.2	4.8
14	48.6	46.3	5.1
21	50.9	44.5	4.7
28	55.2	40.4	4.4
10mM Histidine pH 6.8	45ÛC	0	37.5	58.2	4.3
7	44,8	51.3	4.0
14	51.2	41.8	7.0
21	58.9	38.0	3.1
28	64.4	32.9	2.8
	45°C	0	36.8	58.7	4.5

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lOmM Citrate pH5.2		7	44.0	49.3	6.7
14	52.5	44.0	3.5
21	57.7	35.3	7.0
28	62.6	30.7	6.8
10mM Citrate pH 6.0	45 °C	0	36.7	58.6	4.6
7	41.8	52.8	5.4
14	46.2	49.0	4.8
21	53.9	41.2	4.9
28	58.7	36.8	4.5
lOmM Citrate pH 6.8	45ÛC	0	36.8	58.2	5.1
7	43.9	51.2	4.9
14	46.4	47.0	6,6
21	57.7	38.1	4.1
28	63.0	33.3	3.7

Table 24: Effect of Buffer and pH on the Stability of 100 mg/mL H1H17161P Incubated at 45°C for 28 Days - CEX-UPLC Results

Formulation	Stress	Days	H1H17161P
10mM Histidine pH5.2			% Acidic	%Main	% Basic
45°C	0	52.0	42.0	6.0
7	59.4	35.4	5.2
14	72.8	22.4	4.9
21	73.0	21.7	5.3
28	73.1	21.3	5.7
10mM Histidine pH 6.0	45°C	0	52.0	42.2	5.9
7	59.4	36.1	4.5
14	72.1	23.7	4.2
21	75.7	20.1	4.2
28	74.8	20.9	4.3
lOmM Histidine pH 6.8	45°C	0	52.1	41.9	6.0
7	65.2	30.2	4.5
14	78.5	17.5	4.0
21	83.2	13.1	3.7
28	84.6	11.8	3.7
ΙΟιηΜ Citrate pH 5.2	45°C	0	51.7	42.4	5.9
7	69.2	25.5	5.3
14	71.2	23.0	5.9
21	81.4	13.4	5.2
28	78.7	15.5	5.8
10mM Citrate pH6.0	45ÛC	0	51.5	42.3	6.1
7	58.8	35.9	5.3
14	69.8	24.9	5.3

		21	78.6	16.4	5.0
28	74.6	19.9	5.5
lOmM Citrate pH6.8	45°C	0	52.2	41.3	6.4
7	63.2	31.8	5.0
14	74.5	19.8	5.7
21	85.3	9.7	5.0
28	80.2	13.8	6.0

Table 25: Effect of Buffer and pH on the Stability of 100 mg/mL Total H1H17203P, H1H17139P, and H1H17161P Combination Incubated at 45°C for 28 Days - CEX-UPLC Results

Formulation	Days	H1H17139P	H1H17203P	H1H17161P
		% Acidic	% Main	% Basic	% Acidic	% Main	% Basic	% Acidic	% Main	% Basic
lOmM Histidine pH 5.2	0	36.2	61.1	2.6	31.5	47.1	21.4	41.7	54.3	4.0
7	41.5	54.2	4.4	38.3	45.6	16.1	55.2	39.1	5.7
14	47.1	47.8	5.2	42.0	39.5	18.5	65.1	28.8	6.1
21	51.9	42.5	5.6	45.2	34.9	19.9	70.4	23.4	6.2
28	55.8	38.5	5.7	47.6	32.0	20.4	67.6	25.0	7.3
lOmM Histidine pH6.0	0	36.6	60.8	2.6	31.9	46.8	21.2	44.0	51.4	4.5
7	41.5	54.7	3.7	38.8	47.2	14.0	56.5	38.7	4.8
14	46.7	49.2	4.1	43.0	41.7	15.3	69.3	25.8	4.9
21	51.7	44.2	4.1	46.8	37.1	16.1	73.3	21.9	4.8
28	55.1	40.5	4.3	49.5	34.0	16.5	70.7	24.5	4.8
lOmM Histidine pH 6.8	0	37.1	60.4	2.5	32.4	46.2	21.4	42.7	52.8	4.5
7	46.5	50.9	2.6	43.3	43.2	13.6	63.0	31.8	5.2
14	54.9	42.6	2.5	50.0	34.8	15.2	76.7	18.5	4.8
21	61.7	36.0	2.3	57.8	30.0	12.2	89.1	7.3	3.6
28	65.9	31.9	2.2	57.2	25.3	17.4	83.2	12.5	4.4
lOmM Citrate pH 5.2	0	36.2	61.0	2.8	31.9	47.4	20.7	42.9	52.6	4.6
7	43.8	51.7	4.5	40.1	43.8	16.1	55.9	37.9	6.2
14	50.9	43.8	5.2	44.7	35.9	19.4	77.0	15.8	7.2
21	57.1	37.5	5.5	54.0	34.0	12.0	82.8	11.8	5.4
28	NA	NA	NA	NA	NA	NA	NA	NA	NA
lOmM Citrate pH 6.0	0	36.4	60.9	2.6	37.1	54.6	8.3	53.0	43.3	3.7
7	42,0	54.2	3.8	39.4	46.9	13.8	54.3	40.0	5.7
14	47.9	48.0	4.1	44.0	40.8	15.2	60.3	34.0	5.6
21	53.2	42.3	4.5	52.1	38.6	9.3	81.5	14.0	4.5
28	57.7	38.6	3.7	50.8	31.3	17.9	69.1	24.9	6.0
10mM Citrate	0	37.2	60.0	2.8	37.4	53.3	9.3	52.8	42.0	5.3
7	44.3	52.9	2.8	41.8	45.4	12.8	57.8	36.2	6.0

pH6.8	14	51.8	45.5	2.7	47.5	38.2	14.3	66.0	27.5	6.5
21	58.0	39.5	2.5	54.5	33.8	11.7	78.7	16.6	4.7
28	62.6	35.0	2.4	55.4	28.4	16.3	76.1	17.6	6.2

Example 7: Sélection of Stabilizer Under Stress Conditions

[000226] From Example 6, pH 6.0 and 10 mM L-histidine was identifïed as the optimal buffer System for the individually formulated antîbodies and the 100 mg/mL 3 way co-formulation.

Additional excipients such as thermal stabilizers, surfactants, and anti-oxidants were assessed in this Example for effects on forced dégradation and stability. Stabilizers such as sucrose, surfactants, proline, or méthionine are often added to antibody formulations to increase the thermal stability of the protein in liquid formulations. Anti-EBOV antîbodies formulated separately or in combination in a liquid formulation exhibited improved stability under accéléra ted conditions when formulated with 5% w/v sucrose and 0.1% w/v Polysorbate 80 or 0.1% Polysorbate 20 and show comparable stability outcomes under vortex stress. (Tables 27-32). Table 26 provides the excipient variables and the respective formulations for Tables 16-21. Base formulations contain 33.3mg/mL Anti-EBOV Antibody 5% w/v Sucrose and lOmM Histidine.

Table 26: Excipients Tested and Formulation Components

Formulations	Buffer pH	Additional Sucrose %W/V	Surfactant PS20 %W/V	Surfactant PS 80 %W/V	Arginine, mM	Pro line, mM	Méthionine, mM
Fl	10 mM L-histidine pH 6.0	0.0%	0.00%	0.00%	0	0	0
F2	10 mM L-histidine pH 6.0	5.0%	0.10%	0.00%	0	0	20
F3	10 mM L-histidïne pH 6.0	5.0%	0.00%	0.00%	0	0	0
F4	10 mM L-histidine pH 6.0	0.0%	0.00%	0.10%	0	0	20
F5	10 mM L-histidine pH6.0	5.0%	0.10%	0.00%	100	0	0
F6	10 mM L-histidine pH 6.0	0.0%	0.10%	0.00%	100	0	20
F7	10 mM L-histidine pH 6.0	0.0%	0.00%	0.10%	100	0	0
F8	10 mM L-histidine pH 6.0	5.0%	0.00%	0.00%	100	0	20
F9	10 mM L-histidine pH 6.0	5.0%	0.00%	0.10%	0	200	0
F10	10 mM L-histidine pH 6.0	0.0%	0.10%	0.00%	0	200	0

Formulât ions	Buffer pH	Additional Sucrose %W/V	Surfactant PS20 %W/V	Surfactant PS 80 %W/V	Arginine, mM	Pro line, mM	Méthionine, mM
Fil	10 mM L-histidine pH 6.0	0.0%	0.00%	0.00%	0	200	20
F12	10 mM L-histidine pH6.0	5.0%	0.00%	0.10%	0	200	20

Table 27: Effect of Excipients on the Stability of 33 mg/mL H1H17203P Antibody Incubated at 40°C for up to Two Months - Visual, OD, pH, SE-UPLC, RP-UPLC Concentration, CEXUPLC

Formulatio n	Sample	Visua 1	OD @ 405nm	P H	%HM W	%Nativ e	%LM W	Con, mg/mL	%Acidi c	%Mai n	%Basi c
Fl	t=0	0	0087	6. 1	1.0	98.1	0.9	34.9	33.57	54.25	12.19
VTX 120 minutes	0	0086	6. 1	1.0	98 J	0.9	34.7	33.44	54.28	12.26
F/T 8 cycles	0	0090	6. 1	10	98.2	0.9	33.4	33.47	54 5	12.03
40°C 8 days	0	0087	6. 2	0 9	97.9	13	33.4	35 36	53.43	11.22
40°C 14 days	0	0.088	6. 0	0 9	97 6	1.5	33.3	37.3	51.88	10 81
40°C 28 days	0	0092	6. 1	10	97.1	1.9	33.8	43.52	46.39	10.09
4Q°C 2 inonth	0	0.093	6. 1	1.3	95.6	3.1	34.5	53.22	37.88	8.9
F2	t=0	0	0.089	6. 1	0.9	98.2	0.9	34.6	33.56	54.22	12,21
VTX 120 minutes	0	0.091	6, 1	0.9	98.2	0.9	34.3	33.46	54.33	12.21
F/T 8 cycles	0	0.089	6. 0	0 9	98.2	0.9	33.6	33.49	54.43	12.08
40 °C 8 days	0	0.089	6. 1	0.8	980	1.2	33.7	35.19	5366	11.16
40°C 14 days	0	0.090	6. 0	0.8	97.7	1.5	33.7	37.14	52.06	10.8
40’C 28 days	0	0.091	6. 1	0.9	97 I	1.9	33.7	43.38	46.39	10.23
40°C 2 month	0	0094	6. 0	1.2	95.7	3.1	34.6	52.95	38.02	903
F3	t=0	0	0.087	6. 1	0.9	98.2	0.9	33.9	33.46	54.56	11.97
VTX 120 minutes	0	0.086	6. 1	1.0	98 1	0.9	33.8	33.38	54.63	12
F/T 8 cycles	0	0091	6. 0	0.9	98.2	0.9	330	33.41	54.5	12,08
40’C 8 days	0	0.087	6. 1	0.8	98.0	12	32.9	35.15	53.59	J 1.27
40°C 14 days	0	0.087	6. 0	0.8	97.8	1.4	32.7	37.07	52.09	10.84
40°C 28 days	0	0.089	6. 1	0.9	97.2	1.9	33.1	43.25	46.52	10,22
4ÜqC 2 month	0	0.092	6. 1	1.2	95.8	3.1	34.0	52.67	38.19	9,14
F4	1=0	0	0.088	6. 1	0.9	98.2	09	33 6	33.57	54.61	11.82
VTX 120 minutes	0	0.089	6. 1	0.9	98.2	1.0	33.4	33.45	54.55	12.01
F/T 8 cycles	0	0.089	6. 0	0.9	98.2	0.9	32.9	33.43	54.4	12.18

	40°C 8 days	0	0.089	6. 1	0.8	98.0	1.2	32.6	35.29	53.64	11.06
40°C 14 days	0	0.088	6. 1	0.8	97.7	1.5	32.6	37.35	52.02	10.63
40”C 28 days	0	0.090	6. 1	0.9	97.1	1.9	33.1	43.71	46.4	9.8S
40°C 2 month	Û	0.094	6. 1	12	95.7	3.1	34.4	53.4	37 85	8.76
F5	t=0	0	0.098	6. 1	0.9	98.2	0.9	33.3	33.23	54.61	12.16
VTX 120 minutes	0	0.098	6. 1	0.9	98.2	0.9	33 4	33.01	54.87	12.13
F/T 8 cycles	0	0.099	6. 1	0.9	98.2	0.9	33.0	33.12	54.53	12.36
40 °C8 days	0	0.098	6. 1	0.8	98.0	1.2	32.9	33.5	54.31	12.21
40°C 14 days	0	0.098	6. 1	09	97.6	1.5	33.0	34.66	53.21	12.13
40°C 28 days	0	0400	6. 1	1.2	96.9	2.0	33.1	40.01	48.03	11.95
40 ’C 2 month	0	0.101	6. 1	1.8	95.1	3.1	34.2	48.34	41.07	10.59
F6	t=0	0	0.098	6 I	09	98.2	0.9	32.6	33.21	547	12.08
VTX 120 minutes	0	0.098	6. 1	0.8	98.2	0.9	32.5	33.15	54.67	12.18
F/T 8 cycles	0	0.100	6 1	0.9	98.2	0.9	32.0	33.23	54.5	12.27
40°C8 days	0	0.099	6. 1	0.9	97.9	1.2	31.8	33.61	54.42	11.97
40“C 14 days	0	0.097	6. 1	1.0	976	1.5	32.0	34.91	53.31	11.77
40’0 28 days	0	0.099	6. 1	1.3	96.8	2.0	32.1	40.39	48.17	11.45
40°C 2 month	0	0.100	6. 1	20	95.0	3.1	33.1	48.96	41.05	9.99
F7	t=0	0	0.099	6. 1	0.9	98.1	10	33.1	33.3	54.63	12.07
VTX 120 minutes	0	0.102	6. 1	0.9	98 2	1.0	33.3	33.13	54.53	12.33
F/T 8 cycles	0	0.100	6. 1	0.9	98 2	1.0	33.0	33.27	54.49	12.23
40°C 8 days	0	0.099	6. 1	0.9	97.9	1.3	33.1	33.64	54.23	12.13
40°C 14 days	0	0.098	6. 1	0.9	97.6	1.5	32.7	35.05	52 89	12.06
40’C 28 days	0	0.100	6. 1	1.2	96.9	1.9	32.9	40.34	48.1	11.57
40°C 2 month	0	0.103	6. 1	1.8	95.1	3.1	33.9	48.94	40.76	10.29
FS	t=0	0	0.097	6. 1	0.9	98.2	0 9	34.4	33.36	54.61	12.03
VTX 120 minutes	0	0.101	û. 1	1.0	98.1	0.9	34.0	33.09	54.58	12.34
F/T 8 cycles	0	0098	6. 1	09	98.2	09	33 5	33.21	54.47	12.33
40’C 8 days	0	0.097	6. 1	0.8	98.0	1.3	33 5	33.52	54.38	12.1
40%? 14 days	0	0.098	6. 1	0 8	97 8	1.5	33 3	34.92	53.05	12.05
40’C 28 days	0	0.100	6. J	0.9	97.2	2.0	33.4	40.11	48.22	11.67
40” C 2 month	0	0.102	6. 1	1.2	95.8	3.1	34.5	48.51	41.2	10.29
F9	t=0	0	0.089	6. 1	0.9	98.2	0.9	34.6	33.6	54.38	12.01
VTX 120 minutes	0	0.091	6, 1	09	98.2	1.0	34.8	33.61	54.3	12.1

	F/T S cycles	0	0.090	6. 0	0.9	98.2	0.9	34.1	33.64	5407	12.29
40°C 8 days	0	0.090	6. 1	0.7	98.1	1.2	34.0	35.24	53.74	11.02
40°C 14 days	0	0.091	6. 1	0.7	97.8	1.4	33.6	37.17	52.17	10.67
40°C 28 days	0	0091	6. 1	0.8	97.3	1.9	34.0	43.32	46.82	9.85
40°C 2 month	0	0096	6. 1	1.0	95.9	3.1	35.2	52.79	38.64	8.57
F10	t=0	0	0.088	6. 1	0.9	98.2	0.9	33.1	33.47	54.48	12.05
VTX 120 minutes	0	0092	6. 1	Ü.9	98.2	0.9	33.3	33.47	5422	12.31
F/T 8 cycles	0	0.090	6. 1	0.9	98.2	0.9	32.9	33.64	54.22	12.14
40°C 8 days	0	0.090	6. 1	0.8	98.0	1.2	33.1	35.4	53.71	10.89
40°C 14 days	0	0.090	6. 1	0.8	97.8	1.4	32.4	37.37	52.15	10.47
4O’C28days	0	0.090	6. J	0.9	97.1	2.0	32.9	43.57	46.76	9.65
40 “C 2 month	0	0.093	6 1	1.2	95.7	3.1	34.2	53.03	38.64	8.33
F11	W)	0	0.087	6 1	0.9	98.2	0.9	33.3	33.51	54.53	11.98
VTX 120 minutes	0	0.088	6. 1	0.9	98.2	0.9	33.6	33.48	54.66	11.87
F/T 8 cycles	0	0.088	6. i	0.9	98.2	0.9	32.7	33.75	54.16	12.08
40°C S days	0	0.088	6. 1	0.7	98.1	1.2	32.4	35 31	53.79	10.9
40°C14days	0	0.090	6. 1	0.7	97.9	1.4	32.6	37.4	52.26	10.34
40“C28days	0	0.090	6. I	0.8	97.3	2.0	32.6	43.56	4689	9.56
4Û&C 2 month	0	0.094	6. 1	0.9	96.0	3.1	34.0	53.08	38.74	8.16
Fi2	t=0	1	0.087	6. 1	0.9	98.2	1.0	33.5	33.48	54.38	12.14
VTX 120 minutes	1	0.088	6. 1	0.9	98.2	0.9	33.6	33.49	54.56	11.95
F/T 8 cycles	0	0.089	6. 0	0.9	98.2	0.9	32.8	33.72	54.22	12.06
40’C 8 days	0	0.089	6. 1	0.7	98.1	1.2	32.5	35.29	53.69	11.02
40’C 14 days	0	0.090	6. 1	0.7	97.9	1.4	32.7	37.14	52.24	10.62
40°C28days	0	0.091	6. 1	0.8	97.3	1.9	32.9	43.38	469	9.73
40ùC 2 month	0	0.095	6. 1	0.9	96.0	3.1	34.1	52.74	38.78	8.47

Table 28: Effect of Excipients on the Stability of 33 mg/mL H1H17139P Antibody Incubated at 40°C for up to Two Months - Visual, OD, pH, SE-UPLC, RP-UPLC Concentration, CEXUPLC

Formuiatio n	Sample	Visua !	OD® 405nm	P H	%HM W	%Nativ e	%LM W	Cûn, mg/mL	%Acidi c	%Mai n	%Basi c
Fl	t=0	0	0.084	6.1	0J	98 P2	LJ	31 1	36.5	60.0	3.6
VTX 120 minutes	0	0.082	6.1	0.7	98.2	II	31.5	36 4	59.9	3.7
F/T 8 cycles	O	0.083	6.0	0.7	98.1	IL	31.]	36.7	59.6	3.7

	40“C 8 days	0	0.083	6.1	0.6	97 9	1.4	31.3	38.4	57.2	4.3
40°C 14 days	0	0.083	6,1	0.7	97.7	1.6	31.6	39.6	56.2	4.2
40°C 28 days	0	0.083	6.2	0.7	97.2	2.1	31.9	43.9	51.8	4.3
40°C 2 month	0	0.089	6.1	0.9	95.8	3.3	31.8	52.4	43.9	3.8
F2	t=0	0	0,086	6.1	0.7	98.2	1.2	32,5	36,5	60.0	3.5
VTX 120 minutes	0	0.085	6,1	0.7	98.2	1.1	32.5	36.5	59.8	3.7
F/T 8 cycles	o	0,085	6,0	0,7	98.2	1.1	32,4	36.8	59.5	3.7
40sC 8 days	0	0.086	6.1	0.6	98,0	1.4	32.3	38.5	57 2	4 3
40°C 14 days	0	0 066	6.0	0.6	97.8	1.6	32.4	39.5	56.3	4.2
40°C 28 days	0	0.086	6.L	0.6	97,2	2,2	32.7	43 6	51.9	4 3
40°C 2 mûnlh	0	0 092	6 0	0.7	96.0	3.3	32.9	52.3	44.0	3.7
F3	t=0	0	0.085	6 1	0.7	98.1	1.1	32.4	36.4	60.0	3.6
VTX 120 minutes	0	0.086	6,1	0.7	98.2	1.1	32.7	36.4	59.9	3.7
FAT 8 cycles	0	0.084	6.0	0.7	98.1	1.1	32.3	36.8	59,5	3.8
40°C 8 days	0	0,083	6.1	0.6	98.0	14	32.3	38.4	57.3	4.3
40°C 14 days	0	0.084	6,0	0,6	97.7	16	32.2	39.3	56 4	4.2
40°C 28 days	ΰ	0,084	6,1	0,7	97.2	2.1	32 9	43.6	52.1	4.3
40°C 2 month	ΰ	0,090	6.0	0.8	95.9	3.3	32.8	52.4	43.7	4.0
F4	t=0	0	0 086	6,1	0,7	98.2	Lt	32.7	36.5	60 0	3.6
VTX 120 minutes	1	0 087	6 1	0.7	98.2	1,1	32.9	36.5	59,9	3.7
F/T 8 cycles	0	0 088	6.0	0.7	98.2	1.1	32.8	36.8	59.4	3.8
40“C 8 days	ΰ	0,088	6.1	0.6	98 0	1.4	32.4	38.5	57.3	4.2
4ü°C 14 days	0	0.087	6.1	0.6	97 8	16	32.9	39,6	563	4,2
4O’C28 days	0	0,087	6.1	0.7	97.2	2.1	33,2	43.9	52.0	4.2
40°Ό 2 month	0	0.092	6.1	0.8	96.0	3.3	33.4	52.8	43.4	3.8
F5	t=0	0	0.094	6.1	0.7	98.2	1.2	32.2	36,1	60.2	3.7
VTX 120 minutes	0	0.094	6.1	0,7	98.2	1.2	32.3	36,1	60.1	3.8
F/T 8 cycles	0	0 094	6.1	0.7	98.2	1.1	32 0	36.4	59.7	3.9
40°C 8 days	0	0.094	6.1	0,6	98.0	1.5	31 9	37.2	58 1	4 8
40°C 14 days	0	0,092	6.1	0.6	97,8	1.7	32.2	37.8	57.5	4.7
40’C 28 days	0	G.093	6.1	0.7	97,2	2.2	32.5	41.4	53.5	5.1
40°C 2 month	0	0.095	6.1	0.8	95.9	3.3	33.0	48.6	46.3	5.1
F6	H)	0	0.095	6.1	0,7	98.2	1.2	31.6	36 l	60.3	3.7
VTX 120 minutes	0	0.094	6.1	0.7	98.2	U	31.9	36.2	60.0	3.8
F/T 8 cycles	0	0.096	6.1	0.7	98.2	1.2	31.5	36.3	59,8	3,9
40°C 8 days	0	0.096	6.1	0.6	98.0	LS	31.6	37.3	58,1	4.6
40°C 14 days	G	0.095	6.1	0.6	97.8	1.7	31.8	38,2	57.3	4.5
40C 28 days	0	0.093	6 1	0.6	97.2	2.2	32.0	41.7	53.4	4.9
40ûC 2 month	0	0.097	6 1	0.7	96.0	3.3	32.6	49 4	46.0	4.7

F7	t=0	0	0.095	6,1	0.7	98 1	1.2	32.1	36.1	60.3	3.7
VTX Î20 minutes	0	0.096	6. [	0.7	98.1	1.2	32,5	36.1	60 L	3.8
F/T 8 cycles	0	0.097	6.1	0.7	98.1	L.2	32,0	36.4	59.7	3 9
40°C 8 days	0	0.098	6.1	0.6	98.0	1.5	32.5	37,3	58.0	4.7
40°C 14 days	0	0,095	6 1	0 6	97.7	1.6	32.3	37,9	57.4	4.7
40°C 28 days	0	0.096	6.1	Û.7	97.2	2.1	32.0	41.6	53,4	5.0
40 ’C 2 month	0	0.096	6.1	6.8	95.8	3.4	33.1	49.1	46.1	4.9
F8	t=0	0	0.093	6.1	0.7	98.2	11	32,7	36.1	60.2	3,6
VTX 120 minutes	O	0.100	6.1	0.7	98.2	1.2	32.6	36.1	60,2	3.7
F/T 8 cycles	0	0,097	6.1	0.7	98,2	1.2	32.6	36.4	59.7	3.9
40°C 8 days	0	0.098	6 1	0 6	98.0	1.5	32 6	37.2	58.2	4.7
40 “C 14 days	0	0.095	6.1	0.6	97.8	1.7	32.9	38.1	57.3	4.6
40°C28 days	0	0.101	6.1	0.6	97,3	2 J	33.0	41.4	53,6	50
40°C 2 month	0	0.096	6.1	0.6	96.1	3.3	33.4	48.9	46,2	49
F9	t=0	0	0 086	6 1	0.7	98 1	1.2	32.9	36.5	599	3,6
VTX 120 minutes	0	0.087	6.1	0.7	98 2	1.2	32.8	36.6	59.7	3.7
F/T 8 cycles	0	0.087	6.1	0.7	98.2	1.1	32.7	36.8	59.4	3.8
40°C 8 days	0	0.090	6.1	0.5	98.0	1.5	32.6	38.4	57.2	4,3
40°C 14 days	0	0.088	6.1	0.6	97.9	16	33.1	39.6	56 3	4.2
40°C 28 days	ΰ	0,090	6.1	0.6	97.3	2.1	33 2	43.9	51.8	4.4
4O°C 2 month	0	0.092	6.1	0.7	96 L	3.2	33,6	52.1	43.9	3.9
FIO	t=0	1	0.087	6 1	0.7	98.2	1.1	33.0	36.5	59.9	3,6
VTX 120 minutes	0	0.089	6.1	0.7	98 2	1.1	33,5	36,6	59,7	3.7
F/T 8 cycles	0	0.088	6 i	07	98 2	1.1	33.1	36,8	59 4	3.8
4Û°C 8 days	0	0.09O	6.1	0.6	98.0	14	33 0	38.1	58.0	4 0
40°C 14 days	0	0.088	6,1	0.6	97.8	L6	33,1	39.7	56.1	4.2
40°C 28 days	0	0.090	6.1	0.6	97,3	2 J	33.6	44.1	51.7	4.2
40°C 2 month	0	0 093	6.1	0,7	96.0	3.3	34.2	52.6	43.7	3.8
Fil	t=0	0	0.084	6.1	0.7	98.2	1.1	31.8	36 6	59.8	3.6
VTX 120 minutes	0	0.085	6.1	0.7	98.2	1.1	32,2	36.6	59,7	3.7
F/T 8 cycles	0	0.085	6.1	0.7	98.2	1.1	31.9	36,9	59,3	3.8
40°C 8 days	0	0.088	6.1	0.5	98 1	1.4	31.6	38.2	57.8	4,0
40°C 14 days	0	0,085	6.1	0.5	97.9	1.6	32.0	39.6	56,3	4.1
40°C 28 days	0	0.088	6,1	0.6	97.3	2.1	32.3	44.1	51.8	4.1
40°C 2 month	0	0.093	6.1	0.6	96.1	3.3	32.7	52.5	43.8	3,7
F12	tMj	0	0.086	6.1	0.7	98.2	1.2	33.1	366	59.7	3.6
VTX 120 minutes	0	0.086	6.1	0.7	98.2	1.1	33,4	36.7	59.6	3.7
F/T 8 cycles	0	0 089	6.1	0.7	98.2	L.2	33,0	37.0	59.2	3.8
40 °C 8 days	0	0.089	6.1	0.5	98.1	1.4	32.8	38 L	57.9	4 1

100

	40°C 14 days	0	0.036	6.1	0.5	97.9	1.6	33.0	39,7	56.2	4.2
40°C 28 days	ΰ	0.900	6,1	0,6	97,3	2 1	33.3	43.9	51.9	4.2
40°C 2 month	0	0.095	6.1	0.6	96]	3,3	33.8	52.3	44,0	3.7
Table 29: Effect of Excipients on the Stability of 33 mg/m	L H1H17161P Antibody Incubated
at 40°C for up to Two Months - Visual, OD, pH, SE-UPLC, RP-UPLC Concentration, CEX-

UPLC

Formulatio n	Sample	Visua 1	OD @ 405nm	pH	%HM W	%Nativ e	%LM W	Con, mg/mL	%Acidi c	%Mai n	%Basi c
Fl	t=0	0	0.109	6.1	1.6	97.2	1.2	34	53.5	42.6	4.0
VTX 120 minutes	0	0.109	6.1	1.6	97.2	1.2	34	54.1	42.2	3.7
F/T 8 cycles	0	0.108	6.0	1.7	97.2	1.2	34	54.3	42.2	3.5
40°C 8 days	0	0.105	6.0	1.4	97.1	1.5	34	57.4	38 8	3.9
40°C 14 days	0	0.107	6.0	1.4	96.9	1.7	34	59.6	36.4	3 9
40’C 28 days	0	0.109	6.1	1.6	96.1	23	34	63 5	31.2	5.3
40°ε 2 month	0	0.112	6.2	1.7	95 0	3.3	33	74.3	22.4	3.3
F2	t=0	0	0.111	6.1	1.6	97.2	1.2	33	53.1	43.0	4.0
VTX 120 minutes	0	0.100	6.1	1.6	97.2	13	33	53.7	42.8	3.5
F/T 8 cycles	0	0.112	6.0	1.6	97.2	1.2	34	53.5	42.9	3.6
40°C 8 days	0	0.106	6.0	1.3	97.2	1.5	34	55.5	4Û.5	4.0
40°C 14 days	0	0.110	6 0	1.3	97.0	1.7	34	57.5	38.4	4.1
40°C 28 days	0	0.110	6.1	1.4	96.3	2.3	34	59.9	34.7	5.5
40 “C 2 month	0	0.114	6.1	1.5	95.2	3 3	33	69.7	26.5	3.8
F3	t=0	0	0 110	6.1	1.6	97.2	1.2	34	53 5	42.7	3 9
VTX 120 minutes	0	0.109	6.1	1.8	96.9	1.3	33	54.0	42.3	3.7
F/T 8 cycles	0	0.109	6.0	1.6	97.1	1.2	34	54.3	42.3	3.4
40°C 8 days	0	0.105	6.0	1.3	97.1	1.5	34	57.2	390	3.8
40°C 14 days	0	0.107	6.0	1.4	96.9	1.7	34	59.8	36.2	4.1
40°C 28 days	0	0.109	6.1	1.5	96.2	2.3	34	63.2	31.7	5.2
40 °C 2 month	0	0.111	6.1	1.6	95.1	3.3	33	74.0	22.9	3.1
F4	1=0	0	0.110	6.1	1.6	97.2	1.3	34	53.3	43.3	3.4
VTX 120 minutes	0	0.109	6.1	16	971	1.3	34	53.5	42.9	3.7
F/T 8 cycles	0	0.113	6.1	1.6	97.2	1.2	34	53.9	42.5	3 6
40°C 8 days	0	0.106	6.0	13	97.2	1.5	34	55.5	40.6	3.9
40°C 14 days	0	0.113	6.0	1.4	96.9	1.7	34	57.8	38.2	4.0
40°C 28 days	0	0.110	6.1	1.4	96.3	2.3	34	60.0	34.8	5.3
40°C 2 month	0	0.114	6.1	1.6	95.1	3.4	33	70.2	26.4	3.4
F5	t=0	0	0.121	6.1	1.6	97.2	1.2	33	53.6	43.0	3.5
VTX 120 minutes	0	0.122	6.1	1.6	97.1	1.3	34	53.9	42.4	3.7
F/T 8 cycles	0	0.124	6.1	16	97.2	1.2	34	54.3	41.9	3.8

101

	40°C 8 days	0	0.114	6.1	1.4	97.1	16	34	56.0	39.8	4.2
40°C 14 days	0	0.118	6.1	1.5	96.8	1.8	34	59.0	36.6	4.5
40°C 28 days	0	0.116	6.2	1.5	96.1	2.4	34	61.9	32.5	5 6
40 °C 2 inonth	0	0.117	6.1	I.7	95.0	3.4	33	72.6	23 9	3.5
F6	t=0	0	0 121	6.1	1.6	97.2	1.2	33	53.0	43.1	3.8
VTX 120 minutes	0	0 121	6.1	1.6	97 l	1.3	33	53.1	43.1	3.8
F/T 8 cycles	0	0.123	6.1	1.6	97.2	1.2	33	53 3	42,8	3.9
40°C 8 days	0	0.117	6.1	1.4	97.1	1.6	34	53.8	41.9	4.3
40°C 14 days	0	0.121	6.1	1.4	96.8	1.8	33	56.2	39.2	4.6
40’0 28 days	0	0.118	6.2	1.5	96.1	2.4	33	57.1	36.8	6.1
40GC 2 month	0	0.J 19	6.1	1.6	95.0	3.4	33	66.1	30.0	3.9
F7		0	0.121	6.1	1.6	97.1	1.3	34	53.7	42.6	3.7
VTX 120 minutes	0	0.122	6.1	1.6	97.0	1.4	34	53.9	42.3	3.9
F/T 8 cycles	0	0.123	6.1	1.6	97.2	1.2	34	54.1	42.2	3.7
40°C 8 days	0	0.115	6.1	1.5	97,0	1.6	34	56.3	39.5	4.2
40°C 14 days	0	0.120	6.1	1.5	96.7	1.8	34	59.1	36.4	4.6
40C 28 days	0	0.117	6.2	1.6	96.0	2.4	34	63.2	311	5.7
40 ’C 2 month	0	0.119	6.1	1.7	94.9	3.4	33	73.7	22.5	3.9
F8	t=0	0	0.120	6.1	1.6	97.2	1.2	33	53.3	43.2	3.5
VTX 120 minutes	0	0.120	6.1	2.5	96.1	1.3	33	53 l	43.1	3.8
F/T 8 cycles	0	0,121	6.1	1.6	97.2	1.2	34	52.9	43.1	4Ό
40“C 8 days	0	0.117	6.1	1.4	97,1	1.5	34	53.8	41.9	4.3
40°C 14 days	0	0.119	6.1	1.4	96.8	1.8	34	55.8	39.5	4.7
40°C 28 days	0	0.115	6.2	1.5	96.2	2.3	34	56.6	37.5	6.0
40 °C 2 inonth	0	0.117	6.1	1.5	95.1	3.4	33	65.4	30.4	4.3
F9	t^O	0	0.112	6.1	1.6	97.2	1.3	33	53.9	42.5	3.6
VTX 120 minutes	0	0.112	6.1	1.6	97.2	1.3	33	54.2	42.2	3.6
F/T 8 cycles	0	0 114	6.1	1.6	97.2	1.2	34	54.4	42.0	3.6
40°C 8 days	0	0.107	6.1	1.2	97.3	1.5	34	57.1	39.1	3.8
40°C 14 days	0	0.114	6.0	1.3	97.0	1.8	34	59.9	360	4.1
40°C 28 days	0	0.110	6.2	1.3	96.4	2.3	34	63.0	31.5	5.6
40°C 2 month	0	0.114	6.1	1.4	95.2	3 4	33	73 5	23.1	3.4
FIO	t=0	0	0.113	6.1	1.6	97.2	1.2	33	54.2	42.8	3.1
VTX 120 minutes	0.112	0000	FD G	1.6	972	1.2	33	54.3	42.3	3.5
F/T 8 cycles	0.114	0.001	FD G	1.6	97.2	1.2	33	54.5	42.0	3.6
40&C 8 days	0	0.112	6.1	1.3	97.2	1.6	34	57 1	39.1	3.7
40°C 14 days	0	0.111	6.1	1.3	97.0	17	33	59.9	36.0	4.1
40°C 28 days	0	0.111	6.2	1.4	96.3	2.4	34	62.9	31.7	5.4
40“C 2 month	0	0.115	6.1	1.5	95.2	3.4	33	73.0	23.7	3.3
Fil	t=0	0	0.110	6.1	1.6	97.2	1.3	33	53 6	43.1	3.4

102

	VTX 120 minutes	0	0.112	6.1	1.7	97.1	1.2	33	53.6	42.8	3.6
F/T 8 cycles	0	OUI	6.1	1.6	97.3	1.2	34	53.6	42 8	3.6
40°C Sdays	0	0.107	6.1	1.2	97.2	1.5	34	55.6	40.6	3.8
40°C 14 days	0	0.112	6.1	1.3	97.0	1.7	34	57.9	38.0	4.1
40°C 28 days	0	0.114	6.1	1.3	96.4	2.3	34	59.7	34.9	5.4
40 °C 2 month	0	0.118	6.1	1.4	95 3	3.3	33	69.5	27.1	3.5
FI2	t=0	0	0.114	6.1	1.6	97.1	1.3	34	53.8	42.8	3.4
VTX 120 minutes	0	0.114	6.1	1.5	97.2	1.3	34	53.8	42.6	3.6
F/T 8 cycles	0	0 113	6.1	1.6	97.2	1.2	34	53.8	42.7	3.6
40’0 8 days	0	0.109	6.1	1.2	97.3	1.5	34	55.5	40.7	3.8
40°C 14 days	0	0.113	6.0	1.2	97.0	1.7	34	57.9	37.9	4.2
40°C 28 days	0	0.113	6.1	1.3	96.4	2.4	34	60.0	34.4	5.7
40“C 2 month	0	0.120	6 1	1.4	95.3	3.3	33	69.4	26.8	3.8

Table 30; Effect of Excipients on the Stability of 100 mg/mL H1H17203P, H1H17139P, and H1H17161P Antibodies (ratio at 1:1:1) Incubated at 40°C for up to Two Months - Visual, OD, pH, SE-UPLC, RP-UPLC Concentration

Formulation	Sample	Visual	OD @ 405nm	AOD	pH	%HMW	%Native	%LMW	Cou, mg/mL
Fl	t=0	Û	0.178	0.00	6.1	1.24	97.70	1.06	99
120 minutes	0	0.175	0.00	6.1	1.76	96.83	1.41	100
8 cycles	0	0.176	0.00	6.1	1.95	96.41	1.64	99
40 °C 8 days	0	0.176	0.00	6.1	2.29	95.56	2.16	98
40°C 14 days	0	0.179	0.00	6.1	2.91	93.82	3.27	99
40°C 28 days	0	0.189	0.01	6.1	4.01	91.58	4.41	103
40°C 2 month	0	0.191	0.01	6.1	1.32	97.63	1.04	98
40°C 3 months	0	0.203	0.02	6.3	1.25	97.68	1.07	99
Light Stress Contre l	0	0.177	0.00	6.1	1.43	97.19	1.39	98
Light Stress Mild	0	0.178	0.00	6.1	5.56	93.21	1.24	99
Light Stress Extrême	0	0.286	0.11	6.1	21.67	76.26	2.07	98
F2	t=0	0	0.177	0.00	6.1	1.15	97.79	1.06	97
120 minutes	0	0.179	0.00	6.1	1.52	97.08	1.41	98
8 cycles	0	0.177	0.00	6.1	1.68	96.67	1.65	97

103

	40°C 8 days	0	0.175	0.00	6.1	1.96	95.88	2.16	97
40°C 14 days	0	0.180	0.00	6.1	2.47	94.24	3.30	97
40°C 28 days	0	0.185	0.01	6.1	3.33	92.34	4.33	102
40°C 2 month	0	0.193	0.02	6.1	1.14	97.81	1.04	97
40°C 3 months	0	0.203	0.03	6.2	1.17	97.76	1.08	97
F3	t=0	0	0.173	0.00	6.1	1.21	97.71	1.08	97
120 minutes	0	0.174	0.00	6.1	1.64	96.97	1.40	101
8 cycles	0	0.181	0.01	6.1	1.81	96.57	1.63	98
40°C 8 days	0	0.171	0.00	6.1	2.11	95.74	2.15	97
40°C 14 days	0	0.178	0.00	6.1	2.65	94.13	3.23	97
40°C 28 days	0	0.185	0.01	6.1	3.37	92.40	4.23	102
40°C 2 month	0	0.188	0.02	6.1	1.30	97.62	1.08	97
40°C 3 months	0	0.203	0.03	6.3	1.22	97.70	1.08	100
F4	t=0	0	0.180	0.00	6.1	1.18	97.75	1.08	97
120 minutes	0	0.182	0.00	6.1	1.57	97.04	1.38	97
8 cycles	0	0.178	0.00	6.1	1.76	96.62	1.62	97
40°C 8 days	0	0.172	0.00	6.1	2.09	95.76	2.15	98
40°C 14 days	0	0.179	0.00	6.1	2.68	94.07	3.24	99
40°C28 days	0	0.187	0.01	6.1	3.48	92.26	4.26	104
40cC 2 month	0	0.194	0.01	6.1	1.17	97.77	1.07	99
40°C 3 months	0	0.205	0.02	6.3	1.19	97.73	1.08	98
Light Stress Control	0	0.178	0.00	6.1	1.27	97.47	1.26	98
Light Stress Mild	0	0.178	0.00	6.1	4.60	94.18	1.22	98
Light Stress Extrême	0	0.233	0.05	6.1	17.01	81.07	1.92	97
F5	t=0	0	0.194	0.00	6.1	1.12	97.78	1.10	96
120 minutes	0	0.196	0.00	6.1	1.30	97.26	1.44	96
8 cycles	0	0.198	0.00	6.1	1.43	96.89	1.68	96
40°C 8 days	0	0.187	0.00	6.1	1.65	96.14	2.22	98
40°C 14 days	0	0.190	0.00	6.1	2.07	94.59	3.34	97

104

	40°C 28 days	0	0.195	0.00	6.1	2.88	92.77	4.35	102
40°C 2 month	0	0.198	0.00	6.1	1.11	97.79	1.10	96
40ûC3 months	0	0.204	0.01	6.3	1.13	97.78	1.10	97
F6	t=0	0	0.197	0.00	6.1	1.10	97.82	1.07	96
120 minutes	0	0.197	0.00	6.2	1.31	97.25	1.44	96
8 cycles	0	0.200	0.00	6.1	1.44	96.86	1.70	96
40°C 8 days	0	0.191	0.00	6.1	1.69	96.09	2.22	96
40aC 14 days	0	0.195	0.00	6.1	2.28	94.37	3.35	96
40°C 28 days	0	0.200	0.00	6.2	3.02	92.66	4.32	102
40°C 2 month	0	0.199	0.00	6.1	1.10	97.78	1.13	96
40:C 3 months	0	0.208	0.01	6.3	1.12	97.77	1.11	96
F7	t=0	0	0.198	0	6.13	1.13	97.82	1.05	95
120 minutes	0	0.196	0	6.14	1.38	97.19	1.43	97
8 cycles	0	0.209	0.011	6.13	1.53	96.79	1.69	96
40°C 8 days	0	0.189	0	6.09	1.75	96.04	2.22	98
40°C 14 days	0	0.1917	0	6.08	2.26	94.41	3.34	97
40°C 28 days	0	0.1973	0	6.15	3.38	92.08	4.54	104
40°C2 month	0	0.1994	0.0014	6.15	1.14	97.79	1.08	97
40°C 3 months	0	0.2086	0.0106	6.28	1.14	97.76	1.09	97
Light Stress Contre 1	0	0.1977	0	6.12	1.15	97.56	1.28	98
Light Stress Mild	0	0.2001	0.0021	6.11	4.87	93.85	1.28	98
Light Stress Extrême	0	0.287	0.089	6.11	17.14	80.69	2.17	97
F8	t=0	0	0.191	0.00	6.1	1.10	97.84	1.06	97
120 minutes	0	0.192	0.00	6.1	1.24	97.33	1.44	96
8 cycles	0	0.195	0.00	6.1	1.32	97.00	1.67	96
40°C 8 days	0	0.184	0.00	6.1	1.49	96.29	2.22	97
40°C 14 days	0	0.189	0.00	6.1	1.85	94.82	3.32	97
40°C 28 days	0	0.198	0.01	6.2	2.35	93.33	4.32	102
40°C 2 month	0	0.194	0.00	6.2	1.26	97.69	1.06	97

105

	40°C 3 months	0	0.204	0.01	6.3	1.11	97.79	1.10	101
F9	t=0	0	0.177	0	6.11	1.15	97.77	1.09	97
120 minutes	0	0.18	0.003	6.11	1.38	97,25	1.38	97
8 cycles	0	0.181	0.004	6.1	1.51	96.87	1.63	96
40°C 8 days	0	0.177	0	6.08	1.71	96.12	2,17	97
40°C 14 days	0	0.1813	0.0043	6.08	2.09	94.63	3.28	97
40°C 28 days	0	0.187	0.01	6.13	2.63	93.08	4.29	103
40°C 2 month	0	0.1914	0.0144	6.11	1.12	97.84	1.03	97
40°C 3 months	0	0.1987	0.0217	6.23	1.15	97.78	1.08	98
Light Stress Control	0	0.1776	0.0006	6.12	1.19	97.56	1.26	99
Light Stress Mild	0	0.1777	0.0007	6.12	4.15	94.59	1.26	98
Light Stress Extrême	0	0.2888	0.1118	6.11	15.33	82.28	2.39	99
F10	t=0	0	0.18	0	6.11	1.17	97.77	1.07	96
120 minutes	0	0.179	0	6.12	1.45	97.13	1.41	96
8 cycles	0	0.184	0.004	6.1	1.59	96.76	1.65	96
40 °C 8 days	0	0.177	0	6.08	1.83	95.99	2,19	97
40°C 14 days	0	0.1812	0.0012	6.09	2.28	94.43	3.30	96
40°C 28 days	0	0.1892	0.0092	6.143	2.95	92.76	4.28	102
40°C 2 month	0	0.1873	0.0073	6.11	1.15	97.81	1.04	96
40°C 3 months	0	0.1982	0.0182	6.23	1.17	97.76	1.07	97
Fil	t=0	0	0.177	0	6.12	1.13	97.79	1.08	100
120 minutes	0	0.178	0.001	6.12	1.34	97.25	1.40	97
8 cycles	0	0.18	0.003	6.1	1.46	96.90	1.65	97
40°C 8 days	0	0.177	0	6.09	1.67	96.16	2.18	96
40°C 14 days	0	0.1807	0.0037	6.08	2.02	94.66	3.31	97
40°C 28 days	0	0.1897	0.0127	6.14	2.48	93.26	4,26	102
40°C2 month	0	0.1886	0.0116	6.13	1,20	97.75	1.04	97
40°C3 months	0	0.1934	0.0164	6.24	1.15	97.80	1.06	101
F12	t=0	0	0.178	0	6.1	1.13	97.78	1.10	99

106

	120 minutes	0	0.178	0	6.11	1.30	97.30	1.40	96
8 cycles	0	0.181	0.003	6.09	1.40	96.96	1.64	97
40°C 8 days	0	0.176	0	6.07	1.59	96.25	2.16	98
40°C 14 days	0	0.1815	0.0035	6.07	1.92	94.82	3.26	97
40°C 28 days	0	0.1895	0.0115	6.1	2.35	93.42	4.24	102
40°C 2 month	0	0.1955	0.0175	6.11	1.10	97.86	1.04	97
40°C 3 months	0	0.2008	0.0228	6.22	1.12	97.78	1.10	98
Light Stress Control	0	0.1786	0.0006	6.12	1.13	97.60	1.26	99
Light Stress Mild	0	0.179	0.001	6.11	3.37	95.38	1.26	98
Light Stress Extrême	0	0.241	0.063	6.12	11.99	85.85	2.16	99

Table 31: Effect of Excipients on the Stability of 100 mg/mL H1H17203P, H1H17139P, and

H1HÏ7161P Antibodies (at ratio 1:1:1) Incubated at 40°C for up to Two Months - CEX-UPLC

Formulation	Sample	H1H17139P	H1H17203P	H1H17J61P
	was»	% Acidic	%Main	% Basic	% Acidic	%Main	% Basic	% Acidic	%Main	% Basic
F1	t=0	36.1	61.2	2.7	31.9	47.6	20.6	41.2	49.9	8.9
120 minutes	36.0	61.3	2.7	31.8	47.8	20.4	40.9	49.5	9.7
8 cycles	36.2	61.1	2.7	31.8	47.7	20.5	40.3	49.8	9.8
40 °C 8 days	38.2	58.6	3.3	33.9	46.8	19.3	46.1	44.1	9,9
40°C 14 days	39.9	56.6	3.5	35.9	45.3	18.8	48.4	42.2	9.4
40°C 28 days	44.8	51.3	3.9	39.6	41.1	19.3	56.8	37.0	6.2
40°C 2 month	54.5	42.0	3.5	46.7	32.6	20.7	68.5	27.6	3.8
40°C 3 months	62.2	32.8	5.0	54.2	27.0	18.8	78.3	16.9	4.8
F2	t=0	36.2	61.1	2.7	31.7	47.8	20.5	40.6	50.2	9.1
120 minutes	36.0	61.4	2.6	31.6	48.1	20.3	41.2	51.2	7.6
8 cycles	36.3	61.1	2.7	31.8	47.8	20.4	39.6	49.6	10.7
40°C8 days	38.1	58.6	3.3	33.6	46.9	19.4	42.2	46.7	11.1
40°C 14 days	39.8	56.7	3.5	35.4	45.6	19.0	44.9	45.1	10.0
40°C 28 days	44.9	51.1	4.0	39.3	41.2	19.5	56.7	36.8	6.4
40°C 2 month	54.2	42.3	3.5	46.1	32.6	21.3	62.9	32.7	4.4
40°C 3 months	61.5	33.9	4.7	54.5	28.3	17.2	71.3	23.5	5.2
F3	t=0	36.1	61.2	2.7	31.7	47.8	20.5	41.4	50.2	8.4
120 minutes	36.0	61.4	2.6	31.6	48.1	20.3	41.2	50.4	8.4
8 cycles	36.2	61.2	2.6	31.8	47.8	20.4	40.3	49.6	10.0

107

	40°C 8 days	38.1	58.7	3.3	33.6	46.9	19.4	44.8	45.5	9.6
40°C 14 days	39.6	56.8	3.6	35.4	45.6	19.0	47.4	42.5	10.1
40’0 28 days	44.5	51.5	4.0	39.3	41.2	19.5	56.6	37.3	6.1
40°C 2 month	53.9	42.5	3.6	46.1	32.6	21.3	67.8	27.8	4.5
40°C 3 months	61.6	34.9	3.5	54.5	28.3	17.2	77.8	17.7	4.4
F4	1=0	36.2	61.1	2.7	31.9	47.8	20.3	40.5	50.7	8.8
120 minutes	35.9	61.5	2.6	31.7	48.2	20.1	40.2	51.5	8.3
8 cycles	36.2	61.1	2.7	31.8	47.9	20.3	39.2	50.8	10.0
40°C 8 days	38.1	58.6	3.4	33.8	47.1	19.1	42.6	47.8	9.6
40°C 14 days	40.0	56.6	3.5	35.7	45.9	18.4	44.9	45.6	9.6
40°C 28 days	45.1	51.1	3.8	40.0	41.1	18.9	53.0	40.4	6.6
40°C 2 month	54.6	42.1	3.4	47.3	32.7	20.0	63.9	32.2	3.9
40°C 3 months	61.5	34.0	4.6	54.7	28.4	16.9	72.6	23.0	4.4
F5	t=0	35.9	61.4	2.7	31.5	48.0	20.5	41.5	50.7	7.9
120 minutes	35.7	61.8	2.5	31.2	48.5	20.2	41.6	50.1	8.3
8 cycles	35.9	61.5	2.7	31.4	48.1	20.5	40.3	50.1	9.6
40°C 8 days	36.8	59.8	3.3	32.4	48.0	19.6	45.2	46.5	8.3
40°C 14 days	38.4	57.7	3.8	34.0	46.4	19.6	46.6	42.1	11.3
40°C 28 days	42.4	53.3	4.3	37.1	43.0	19.9	55.9	37.5	6.5
40^0 2 month	50.5	45.7	3.8	43.7	36.0	20.3	68.8	27.3	3.9
40°C 3 months	56.9	38.2	4.9	51.0	32.3	16.7	76.8	17.9	5.4
F6	t=0	36.0	61.2	2.8	31.7	47.8	20.5	40.3	50.2	9.6
120 minutes	36.2	60.9	2.9	31.6	47.8	20.6	39.1	50.5	10.4
8 cycles	35.8	61.4	2.8	31.5	48.0	20.4	39.2	50.5	10.3
40°C 8 days	37.0	59.6	3.4	32.7	47.9	19.4	41.7	48.4	9.9
40°C 14 days	38.8	57.5	3.8	34.3	46.7	19.0	43.0	45.7	11.3
40°C 28 days	42.7	53.2	4.1	37.6	43.2	19.1	50.3	42.8	6.9
40°C 2 month	51.2	45.1	3.7	44.7	36.1	19.2	60.1	35.4	4.5
40°C3 months	57.5	37.8	4.7	52.1	32.5	15.5	68.3	26.4	5.4
F7	t=0	36.0	61.2	2.8	31.6	47.8	20.5	41.0	49.4	9.6
120 minutes	36.1	61.2	2.8	31.6	47.8	20.7	40.0	50.2	9.9
8 cycles	35.9	61.3	2.7	31.5	48.1	20.4	40.1	49.6	10.3
40°C 8 days	37.1	59.4	3.5	32.8	47.6	19.5	44.9	44.8	10.3
40°C 14 days	38.8	57.4	3.8	34.3	46.5	19.2	47.2	42.8	10.1
40°C 28 days	42.8	53.0	4.1	37.5	43.0	19.5	56.3	37.3	6.4
40°C 2 month	51.2	45.1	3.7	44.8	36.2	19.0	69.5	27.1	3.4
40’C 3 months									Λ>·': f
F8	t=0	35.8	61.5	2.7	31.5	48.0	20.5	40.5	51.5	8.0
120 minutes	36.0	61.2	2.7	31.6	47.9	20.6	39.5	50.9	9.7
8 cycles	35.7	61.8	2.5	31.3	48.7	19.9	40.2	49.9	10.0
40°C 8 days	36.9	59.6	3.5	32.7	47.6	19.7	41.5	48.0	10.5

108

	40eC 14 days	38.7	57.5	3.9	34.3	46.5	19.2	43.2	45.7	11.1
40°C 28 days	42.6	53.3	4.2	37.4	43.1	19.5	50.4	42.9	6.7
40°C 2 month	50.8	45.5	3.7	44.3	36.0	19.7	60.1	35.7	4.2
40°C 3 months	57.8	37.3	4.9	52.1	32.1	15.9	68.8	25.8	5.4
F9	t=0	36.2	61.1	2.7	31.9	47.8	20.2	41.3	49.7	9.0
120 minutes	36.4	60.9	2.7	31.9	47.7	20.5	40.0	50.2	9.9
8 cycles	36.1	61.3	2.7	3 i.S	47.9	20.3	39.2	51.0	9.9
4Û°C 8 days	37.9	58.8	3.3	33.6	47.3	19.1	44.9	45.8	9.3
40“C 14 days	40.0	56.3	3.7	35.7	45.5	18.8	46.8	42.2	11.0
40°C 28 days	44.7	51.3	4.0	39.5	4J.5	19.0	56.3	37.9	5.8
40°C 2 month	53.8	42.6	3.6	46.2	33.3	20.5	67.7	28.9	3.3
4Û°C 3 months	60.8	34.4	4.9	54.3	29.2	16.5	76.9	18.2	4.9
F10	t=0	36.0	61.5	2.5	31.9	47.7	20.4	41.1	50.5	8.4
120 minutes	36.4	60.9	2.7	31.9	47.8	20.3	40.1	50.8	9.1
8 cycles	36.2	61.2	2.6	31.8	48.0	20.2	39.1	51.1	9.8
40°C 8 days	37.9	58.8	3.3	33.8	47.2	18.9	44.8	46.0	9.2
40°C 14 days	40.2	56.4	3.5	35.8	45.6	18.7	46.3	42.0	11.6
40°C 28 days	44.9	51.1	3.9	39.7	41.7	18.6	56.9	37.5	5.6
40°C 2 month	54.2	42.4	3.4	46.6	33.2	20.2	67.5	29.2	3.3
40°C 3 months	60.9	34.6	4.5	53.9	29.0	17.1	75.8	19.5	4.7
Fil	t=0	36.0	61.5	2.5	31.7	48.4	20.0	41.0	51.8	7.2
120 minutes	36.4	60.9	2.7	31.8	47.8	20.4	39.9	50.5	9.6
8 cycles	36.2	61.2	2.6	31.7	48.1	20.2	38.9	50.8	10.3
40°C 8 days	37.9	58.8	3.3	33.8	47.3	18.9	42.4	47.5	10.1
40°C 14 days	40.2	56.4	3.5	35.7	45.8	18.5	44.2	44.8	10.9
40“C 28 days	44.9	51.1	3.9	39.8	4i.7	18.5	52.5	41.6	5.9
40°C 2 month	54.2	42.4	3.4	45.0	32.1	22.9	59.7	36.2	4.1
40° C 3 months	60.9	34.6	4.5	54.5	29.4	16.1	72.0	24.3	3.7
F12	t=0	36.1	61.3	2.6	31.9	48.1	20.0	40.8	51.5	7.7
120 minutes	36.1	61.2	2.7	31.8	47.8	20.4	39.5	49.5	11.0
8 cycles	36.1	61.2	2.7	31.8	47.9	20.3	38.4	50.8	10.8
40°C 8 days	38.2	58.4	3.4	33.8	47.3	19.0	42.6	47.0	10.3
40°C 14 days	40.0	56.4	3.6	35.6	45.9	18.5	44.1	45.4	10.4
40°C 28 days	44.7	51.3	4.0	39.6	41.7	18,7	52.4	41.7	5.9
40°C 2 month	53.9	42.6	3.5	44.2	32.0	23.8	58,9	36.6	4.6
40°C 3 months	60.2	35.1	4.7	53.2	29.4	J 7.4	71.3	25.1	3.5

Table 32: Effect of Excipients on the Stability of 100 mg/mL H1H17203P, H1H17139P, and H1H17161P Antibodies (at ratio 1:1:1) Incubated at 40°C for up to Two Months-MPI Results

109

		2-10 μιη	>2 μιη	>10μηι	>25 μιη
Sample	Stressed Condition	Conc.(#/ml)	Conc.(#/ml)	Conc.(#/ml)	Conc.(#/ml)
Fl	t=0	1127	1150	23	0
F2	4778	1044	79	13
F3	4112	4201	90	6
F4	1459	1509	50	10
F5	649	695	46	8
F6	831	929	98	27
F7	1136	1249	113	13
F8	2311	2414	102	13
F9	632	655	23	0
F10	990	1028	38	4
Fil	1845	1931	86	4
F12	678	722	44	4
Fl	VTX	4778	4995	217	31
F2	2461	2544	83	8
F3	3003	3064	61	0
F4	2497	2553	56	6
F5	1744	1771	27	0
F6	4427	4540	113	8
F7	2734	2797	63	13
F8	3874	4066	192	21
F9	1697	1730	33	4
F10	1876	1926	50	4
Fil	2464	2530	67	6
F12	1104	1154	50	8
Fl	F/T	6406	6657	250	42
F2	2011	2074	63	6
F3	2572	2616	44	17
F4	2864	2960	96	25
F5	1354	1396	42	2
F6	4141	4379	238	23
F7	3905	3982	77	4
F8	3377	3471	94	4
F9	1965	1996	31	2
F10	1746	1792	46	2
Fil	5040	5134	94	6
F12	1304	1323	19	2

Example 8: Sélection of Organic Cosolvent Against Agitation Stress

[000227] Stabiiizers such as surfactants and organic cosolvents are often added to the antibody

110 formulations to protect the protein from agitation-induced aggregation. The effect of organic cosolvents and surfactants on the agitation stress stability and thermal stability of 33.3 mg/mL indîvidual anti-EBOV antibody, and 100 mg/mL of the three antibody co-formulated cocktail (ratio at 1:1:1) were examined in liquid formulations. The previous example identified Polysorbate 80 as a critîcal excipient comportent. The présent Example évaluâtes different Polysorbate 80 by % w/v under agitation stress induced by orbital shaking at 250 rpm for 48 hours. See Tables 33-40. Base formulations contain 33.3. mg/mL single antibody (or 100 mg/mL total antibody in co-formulation), 10 mM histidine, pH 6.0, 5% w/v sucrose, with 0.04% to 0.2% Polysorbate 80 as shown. Formulations containing no surfactant are less stable under agitation stress in comparison to formulation with > 0.04% w/v PS80. In addition, there are no signifîcant différences in the MFI and SE-UPLC results among formulations containing > 0.04% w/v Polysorbate 80.

Table 33: Effect of Polysorbate 80 on Agitation Stress in Formulation Containing H1H17203P Anti-EBOV - Visual, OD, pH, %HMW, %Native, %LMW, and PS80 %w/v Concentration

Base Formulation +	Stress	Visual	OD @ 405nm	pH	%HMW	%Native	%LMW	Con, mg/mL
0.04% w/v PS80	t=0	0	0.087	6.1	1.3	97.7	1.0	33.9
OB 250 rpm 48 hr	0	0.088	6.0	1.2	97.8	1.0	34.5
0.08% w/v PS80	t=0	0	0.087	6.0	1.3	97.7	LO	33.8
OB 250 rpm 48hr	0	0.087	6.0	1.2	97.8	1.0	34.8
0.12% w/v PS80	t=0	0	0.086	6.0	1.9	97.0	1.1	33.4
OB 250 rpm 48hr	0	0.086	6.0	1.8	97.2	1.1	33.8
0.20% w/v PS80	t=0	0	0.087	6.0	1.3	97.6	1.1	33.3
OB 250 rpm 48hr	0	0.087	6.0	1.2	97.8	1.1	34.2
0.00% w/v PS 80	t=0	0	0.086	6.0	2.4	96.7	1.0	32.5
OB 250 rpm 48hr	2	0.365	6.0	55.2	44.1	0.7	32.6

Table 34; Effect of Polysorbate 80 on Agitation Stress in Formulation Containing H1H17139P Anti-EBOV - Visual, OD, pH, %HMW, %Native, %LMW, and PS80 %w/v Concentration

Base Formulation Ή	Stress	Visual	OD @ 405nm	pH	%HMW	%Native	%LMW	Con, mg/mL
0.04% w/v PS80	t=0	0	0.084	6.0	0.9	97.8	1.2	32.4
OB 250 rpm 48hr	0	Û.083	6.0	0.8	97.9	1.2	32.6
0.08% w/v PS8O	t=0	0	0.083	6.0	0.9	97.8	1.2	32.4
OB 250 rpm 48hr	0	0.082	6.0	0.8	97.9	1.2	32.5

111

0.12% w/v PS80	t=0	0	0.084	6.0	0.9	97.8	1.2	32.5
OB 250 rpm 48hr	0	0.083	6.0	0.8	97.9	1.2	32.8
0.20% w/v PS80	t=0	0	0.084	6.0	0.9	97.8	1.3	32.7
OB 250 rpm 48hr	0	0.082	6.0	0.8	97.9	1.3	32.9
0.00% w/v PS80	t=0	0	0.090	6.0	1.6	97.3	l.l	32.3
OB 250 rpm 48hr	0	0.086	6.0	3.3	95.6	1.1	32.0

Table 35: Effect of Polysorbate 80 on Agitation Stress in Formulation Containing H1H17161P Anti-EBOV - Visual, OD, pH, %HMW, %Native, %LMW, and PS80 %w/v Concentration

Base Formulation +	Stress	Visual	OD @ 405 nm	pH	%HMW	%Native	%LMW	Con, mg/mL
0.04% w/v PS 80	t=0	0	0.114	6.0	1.9	96.8	1.3	33
OB 250 rpm 48hr	0	0.111	6.1	1.8	96.9	1.3	33
0.08% w/v PS80	t=0	0	0.112	6.0	1.9	96.8	1.3	33
OB 250 rpm 48 hr	0	0.111	6.1	1.8	97.0	1.3	33
0.12% w/v PS8Û	t=0	0	0.110	6.0	1.9	96.8	1.3	33
OB 250 rpm 48hr	0	0.110	6.0	1.8	97.0	1.3	34
0.20% w/v PS80	t=0	0	0.106	6.0	1.9	96.8	1.3	33
OB 250 rpm 48hr	0	0.111	6.1	1.8	96.9	1.3	33
0.00% w/v PS80	t=0	0	0.111	6.0	1.9	96.9	1.2	33
OB 250 rpm 48hr	0	0.112	6.0	10.7	88.2	1.1	33

Table 36: Effect of Polysorbate 80 on Agitation Stress in Formulation Containing H1H17203P, H1H17139P, and H1H17161P Anti-EBOV - Visual, OD, pH, %HMW, %Native, %LMW, and PS80 %w/v concentration

Formulât! on	Stress	Visua 1	OD @ 405nm	pH	%HM W	%Nativ e	%LM W	Con, mg/mL	PS 80 %w/v
F1	t=0	0	0.182	6.1	1.6	97.3	1.2	98	0.058
OB 250 rpm 48hr	0	0.188	6.1	1.6	97.3	1.1	98	0.059
F2	t=0	0	0.180	6.1	1.6	97.3	1.1	97	0.095
OB 250 rpm 48hr	0	0.180	6.1	1.6	97.3	1.1	98	0.095
F3	t=0	0	0.175	6.1	1.8	97.1	1.1	93	0.13
OB 250 rpm 48hr	0	0.176	6.1	1.7	97.2	1.1	93	0.129
F4	t=0	0	0.179	6.1	1.6	97.3	Ll	97	0.207
OB 250 rpm 48hr	0	0.182	6.1	1.6	97.3	1.1	97	0.207
F5	t=0	0	0.191	6.1	2.1	96.9	1.1	99
OB 250 rpm 48hr	0	0.178	6.0	8.8	90.2	1.0	98	SI

112

Table 37: Effect of Polysorbate 80 on Agitation Stress in Formulation Containing H1H17203P Anti-EBOV - MFI Results

Base Formulation +	Stress	10-300 pm (#/mL)	25-300 pm (#/mL)
0.04% w/v PS80	t=0	405.12	10.44
OB 250 rpm 48hr	513.71	20.88
0.08% w/v PS 80	t=0	279.82	4.18
OB 250 rpm 48hr	743.41	31.32
0.12% w/v PS80	t=0	281.91	12.53
OB 250 rpm 48hr	[150.62	18.79
0.20% w/v PS 80	t=0	524.15	12.53
OB 250 rpm 48hr	657.45	8.35
0.00% w/v PS80	t=0	389.9	22.94
OB 250 rpm 48hr	1524.14	129.27

Table 38: Effect of Polysorbate 80 on Agitation Stress in Formulation Containing H1H17139P Anti-EBOV - MFI Results

Base Formulation +	Stress	10-300 pm (#/mL)	25-300 pm (#/mL)
0.04% w/v PS80	t=0	1675.63	37.61
OB 250 rpm 48hr	421.82	18.79
0.08% w/v PS80	t=0	208.82	10.44
OB 250 rpm 48hr	355	12.53
0.12% w/v PS80	t=0	402.82	64.70
OB 250 rpm 48hr	1002.87	22.98
0.20% w/v PS 80	t=0	421.82	18.79
OB 250 rpm 48hr	1423.56	10.45
0.00% w/v PS80	[=0	98	8.34
OB 250 rpm 48hr	369.24	6.26

Table 39: Effect of Polysorbate 80 on Agitation Stress in Formulation Containing H1H17161P Anti-EBOV - MFI Results

Base Formulation +	Stress	10-300 pm (#/mL)	25-300 pm (#/mL)
0.04% w/v PS 80	t=0	17	0
OB 250 rpm 48hr	2	0
0.08% w/v PS80	t=0	6	0
OB 250 rpm 48hr	25	4 _

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0.12% w/v PS80	t=0	8	4
OB 250 rpm 48hr	17	8
0.20% w/v PS80	t=0	33	4
OB 250 rpm 48hr	10	2
0.00% w/v PS80	t=0	15	2
OB 250 rpm 48hr	8	4

Table 40: Effect of Polysorbate 80 on Agitation Stress in Formulation Containing H1H17203P, H1H17139P, and H1H17161P Anti-EBOV - MFI Results

Base Formulation +	Stress	10-300 pm (#/mL)	25-300 pm (#/mL)
0.04% w/v PS 80	t=0	21	6
OB 250 rpm 48hr	15	0
0.08% w/v PS80	t=0	8	0
OB 250 rpm 48hr	2	0
0.12% w/v PS80	t=0	25	2
OB 250 rpm 48hr	15	0
0.20% w/v PS80	t=0	8	0
OB 250 rpm 48hr	19	2
0.00% w/v PS 80	t=0	2	0
	OB 250 rpm 48hr	25	6

[000228] The anti-EBOV antibodies were (instable when agitated by orbital shaking at 250 rpm in the absence of an organic cosolvent or surfactant. After agitation by orbital shaking at 250 rpm in the absence of cosolvent or surfactant, the solution became cloudy, exhibited a substantial increase in turbidity, and had an increase in aggregates as determined by SE-UPLC, as well as loss in protein recovery by RP-UPLC. In contrast, 0.1% polysorbate 80 protected the antibodies from agitationinduced instability.

Example 9: Sélection of Stabiïizer Concentration

[000229] The goal of the présent Example was to identify the levels of stabilizing component that could be used to develop a drug product formulation supporting 33.3 mg/mL individual anti-EBOV antibody, and 100 mg/mL ofthe three antibody co-formulated cocktail (ratio at 1:1:1). 10% sucrose was selected in the initial formulation, and tested at varying amounts to assess any change in antibody stability: 5%, 10%, 15%, and 20%. Base formulations contained 100 mg/mL antibody, 10

114 mM histidine atpH 6.0, and 0.1% polysorbate 80.

[000230] Sucrose was chosen as the thermal stabilizer for anti-EBOV antibodies dursng the low concentration formulation development. For the high concentration formulation development, different concentrations of sucrose were evaluated on the stability of the antibodies at 100 mg/mL concentrations at 25°C for 0 to 6 months and at 40°C for 0 to 3 months. The formation of HMW species decreased with incréas ing sucrose concentrations when the formulations were incubated at 40°C for 28 days.

[000231] This study demonstrated that the protein stability is comparable for the formulation containing 10% w/v sucrose as compared to formulations containing 15% or 20% sucrose, and as such, no additional sucrose was needed beyond 10% w/v. See Tables 41-48.

Table 41: Accelerated Stability of High Concentration (100 mg/mL) H1H17203P Anti-EBOV

Antibody with Thermal Stabilizers - Visual, OD, and pH

Base Formulation -I-	Stress	Visual	OD @ 405nm	pH
5% sucrose	t=0	0	0.085	6.0
25 °C 0.5m	0	0.084	6.0
25 °C 1m	0	0.085	6.1
25 °C 3m	0	0.082	6.1
25°C 6m	0	0.091	6.1
40°C 7d	0	0.085	6.0
40ûC 14d	0	0.086	6.0
40°C 21d	0	0.086	6.1
40°C 28d	0	0.087	6.1
10% sucrose	t=0	0	0.085	6.0
25°C 0.5m	0	0.084	6.0
25°C 1m	0	0.085	6.1
25°C 3m	0	0.084	6.0
25 °C 6m	0	0.093	6.0
40°C 7d	0	0.086	6.0

115

	40°C I4d	0	0.085	6.0
40°C 21d	0	0.086	6.0
40°C 28d	0	0.088	6.1
15% sucrose	t=0	0	0.086	6.0
25°C 0.5m	0	0.084	6.0
25°C 1m	0	0.084	6.0
25°C 3m	0	0.083	6.0
25°C 6m	0	0.090	6.0
40°C 7d	0	0.086	6.0
40°C 14d	0	0.086	6.0
40°C 21d	0	0.087	6.0
40°C 28d	0	0.086	6.0
20% sucrose	t=0	0	0.086	5.9
25°C 0.5m	0	0.087	5.9
25“C Im	0	0.084	6.0
25°C 3m	0	0.095	6.0
25°C 6m	0	0.089	6.0
40°C 7d	0	0.086	6.0
40°C 14d	0	0.085	6.0
40°C 21d	0	0.085	6.0
40°C 28d	0	0.086	6.0

Table 42: Accelerated Stability of High Concentration (100 mg/mL) H1H17203P Anti-EBOV

Antibody with Thermal Stabilizers - SE-UPLC, RP-UPLC and CEX-UPLC Results

Base Formulation +	Stress	SEUPLC %HMW	SE-UPLC %Monomer	SEUPLC %LMW	RPUPLC, mg/mL	CEX %Acidic	CEX %Main	CEX %Basic
5% sucrose	t=0	2.4	96.6	1.0	32.9	33.7	53.4	12.9
25°C 0.5m	2.1	96.9	1.1	32.4	33.9	53.7	12.4
25°C 1m	2.1	96.8	1.2	32.7	35.0	52.8	12.2

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	25°C 3m	2.1	96.3	1.6	32.6	38.6	50.9	10.5
25°C 6m	2.2	95.7	2.1	32.8	42.9	47.1	9.9
40°C 7d	2.0	96.7	1.3	32.3	35.3	52.3	12.5
40°C I4d	2.0	96.5	1.5	32.4	37.5	50.7	11.8
40°C 21d	2.1	96.1	1.8	32.5	40.0	48.7	11.3
40°C 28d	2.2	95.8	2.0	32.8	42.9	46.2	10.9
10% sucrose	t=0	2.4	96.6	1.0	33.1	33.7	53.3	13.0
25°C 0.5m	2.0	96.9	1.1	32.7	33.9	53.6	12,5
25°C Im	2.0	96.8	1.2	33.0	35.0	52.7	12.3
25°C 3m	2.1	96.3	1.6	32.8	38.4	50.8	10.8
25°C 6m	2.2	95.7	2.2	33.1	42.7	47.3	10.1
40°C 7d	2.0	96.8	1.2	32.5	35.1	52.3	12.6
40°C 14d	2.0	96.5	1.5	32.7	37.6	50.6	11.9
40°C 21d	2.1	96.2	1.8	32.8	39.8	48.7	11.5
40°C 28d	2.1	95.9	2.0	32.9	42.6	46.3	11.2
15% sucrose	t=0	2.4	96.7	1.0	33.1	33.7	53.3	13.0
25°C 0.5m	2.0	96.9	1.1	33.0	33.9	53.5	12.6
25°C Im	2.0	96.8	1.2	32.6	34.8	52.7	12.5
25°C 3m	2.1	96.4	1.6	32.8	38.2	50.9	10.9
25°C 6m	2.1	95.8	2.2	32.8	42.4	47.1	10.4
40°C 7d	2.0	96.8	1.2	32.9	35.1	52.4	12.6
40°C 14d	2.0	96.5	1.5	32.4	37.3	50.6	12.2
40°C 21d	2.0	96.2	1.8	32.6	39.5	48.8	11.7
40°C 28d	2.1	96.0	1.9	32.8	42.3	46.3	11.4
20% sucrose	t=0	2.4	96.6	1.0	33.0	33.7	53.4	12.9
25°C 0.5m	2.0	96.9	1.1	32.5	33.9	53.6	12.5
25°C 1m	2.0	96.8	1.2	32.8	34.8	52.7	12.5
25°C 3m	2.0	96.4	1.6	32.7	37.9	50.8	11.3
25°C 6m	2.1	95.8	2.1	33.1	41.9	47.5	10.7

117

	40°C 7d	2.0	96.8	1.2	32.4	34.9	52.5	12.6
40°C 14d	1.9	96.6	1.5	32.5	37.3	50.6	12.2
40°C 21d	2.0	96.3	1.7	32.7	39.1	49.0	11.9
40°C 28d	2.0	96.0	1.9	32.8	41.9	46.4	11.7

Table 43: Accelerated Stability of High Concentration (100 mg/mL) H1H17139P Anti-EBOV

Antibody with Thermal Stabilizers - Visual, OD, and pH

Base Formulation	Stress	Visual	OD @ 405nm	pH
5% sucrose	t=0	0	0.083	6.0
25°C 0.5m	0	0.083	6.0
25“C Im	0	0.083	6.0
25°C 3m	0	0.086	6.0
25°C 6m	0	0.085	6.0
40°C 7d	0	0.084	6.0
40°C 14d	0	0.084	6.0
40°C 21d	0	0.084	6.0
40°C 28d	0	0.082	6.1
10% sucrose	t=0	0	0.083	6.0
25°C 0.5m	0	0.082	6.0
25°C 1m	0	0.081	6.1
25°C 3m	0	0.087	6.0
25°C 6m	0	0.084	6.0
40°C 7d	0	0.083	6.0
40°C 14d	0	0.084	6.0
40°C 21d	0	0.084	6.0
40°C 28d	0	0.083	6.0
15% sucrose	t=0	0	0.083	6.0
25°C 0.5m	0	0.082	6.0
25°C 1m	0	0.080	6.0
25°C 3m	0	0.085	6.0
25°C 6m	0	0.084	6.0
40°C 7d	0	0.084	6.0

118

	40°C 14d	0	0.082	6.0
4ÛDC 21d	0	0,083	6.0
4Û°C 28d	0	0.082	6.0
20% sucrose	t=0	0	0.083	5.9
25°C 0,5m	0	0.083	5.9
25°C 1m	0	0.082	6.0
25°C 3m	0	0.085	6.0
25°C 6m	0	0.084	6.0
40°C 7d	0	0.085	6.0
40°C 14d	0	0.083	5.9
40°C 21d	0	0.085	6.0
40°C 28d	0	0.082	6.0

Table 44: Accelerated Stability of High Concentration (100 mg/mL) H1H17139P Anti-EBOV

Antibody with Thermal Stabilizers - SE-UPLC, RP-UPLC and CEX-UPLC Results

Base Formulation +	Stress	SEUPLC %HMW	SE-UPLC %Mon orner	SEUPLC %LMW	RPUPLC, mg/mL	CEX %Acidic	CEX %Main	CEX %Basic
5% sucrose	t=0	1,6	97.2	El	32.1	35.9	59.6	4.5
25°C 0.5m	1.4	97.4	1.3	32.3	35.8	59.7	4.6
25°C 1m	1.3	97.3	1.3	32.5	37.1	58.2	4.7
25°C 3m	1.4	96.9	1.7	32.4	39.9	55,2	4.9
25°C 6m	1.4	96.3	2.3	32.4	43.0	51.8	5.1
40°C 7d	1.3	97.4	1.4	32.2	37.0	58.1	4.9
40°C 14d	1.3	97.1	1.6	32.3	39.0	56.0	5.0
40°C 21d	1.3	96.9	1.9	32.5	40.8	54.1	5.1
40°C 28d	1.3	96.7	2.1	32.4	43.9	51.0	5.2
10% sucrose	t=0	1,6	97.2	1.2	32.3	35.7	59.8	4.5
25°C 0.5m	1.3	97.4	1.2	32.5	35.7	59.7	4.6
25°C 1m	1.3	97.4	1.3	32,6	37.1	58.1	4.8
25°C 3m	1.4	96.9	1.8	32.8	39.5	55.6	4.9
25°C 6m	1.4	96.4	2.3	32.8	42.7	52.2	5.2

119

	40°C 7d	1,3	97.4	1.4	32.4	36.8	58.4	4.9
40°C 14d	1.3	97.1	1.6	32,6	38.8	56.1	5.1
40°C 21d	1.2	96.9	1.9	32,8	40.6	54.2	5.2
40°C 28d	1.3	96.7	2.1	32,6	43.8	51.0	5.3
15% sucrose	t=0	1.6	97.2	1.1	32,3	35.7	59.8	4.5
25°C 0,5m	1.3	97.5	1.2	32,4	35.7	59,7	4.6
25°C 1m	1.3	97.4	1.3	32.6	37.0	58.2	4.8
25°C 3m	1,3	96.9	1.8	32.8	39.6	55.3	5.1
25°C 6m	1.4	96.4	2.3	32.6	42.5	52.3	5.3
40°C 7d	1.3	97.4	1.4	32.4	36.6	58.5	4.9
40°C I4d	1.3	97.1	1.6	32.5	38.7	56,2	5.1
40°C 21d	1.2	96.9	1.9	32,8	40.5	54.2	5.3
40°C 28d	1.3	96.7	2.1	32.7	43.3	51.2	5.5
20% sucrose	t=0	1,6	97.2	1.2	32.6	35.8	59.7	4.5
25°C 0.5m	1.3	97.5	1.2	32.7	35.6	59.7	4.7
25°C 1m	1.3	97.4	1.3	32.9	36,7	58.5	4.8
25°C 3m	1.3	96.9	1.8	33.1	39.4	55.6	5.1
25°C 6m	1.3	96.4	2.3	33.1	42.4	52,3	5.4
40°C 7d	1.3	97.4	1.4	32.7	36.6	58.4	5.0
4Û°C 14d	1.3	97.1	1.6	32.9	38,4	56.4	5.3
40°C 21d	1.3	96,9	1.9	33.0	40.2	54.3	5.5
40°C 28d	1.3	96.7	2.0	33.0	42.9	51.5	5.6

Table 45: Accelerated Stability of High Concentration (100 mg/mL) H1H17161P Anti-EBOV

Antibody with Thermal Stabiiizers - Visual, OD, and pH

Base Formulation +	Stress	Visual	OD @ 405 nm	pH
5% sucrose	1=0	0	0.114	6.0
25°C 0.5m	0	0.113	6.0
25°C 1m	0	0.112	6,1

120

	25°C 3 m	0	0.109	6.0
25“C 6m	0	O.ilO	6.1
40°C 7d	0	0.110	6.1
40°C 14d	0	0.112	6.0
40°C 2 Id	0	0.115	6.0
40°C 28d	0	0.111	6.1
10% sucrose	t=0	0	0.116	6.0
25°C 0.5m	0	0.113	6.0
25°C 1m	0	0.114	6.0
25°C 3m	0	0.111	6.0
25°C 6m	0	0.110	6.1
40°C 7d	0	0.113	6.1
40°C 14d	0	0.114	6.0
40°C 21d	0	0.112	6.0
40°C 28d	0	0.114	6.0
15% sucrose	t=0	0	0.114	6.0
25°C 0.5m	0	0.113	6.0
25°C 1 m	0	0.113	6.0
25°C 3m	0	0.111	6.0
25°C 6m	0	0.113	6.1
40°C 7d	0	0.110	6.1
40°C 14d	0	0.110	6.0
40°C 21d	0	0.112	6.0
40°C 28d	0	0.113	6.0
20% sucrose	1=0	0	0.113	6.0
25°C 0.5m	0	0.113	6.0
25°C 1m	0	0.113	6.0
25°C 3m	0	0.109	6.0
25°C 6m	0	0.113	6.0
40°C 7d	0	0.109	6.0
40°C 14d	0	0.114	6.0
40°C 21d	0	0.112	6.0
40°C 28d	0	0.112	6.0

Table 46: Accelerated Stability of High Concentration (100 mg/mL) H1H17161P Anti-EBOV

121

Antibody with Thermal Stabilizers - SE-UPLC, RP-UPLC and CEX-UPLC Results

Base Formulation +	Stress	SEUPLC %HMW	SE-UPLC %Mon orner	SEUPLC %LMW	RPUPLC, mg/mL	CEX %Acîdic	CEX %Maîn	CEX %Basic
5% sucrose	t=0	1.9	96.9	1.3	33	53.9	41.3	4.8
40°C 7d	1.4	97,2	1,5	33	56.5	39.0	4.5
40°C 14d	1.4	96.9	1.7	33	59.1	36.4	4.5
40°C 21d	1.5	96.5	2.Û	34	61.5	33.9	4.7
40°C 28d	1.5	96.2	2.3	34	64.3	30.1	5.6
25°C 0,5m	1.5	97.2	1.3	33	55,7	40.5	3.8
25°C 1m	1.5	97,1	1,5	34	55,8	38,6	5.7
25°C 3m	1.6	96.6	1,9	33	62.1	35,3	2.6
25°C 6 m	1.7	95.9	2,4	33	69.6	26,9	3.5
10% sucrose	t=0	1.9	96.9	1.3	33	53,9	41,6	4.6
40°C 7d	1.3	97.2	1.5	34	56.3	39.0	4.7
40°C 14d	1.4	96.9	1.7	34	58.9	36.4	4.7
40°C 21d	1.5	96.6	2.0	34	61,5	33.8	4.7
40°C 28d	1.5	96.3	2.2	34	64.3	30.9	4.8
25°C 0.5m	1.4	97.3	1.3	34	54.0	41.6	4.4
25°C 1m	1.5	97.1	1.5	34	56.0	38.3	5.7
25°C 3m	1.5	96.6	1.9	34	62.3	35.0	2.7
25°C 6m	1.6	96.0	2.4	34	69.4	27.4	3.2
15% sucrose	t=0	1.9	96.9	1.2	33	54.6	41.7	3.8
40°C 7d	1.3	97.2	1.5	33	56.5	39.6	3.9
40gC 14d	1.4	97.0	1.7	33	59.1	36.6	4.3
40°C 21d	1.4	96.6	2.0	34	61.4	33.5	5.1
40°C 28d	1.4	96.3	2.3	34	64.2	30.5	5.3
25°C 0,5m	1.4	97.3	1,3	33	54.6	40.5	4.9
25°C 1m	1.4	97.1	1.5	34	55.7	38.7	5.6
25°C 3m	1.5	96.7	1,9	34	61.9	35.3	2.8
25°C 6m	1,5	96.0	2.4	34	69.0	27.6	3.4

122

	t=0	1.9	96.9	1.3	33	54.4	42.0	3.6
	40°C 7d	1.3	97.2	1.5	33	56.3	38.8	4.9
	40°C 14d	1.3	97.0	1.7	33	59.0	36.3	4.7
	40°C 2ld	1.4	96.7	2.0	34	61.4	33.8	4.8
20%	40°C 28d	1.4	96.4	2.2	34	64.1	30.6	5.3
O IAV J MOV	25°C 0.5m	1.4	97.3	1.3	33	54.2	41.5	4.3
	25eC lm	1.4	97.1	1.5	34	55.7	38.4	5.9
	25°C 3m	1.5	96.7	1.9	34	61.6	36.1	2.3
	25°C 6m	1.5	96.1	2.5	34	68.9	27.6	3.6

Table 47: Accelerated Stabilîty of High Concentration H1H17203P, H1H17139P, and H1H17161P Anti-EBOV Antibodies with Thermal Stabilizers - Visual, OD, pH, SE-UPLC, and RP-UPLC

Base Formulation +	Stress	Visual	OD @ 405nm	pH	%HMW	%Native	%LMW	Con, mg/mL
5% sucrose	t=0	0	0.182	6.0	2.08	96.9	1.03	96
25°C 0.5m	0	0.183	6.1	2.2	96.66	1.14	98
25°C lm	0	0.187	6.1	2.34	96.39	1.26	96
25°C 3m	0	0.177	6.1	2.65	95.6	1.75	95
25°C 6m	0	0.184	6.1	2.95	94.84	2.2	94
40°C 7d	0	0.179	6.1	2.29	96.39	1.31	98
40°C 14d	0	0.182	6.1	2.51	95.96	1.54	98
40°C2ld	0	0.191	6.1	2.68	95.45	1.87	95
40°C 28d	0	0.191	6.1	2.83	95.11	2.06	96
4Û°C 2m	0	0.193	6.1	3.56	93.35	3.09	96
4Û°C 3m	0	0.205	6.1	4.22	91.61	4.17	93
10% sucrose	t=0	0	0.175	6.0	2.06	96.89	1.04	97
25°C 0.5m	0	0.180	6.0	2.14	96.71	1,15	99
25°C lm	0	0.195	6.1	2.26	96.44	1.29	96
25°C 3m	0	0.177	6.1	2.56	95.68	1.76	95
25°C 6m	0	0.182	6.1	2.84	94.93	2.22	95
40°C 7d	0	0.180	6.1	2.23	96.44	1.33	97
40°C 14d	0	0.184	6.0	2.42	96.04	1.55	98
40°C21d	0	0.187	6.1	2.57	95.57	1.85	96
40°C 28d	0	0.187	6.1	2.69	95.26	2.05	96
40°C 2m	0	0.194	6.1	3.29	93.66	3.05	97
40°C 3m	0	0.208	6.1	3.93	91.89	4.18	95

123

15% sucrose	t=0	0	0.175	6.0	2.06	96.9	1.04	96
25°C 0.5m	0	0.177	6.0	2.11	96.73	1.16	98
25°C 1m	0	0.178	6.1	2.22	96.52	1.26	96
25°C 3 m	0	0.179	6.1	2.49	95.78	1.73	96
25°C 6m	0	0.179	6.1	2.72	95.09	2.19	95
40°C 7d	0	0.181	6.1	2.17	96.5	1.32	98
40°C I4d	0	0.179	6.0	2.34	96.13	1.54	99
40°C 21d	0	0.183	6.1	2.48	95.72	1.81	95
40°C 28d	0	0.189	6.1	2.61	95.33	2.06	96
40°C 2m	0	0.194	6.1	3.12	93.85	3.03	96
40°C 3m	0	0.201	6.1	3.71	92.13	4.15	95
20% sucrose	t=0	0	0.178	6.0	2.05	96.91	1.03	96
25°C 0.5m	0	0.174	6.0	2.07	96.78	1.14	99
25°C Im	0	0.178	6.1	2.2	96.51	1.31	96
25°C 3m	0	0.181	6.0	2.42	95.81	1.77	95
25°C 6m	0	0.175	6.1	2.64	95.13	2.22	95
40°C 7d	0	0.184	6.1	2.15	96.53	1.33	98
40°C 14d	0	0.178	6.0	2.28	96.18	1.54	99
40°C21d	0	0.185	6.1	2.42	95.71	1.87	96
40°C 28d	0	0.192	6.1	2.53	95.41	2.06	96
40°C 2m	0	0.192	6.0	3.02	93.93	3.05	96
40°C 2m	0	0.199	6.1	3.51	92.37	4.13	95

Table 48: Accelerated Stability of High Concentration (100 mg/mL) H1H17203P, H1H17139P, and H1H17161P Anti-EBOV Antibodies with Thermal Stabilizers - CEX-UPLC Results

Formulation	Stress	H1H17139P	HIH17203P	H1H17161P
% Acidic	%Main	% Basic	% Acidic	%Main	% Basic	% Acidic	%Maîn	% Basic
5% sucrose	t=0	35.7	61.4	2.9	31.1	46.4	22.5	46.1	48.8	5.1
40°C	37.0	59.5	3.5	32.5	45.6	21.9	50.4	44.3	5.3
40°C	39.1	57.1	3.8	34.7	44.1	21.3	53.8	41.1	5.1
40°C	41.2	55.0	3.8	36.7	43.0	20.4	54.8	39.0	6.2
40°C	43.7	52.2	4.1	38.7	41.1	20.2	56.7	36.2	7.1
40°C	53.2	42.5	4.3	46.1	31.7	22.2	71.2	24.4	4.4
40°C	60.6	35.0	4.4	53.6	28.3	18.1	79.8	16.2	4.0
25°C	35.7	61.2	3.2	31.3	46.4	22.3	48.0	46.5	5.5
25°C	36.3	60.4	3.3	31.8	46.8	21.3	46.7	46.7	6.5
25°C	39.3	57.6	3.1	35.3	45.3	19.4	56.9	40.4	2.6
25°C	43.8	52.5	3.8	39.3	42.1	18.5	63.3	32.3	4.4
10% sucrose	t=0	35.9	61.2	2.9	31.1	46.4	22.5	46.1	48.8	5.1
40°C	36.9	59.5	3.6	32.5	45.5	22.0	50.2	44.0	5.8
40°C	38.9	57.2	3.9	34.5	44.1	21.5	53.6	41.3	5.]

124

	40°C	41.1	54.9	4.0	36.6	43.0	20.4	54.1	38.6	7.3
40°C	43.4	52.4	4.2	38.6	41.3	20.1	56.8	35.7	7.5
40°C	52.7	42.9	4.4	45.8	32.4	21.8	71.0	24.6	4.5
40°C	59.5	36.5	4.1	52.9	28.4	18.6	81.0	15.3	3.8
25 °C	35.6	61.2	3.2	31.3	46.3	22.4	48.0	46.6	5.4
25°C	36.2	60.3	3.5	31.7	46.9	21.3	46.5	46.5	7.0
25 °C	39.1	57.7	3.2	35.1	45.1	19.8	56.7	40.2	3.1
25 °C	44.0	52.3	3.7	39.2	41.8	19.1	62.6	32.7	4.7
15% sucrose	t=0	35.9	61.2	2.9	31.1	46.5	22.4	46.0	48.7	5.4
40nC	36.7	59.5	3.8	32.5	45.6	21.9	50.5	43.9	5.6
40°C	38.7	57.4	3.9	34.5	44.1	21.4	53.1	41.2	5.6
40°C	40.9	54.9	4.1	36.4	42.9	20.7	53.4	38.9	7.7
40°C	43.1	52.7	4.2	38.4	41.5	20.1	57.1	36.0	6.9
40°C	52.4	43.0	4.6	45.5	32.8	21.8	70.1	24.9	4.9
40°C	59.4	36.3	4.4	54.2	29.4	16.4	81.2	15.5	3.2
25°C	35.6	61.2	3.2	31.3	46.5	22.2	47.9	46.7	5.4
25°C	36.2	60.5	3.3	31.7	47.0	21.3	46.7	46.6	6.7
25°C	39.0	57.7	3.3	35.0	44.9	20.1	56.1	39.6	4.3
25°C	43.5	52.7	3.8	38.6	41.8	19.6	62.2	33.4	4.4
20% sucrose	t=0	35.9	61.2	2.9	31.1	46.2	22.7	46.1	48.9	5.0
40°C	36.7	59.6	3.6	32.4	45.1	22.5	50.1	44.5	5.4
40°C	38.6	57.4	4.0	34.2	43.9	21.9	53.5	41.1	5.4
40°C	40.6	55.2	4.2	36.2	43.0	20.8	53.5	38.9	7.6
40°C	42.9	52.7	4.4	37.8	41.3	20.9	57.0	36.7	6.3
4Û°C	51.7	43.6	4.7	44.8	32.5	22.7	66.4	27.4	6.2
40°C	58.8	36.8	4.5	55.3	30.7	14.0	79.7	14.4	5.8
25 °C	35.6	61.2	3.2	31.3	46.4	22.3	47.9	46.7	5.5
25°C	35.7	60.9	3.4	31.6	46.8	21.6	46.6	45.8	7.7
25 °C	38.6	58.1	3.3	34.7	45.4	20.0	56.9	40.6	2.5
25°C	43.1	53.0	3.9	38.4	42.0	19.7	61.7	33.3	5.1

Example 10: Formulated Drug Substance (FDS) Research Stability Studies (12 months) for Individually Formulated H1H17203P C2P1 FDS, HÏH17139P C2P1 FDS, and H1H17161P C2P1 FDS

[000232] Research and clinical FDS are manufactured using comparable processes, and the methods used to assess the stability of research material are similar to the methods used to assess the stability of material intended for clinical studies. Consequently, the results obtaîned from the research stability studies can be used to assess the stability of material intended for clinical studies.

[000233] The present long-term storage stability study evaluated H1H17203P C2PI FDS, H1H17139P C2P1 FDS, and HIH17161P C2P1 FDS stability through 12 months of storage

125 at-80 °C and-30 °C. H1H17203P C2P1 FDS, HIH17139P C2P1 FDS, and H1H1716IP C2PI FDS are stable for at least 12 months when stored at -80 °C and -30 °C.

[000234] The long-term, ongoing stability studies continue for the duration of the stability protocol, as presented in Table 49. Samples were analyzed following the analysis plan outlined in Table 50. The analysis plan, preliminary acceptance crîteria, and sampling plan are provided in Table 50.

Table 49: Summary of Formulated Drug Substance Stability Studies for H1H17203P, H1H17139P, and H1H17161P

Study No.	Study Type	Container Closure	Storage Conditions	Study Duration	Available Data
H1H17203P- SS018	Research	5 mL gammairradîated polycarbonate vial with silicone lined closure	-80 °C	84 months	12 months
-30 °C	84 months	12 months
-20 °C	3 months	3 months
5 °C	56 days	56 days
25 °C/60% RH	28 days	28 days
40 °C/75% RH	28 days	28 days
Agitation	120 minutes	120 minutes
Freeze/Thaw	8 cycles	8 cycles
H1H17139P- SS018	Research	5 mL gammairradîated polycarbonate vial with silicone lined closure	-80 °C	84 months	12 months
-30 °C	84 months	12 months
-20 °C	3 months	3 months
5 °C	56 days	56 days
25 °C/60% RH	28 days	28 days
40 °C/75% RH	28 days	28 days
Agitation	120 minutes	120 minutes
Freeze/Thaw	8 cycles	8 cycles
H1H17161P- SS018	Research	5 mL gammatrradiated polycarbonate vial with silicone lined closure	-80 °C	84 months	12 months
-30 °C	84 months	12 months
-20 °C	3 months	3 months
5 °C	56 days	56 days
25 °C/60% RH	28 days	28 days
40 °C/75% RH	28 days	28 days
Agitation	120 minutes	120 minutes
Freeze/Thaw	8 cycles	8 cycles

RH, relative humidity

126

Table 50: Analysis Plan and Preliminary Acceptance Criteria for H1H17203P, H1H17139P, H1H1716ÏP Formulated Drug Substance Research Stability Studies

Assay	Prcliininary Acceptance Criteria	Research Samples to be Analyzed
Physical form / Condition	Liquid essentially free from visible particulates	Ail samples
Clarîty	Not more turbid than Reference Suspension IV	Ail samples
Color	Not more intensely colored than Reference Solution BY2	Ail samples
pH	5.8 to 6.2	AH samples
Total Protein Content (A280)	90 to 110 mg/mL	N/A
Total Protein Content (RP-UPLC)	90 to 110 mg/mL	Ail samples
Potency : Pseu do virus Neutralization Assay	50% to 150% of reference standard	t=0, 6, 12, 24, 36, 48, 60, 72 and 84 months at -80 °C, and -30 °C, 3 months (-20°C), 56 days (5 °C), 28 days (25 °C/60% RH), and 28 days (40 °C/75% RH)
Potency: ADCC assay	50% to 150% of reference standard	t=0, 6, 12, 24,36,48,60, 72 and 84 months at -80 ^C, and -30 °C, 3 months (-20°C), 56 days (5 °C), 28 days (25 °C/6Û% RH), and 28 days (40 °C/75% RH)
Purity by Reduced MCE a. % Purity b. % NGHC c. % LMW	a. HC peak + LC peak > 80% total peak area b. <15% NGHC c. < 10% LMW species	t=0, 6, 12, 24, 36, 48, 60, 72 and 84 months at -80 °C, and -30 °C, 3 months (-20°C), 56 days (5 °C), 28 days (25 °C/60% RH), and 28 days (40 °C/75% RH)
Purity by Nonreduced MCE a, % Purity b. % LMW c. % HMW	a. MP + PGMP > 80% total peak area b. < 15% LMW species c. N/A	t=0, 6, 12, 24, 36, 48, 60, 72 and 84 months at -80 °C, and -30 °C, 3 months (-20°C), 56 days (5 °C), 28 days (25 °C/60% RH), and 28 days (40 °C/75% RH)
Purity by SE-UPLC a. % Main Peak Purity b. % LMW c. % HMW	a. > 90% total peak area b. < 5% LMW species c. < 7% HMW species	Ail samples

127

Assay	Prclitninary Acceptance Criteria	Research Samples to be Analyzcd
Charge Variant Analysis by CEXUPLC a. % Région 1 b. % Région 2 c. % Région 3	a. < 65% Région 1 b. > 35% Région 2 c. < 20% Région 3	AU samples

Aiso, absorbance at 280 nm; CEX, cation-ex ch ange chromatography; SE-UPLC, size-exclusion ultra performance liquid chromatography; HMW, high molecular weight; HC, heavy chain; LC, light chain; LMW, low molecular weight;

MCE, microchip capillary electrophoresis; NGHC, non-glycosylated heavy chain

Formulated Drug Substance Stability Study Results

Long-term Storage Research Stability Study Results of H1H17203P FDS

[000235] In the research stability studies, C2PI FDS was found to be physically and chemically stable when stored at -80 °C and -30 °C (Table 51 and Table 52, respectively). No appréciable change in the physical or Chemical stability was detected in any of the monitored attributes.

Research stability studies examining C2P1 FDS under the long-term storage conditions will continue through 84 months.

Accelerated Stability Study Results of H1H17203P FDS

[000236] The research stability studies indicated that C2P1 FDS was physically and chemically stable when stored at -20 °C for 3 months and 5 °C for 56 days (Table 53 and Table 54). No appréciable change in the physical or Chemical stability was detected in any of the monitored attributes. Following storage at 25 °C/60% RH (Table 54) for 28 days, a minor increase of 0.3% in HMW species was observed by SE-UPLC for H1H17203P. No meaningful change was observed in other monitored attributes following incubation at 25 °C/60% RH for 28 days. Research studies examining C2P1 FDS under the accelerated storage condition of-20 °C, 5°C and 25 °C/60% RH are complété.

Stress Stability Study Results of H1H17203P FDS

[000237] Research stability study results from the analysis of C2P1 FDS under stress conditions of 40 °C/75% RH are provided in Table 55. Increase of 1.2% in HMW and 0.4% in LMW species were observed by SE-UPLC; and increases of 11.1% in Région 1 were observed by CEX-UPLC. No meaningful change in other monitored attributes was observed. The C2P1 FDS maintained potency following incubation at 40 °C/75% RH for 28 days. Research studies examining C2P1 FDS under the stress storage condition of 40 °C/75% RH are complété.

128

[000238] Research stability results from the analysis of C2P1 FDS following agitation and freeze/thaw conditions are provided in Table 56. C2P1 FDS was physîcally and chemically stable when agitated (vortexed at ambient température) for 120 minutes or when subjected to 8 freeze/thaw cycles (freezing at -30 °C and thawing at room température). No appréciable change in the physical or Chemical stability of H1H17203P was observed in any ofthe monitored attributes. Research studies examining C2P1 FDS under agitation and freeze/thaw conditions are complété.

Long-term Storage Research Stability Study Results of H1H17139P FDS

[000239] In the research stability studies, C2P1 FDS was found to be physîcally and chemically stable when stored at -80 °C and -30 °C (Table 57 and Table 58). No appréciable change in the physical or Chemical stability was detected în any of the monitored attributes. Research stability studies examining C2P1 FDS under the long-term storage conditions will continue through 84 months.

Accelerated Stability Study Results of H1H17139P FDS

[000240] The research stability studies indicated that C2P1 FDS was physîcally and chemically stable when stored at -20 °C for 3 months and 5 °C for 56 days (Table 59 and Table 60). No appréciable change in the physical or Chemical stability was detected in any of the monitored attributes. Following storage at 25 °C/60% RH (Table 60) for 28 days, a minor increase of 0.3% in HMW species was observed by SE-UPLC. No meaningful change was observed in other monitored attributes following incubation at 25 °C/60% RH for 28 days. Research studies examining C2P1 FDS under the accelerated storage condition of -20 °C, 5°C and 25 °C/60% RH are complété.

Stress Stability Study Results of H1H17139P FDS

[000241] Research stability study results from the analysis of C2P1 FDS under stress conditions of 40 °C/75% RH are provided in Table 61. An increase of 0.9% in HMW species and 0.4% in LMW species were observed by SE-UPLC; and an increase of 11.1% in Région 1 and decrease of 12.9% in Région 2 was observed by CEX-UPLC. No meaningful change in other monitored attributes was observed. The C2P1 FDS maintained potency following incubation at 40 °C/75% RH for 28 days. Research studies examining C2P1 FDS under the stress storage condition of 40 °C/75% RH are complété.

[000242] Research stability results from the analysis of C2P1 FDS following agitation and freeze/thaw conditions are provided in Table 62. C2P1 FDS was physîcally and chemically stable when agitated (vortexed at ambient température) for 120 minutes or when subjected to 8 freeze/thaw

129 cycles (freezing at -30 °C and thawing at room température). No appréciable change in the physical or Chemical stability of H1H17I39P was observed in any ofthe monitored attrîbutes. Research studies examining C2P1 FDS under agitation and freeze/thaw conditions are complété.

Long-term Storage Research Stability Study Results of H1H17161P FDS

[000243] ίη the research stability studies, C2P1 FDS was found to be physîcally and chemically stable when stored at -80 °C and -30 °C (Table 63 and Table 64). No appréciable change in the physical or Chemical stability was detected in any ofthe monitored attrîbutes. Research stability studies examining C2P1 FDS under the long-term storage conditions will continue through 84 months.

Accelerated Stability Study Results of H1HI7161P FDS

[000244] The research stability studies indicated that C2PI FDS was physîcally and chemically stable when stored at -20 °C for 3 months and 5 °C for 56 days (Table 65 and Table 66). No appréciable change in the physical or Chemical stability was detected in any of the monitored attrîbutes. Following storage at 25 °C/60% RH (Table 66) for 28 days, a minor increase of 0.4% in HMW species was observed by SE-UPLC. No meaningful change was observed in other monitored attrîbutes following incubation at 25 °C/60% RFI for 28 days. Research studies examining C2P1 FDS under the accelerated storage condition of -20 °C, 5°C, and 25 °C/60% RH are complété.

Stress Stability Study Results of H1H17161P FDS

[000245] Research stability study results from the analysis of C2P1 FDS under stress conditions of 40 °C/75% RH are provided in Table 67. An increase of 1.0% in HMW species and 0.4% in LMW species were observed by SE-UPLC; and an increase of 14.4% in Région 1 was observed by CEX-UPLC. No meaningful change in other monitored attrîbutes was observed. The C2P1 FDS maintained potency following incubation at 40 °C/75% RH for 28 days. Research studies examining C2P1 FDS under the stress storage condition of 40 °C/75% RH are complété.

[000246] Research stability results from the analysis of C2P1 FDS following agitation and freeze/thaw conditions are provided in Table 68. C2P1 FDS was physîcally and chemically stable when agitated (vortexed at ambient température) for 120 minutes or when subjected to 8 freeze/thaw cycles (freezing ai -30 °C and thawing at room température). No appréciable change in the physical or Chemical stability of H1H17161P was observed in any ofthe monitored attrîbutes. Research studies examining C2P1 FDS under agitation and freeze/thaw conditions are complété.

130

I Stability Conclusions

[000247] H1H17203P C2P1 FDS, H1H17139P C2PI FDS, and H1H17161P C2P1 FDS can each | withstand short exposures to réfrigération, room température, and agitation stress, and can be frozen and thawed without compromising eîther the physical or Chemical stability of the protein. These | results indicate that the H1H17203P C2P1 FDS, H1H17139P C2PI FDS, and H1H17161P C2P1

FDS are stable during the manufacture of the three-way combination drug product (DP). Exposure | of H1H17203P C2P1 FDS, H1H17139P C2PI FDS, and H1H17161P C2P1 FDS to températures above room température should be avoided.

I

Recommended Storage Conditions

I [000248] The recommended long-term storage température for HIH17203P C2P1 FDS,

HIH17139P C2P1 FDS, and H1H1716IP C2P1 FDS is-30°C.

I

131

I I

I I

I I

I I I I I I

I I I I I I

Table 51: Research Stability of 100 mg/mL H1H17203P C2P1 Formulated Drug Substance Stored at -80 °C

Formulation	100 mg/mL H1H17203P, 10 mM L-histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Container/CIosure	S mL gamma-irradiated poiycarbonate vial with HDPE closure
Assay	Length of Storage at -80 °C (months)
0	1	3	6	9	12
Physical form ! Condition	LEFVP	LEFVP	LEFVP	LEFVP	LEFVP	LEFVP
Clarity	< 6 NTU	<6 NTU	<6 NTU	<6 NTU	<6NTU	<6 NTU
Color	<BY4	< BY4	< BY4	<BY4	< BY4	< BY4
pH	6.0	6.0	6.0	6.1	6.0	6.0
Total Protein Content by RPUPLC (mg/mL)	98.7	99.7	98.7	98.1	99.0	99.2
Non-reduced MCE (%)	Purity	95.9	NR	NR	95.9	NR	95.7
LMW	3.6	NR	NR	3.5	NR	4.0
Reduced MCE (%)	Purity	91.1	NR	NR	92.0	NR	92.1
NGHC	7.2	NR	NR	7.0	NR	7.2
LMW	0.4	NR	NR	0.2	NR	0.2
Purity by SEUPLC (%)	Main	99.1	99.1	99.1	99.1	99.1	99.1
LMW	0.1	ο,ι	0.1	0.1	0.1	0.1
HMW	0.8	0.8	0.8	0.8	0.8	0.8
Charge Variant Analysis by CEX-UPLC (%)	Région 1	34.7	34.7	34.5	34.5	34.7	34.7
Région 2	53.5	53.5	53.7	53.6	54.0	54.0
Région 3	11.8	11.8	11.8	11.9	11.3	11.3
Relative Potency (%)	Pseudovirus Neutralization Assay	90	NR	NR	96	NR	104
ADCC assay	80	NR	NR	118	NR	91

CEX, cation exchange; FDS, fonnuiated drug substance; HDPE, high-density polyethylene; HMW, high molecular weight; LEFVP, liquid essentially free from visible particulates; LMW, low molecular weight; MCE, microchip capillary electrophoresis; NGHC, Non-glycosylated Heavy Chain; NR, not required per protocol; RP, reversed-phase; SE, size exclusion; UPLC, ultra performance liquid chromatography; ADCC, Antibody-De pen dent Cellular Cytotoxicity;

132

Table 52: Research Stability of 100 mg/mL H1H17203P C2P1 Formulated Drug Substance Stored at -30 °C

Formulation	100 mg/mL H1H17203P, 10 mM L-histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Conta iner/Closure	5 mL gamma-irradiated polycarbonate vial with HDPE closure
Assay	Length of Storage at -30 °C (months)
0	1	3	6	9	12
Physical form / Condition	LEFVP	LEFVP	LEFVP	LEFVP	LEFVP	LEFVP
Clarity	S 6 NTU	<6 NTU	S 6 NTU	< 6 NTU	<6 NTU	<6 NTU
Col or	< BY4	< BY4	< BY4	< BY4	<BY4	<BY4
pH	6.0	6.0	6.0	6.1	6.0	6.0
Total Protein Content by RPUPLC (mg/mL)	98.7	99.2	98.0	98.3	99.0	99.6
Non-reduced MCE (%)	Purity	95.9	NR	NR	96.0	NR	95.6
LMW	3.6	NR	NR	3.5	NR	4.1
Reduced MCE (%)	Purity	91.1	NR	NR	91.1	NR	92.2
NGHC	7.2	NR	NR	7.3	NR	7.0
LMW	0.4	NR	NR	0.4	NR	0.2
Purity by SEUPLC (%)	Main	99 1	99.1	99.1	99.1	99.1	99.1
LMW	0.1	0.1	0.1	0.1	0.1	0.1
HMW	0.8	0.8	0.8	0.8	0.8	0.8
Charge Variant Analysis by CEX-UPLC (%)	Région 1	34.7	34.8	34.5	34.5	34.7	34.7
Région 2	53.5	53.5	53.7	53.5	53.9	54.0
Région 3	11.8	11.8	11.8	12.0	11.4	11.3
Relative Potency (%)	Pseudo virus Neutralizatio n Assay	90	NR	NR	90	NR	106
ADCC assay	80	NR	NR	101	NR	84

CEX, cation exchange; FDS, formulated drug substance; FDG, Formulation Development Group; HDPE, high-density polyethylene; HMW, high molecular weight; LEFVP, liquid essentially free from visible particulates; LMW, low molecular weight; MCE, microchip capillary electrophoresis; NGHC, Non-glycosylated Heavy Chain; NR, not required per protocol; OD, optical density; RP, reversed-phase; SE, size-exclusion; UPLC, ultra performance liquid chromatography; ADCC, Antibody-dependent cellular cytotoxicity

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Table 53; Research Stability of 100 mg/mL H1H17203P C2P1 Formulated Drug Substance — Effect of Accelerated Conditions at -20 °C

Formulation	100 mg/mL H1H17203P, 10 mM L-histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pFI 6.0
Container/Closure	5 mL gamma-irradiated polycarbonate vial with HDPE closure
Assay	Length of Storage at -20 °C (months)
0	1	2	3
Physical form / Condition	LEFVP	LEFVP	LEFVP	LEFVP
Clarity	< 6 NTU	<6 NTU	<6 NTU	<6 NTU
Col or	< BY4	<BY4	<BY4	<BY4
pH	6.0	6.0	6.0	6.0
Total Protein Content by RPUPLC (mg/mL)	98.7	99.8	98.2	99.0
Non-reduced MCE (%)	Purity	95.9	NR	NR	95.9
LMW	3.6	NR	NR	3.4
Reduced MCE (%)	Purity	91.1	NR	NR	91.9
NGHC	7.2	NR	NR	6.9
LMW	0.4	NR	NR	0.4
Purity by SEUPLC (%)	Main	99.1	99.1	99.1	99.1
LMW	0.1	0.1	0.1	0.1
HMW	0.8	0.8	0.8	0.8
CEX-UPLC (%)	Région 1	34.7	34.7	34.5	34.5
Région 2	53.5	53.5	53.8	53.6
Région 3	11.8	ILS	11.7	11.9
Relative Potency (%)	Pseu do virus Neutralization Assay	90	NR	NR	92
ADCC assay	80	NR	NR	102

CEX, cation exchange; FDS, formulated drug substance; FDG, Formulation Development Group; HDPE, high-density polyethylene; HMW, high molecular weight; LEFVP, liquid essentially free from visible particulates; LMW, low molecular weight; MCE, microchip capillary electrophoresis; NGHC, Non-glycosylated Heavy Chain; NR, not required per protocol; OD, optical density; RP, reversed-phase; SE, size exclusion; UPLC, ultra performance liquid chromatography; ADCC, Antibody-Dependent Cellular Cytotoxicity;

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Table 54: Research Stability of 100 mg/mL H1H17203P C2P1 Formulated Drug Substance — Effect of Accelerated Conditions

Formulation	100 mg/mL HIH17203P, 10 mM L-histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Container/Closure	5 mL gamma-irradlated polycarbonate vial with HDPE closurc
Assay	t=0	5°C Storage (days)	25°C/60%RH Storage (days)
14	28	56	7	14	28
Physical form / Condition	LEFVP	LEFVP	LEFVP	LEFVP	LEFVP	LEFVP	LEFVP
Clarity	<6 NTL)	<6NTU	< 6 N TU	<6NTU	<6NTU	<6NTU	<6 NTU
Color	<BY4	< BY4	<BY4	<BY4	<BY4	<BY4	< BY4
pH	6.0	6.0	6.0	6.0	6.0	6.0	6.0
Total Protein Content by RP-UPLC (mg/mL)	98.7	98.2	100.0	99.0	99.6	98.0	100.9
Non-reduced MCE (%)	Purity	95.9	NR	NR	95.5	NR	NR	95.5
LMW	3.6	NR	NR	3.5	NR	NR	3.8
Reduced MCE (%)	Purity	91.1	NR	NR	92.2	NR	NR	91.6
NGHC	7.2	NR	NR	7.0	NR	NR	7.1
LMW	0.4	NR	NR	0.1	NR	NR	0.5
Purity by SEUPLC (%)	Main	99.1	99.1	99.0	99.0	99.0	98.9	98.8
LMW	0.1	0.1	04	0.1	0.1	0.1	0.2
HMW	0.8	0.8	0.8	0.9	0.9	0.9	1.1
CEX-UPLC (%)	Région l	34.7	34.7	34.7	34.4	34.6	34.9	35.5
Région 2	53.5	53.6	53.6	53.9	53.8	53.8	53.7
Région 3	11.8	11.7	11.7	11.7	11.6	11.3	10.9
Relative Potency (%)	Pseudovirus Neutralization Assay	90	NR	NR	87	NR	NR	86
ADCC assay	80	NR	NR	142	NR	NR	98

CEX, cation exchange; FDS, formulated drug substance; FDG, Formulation Development Group; HDPE, hîgh-density polyethylene; HMW, high molecular weîght; LEFVP, liquid essentiaily free from visible particulates; LMW, low molecular weight; MCE, microchip capillary electrophoresis; NGHC, Non-glycosyiated Heavy Chain; NR, not required per protocol; OD, optical density; RP, reversed-phase; SE, size-exclusion; UPLC, ultra performance liquid chromatography; ADCC, Antibody-dependent cellular cytotoxicity

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Table 55: Research Stabilîty of 100 mg/mL H1H17203P C2P1 Formulated Drug Substance - Effects of Stress Conditions

Formulation	100 mg/mL H1H17203P, 10 mM L-histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Container/Closure	5 mL gamma-irradiated polycarbonate vial with HDPE closure
Assay	t=0	40°C/75%RH Storage (days)
7	14	28
Physical form / Condition	LEFVP	LEFVP	LEFVP	LEFVP
Clarity	< 6 NTU	< 6 NTU	<6 NTU	<6 NTU
Cofor	< BY4	< BY4	< BY4	< BY4
pH	6.0	6.0	6.0	6.0
Total Protein Content by RP-UPLC (mg/mL)	98.7	100.8	99.2	102.3
Nonreduced MCE (%)	Purity	95.9	NR	NR	93.6
LMW	3.6	NR	NR	5.6
Reduced MCE (%)	Purity	91.1	NR	NR	91.5
NGHC	7.2	NR	NR	6.9
LMW	0.4	NR	NR	0.4
Purity by SE-UPLC (%)	Main	99.1	98.8	98.4	97.5
LMW	0.1	0.2	0.3	0.5
HMW	0.8	LO	1.4	2.0
CEX-UPLC (%)	Région 1	34.7	36.0	39.5	45.8
Région 2	53.5	52.7	49.8	43.8
Région 3	1L8	11.3	10.7	10.4
Relative Potency (%)	Pseudovirus Neutralization Assay	90	NR	NR	85
ADCC assay	80	NR	NR	103

CEX, cation exchange; FDS, formulated drug substance; FDG, Formulation Development Group; HDPE, high-density polyethylene; HMW, high molecular weight; LEFVP, liquid essentially free from visible particuiates; LMW, low molecular weight; MCE, microchip capillary electrophoresîs; NGHC, Non-glycosylated Heavy Chain; NR, not required per protocol; OD, optical density; RP, reversed-phase; SE, size-exclusion; UPLC, ultra performance liquid chromatography; ADCC, Antibody-dépendent cellular cytotoxicity

136

Table 56: Research Stability of 100 mg/mL H1H17203P C2P1 Formulation Drug Substance - Effect of Agitation, and Freezing and Thawing

Formulation	100 mg/mL H1H17203P, 10 mM L-histidine, 10% (w/v) sucrose, 0.1 % (w/v) polysorbate 80, pH 6.0
Conta iner/Closure	5 mL gamma-irradiated polycarbonate vial with HDPE closure
Assay	t-0	Agitation (minutes)	Freeze/Thaw (cycles)
60	120	4	8
Physical form / Condition	LEFVP	LEFVP	LEFVP	LEFVP	LEFVP
Clanty	<6 NTU	<6 NTU	<6 NTU	<6 NTU	<6 NTU
Color	<BY4	<BY4	< BY4	< BY4	<BY4
pH	6.0	6.0	6.0	6.0	6.0
Total Protein Content by RP-UPLC (mg/mL)	98.7	100.2	100.3	99.7	100.2
Non-reduced MCE (%)	Purity	95.9	NR	96.2	NR	95.9
LMW	3.6	NR	3.4	NR	3.5
Reduced MCE (%)	Purity	91.1	NR	91.5	NR	91.4
NGHC	7.2	NR	7.3	NR	7.0
LMW	0.4	NR	0.2	NR	0.3
Purity by SE-UPLC (%)	Main	99.1	99.1	99.1	99.1	99.1
LMW	0.1	0.1	0.1	0.1	0.1
HMW	0.8	0.8	0.8	0.8	0.8
CEX-UPLC (%)	Région 1	34.7	34.8	34.7	34.8	34.8
Région 2	53.5	53.5	53.6	53.5	53.5
Région 3	11.8	11.8	11.7	11.8	11.7
Relative Potency (%)	Pseudovirus Neutralization Assay	90	NR	89	NR	86
ADCC assay	80	NR	109	NR	96

CEX, cation exchange; FDS, formulated drug substance; FDG, Formulation Development Group; HDPE, high-density polyethylene; HMW, high molecular weight; LEFVP, liquid essentialiy free from visible particulates; LMW, low molecular weight; MCE, microchip capillary electrophoresis; NGHC, Non-glycosylated Heavy Chain; NR, not required per protocol; OD, optical densîty; RP, reversed-phase; SE, size-exclusion; UPLC, ultra performance liquid chromatography; ADCC, Antibody-dependent cellular cytotoxicîty

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Table 57: Research Stability of 100 mg/mL H1H17139P C2P1 Formulated Drug Substance Stored at -80 °C

Formulation	100 mg/mL H1H17139P, 10 mM L-histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Container/Closure	5 mL gamma-irradiated polycarbonate vial with HDPE closure
Assay	Length of Storage at -80 °C (months)
0	1	3	6	9	12
Physical form l Condition	LEFVP	LEFVP	LEFVP	LEFVP	LEFVP	LEFVP
Clarity	< 6 NTU	i ù NTU	<6 NTU	<6 NTU	<6 NTU	<6 NTU
Color	< BY4	<BY4	< BY4	< BY4	< BY4	< BY4
pH	6.0	6.0	6.1	6.0	6.0	6.0
Total Protein Content by RPUPLC (mg/mL)	94.4	93.8	96.8	95.3	97.0	96.8
Non-reduced MCE (%)	Purity	95.0	NR	NR	95.2	NR	94.9
LMW	4.8	NR	NR	4.7	NR	4.8
Reduced MCE (%)	Purity	95.6	NR	NR	95.7	NR	95.7
NGHC	3.4	NR	NR	3.4	NR	3.5
LMW	0.2	NR	NR	0.2	NR	0.1
Purity by SEUPLC (%)	Main	99.3	99.4	99.3	99.3	99.4	99.3
LMW	0.1	0.0	0.1	0.1	0.1	0.1
HMW	0.6	0.6	0.6	0.6	0.6	0.6
Charge Variant Analysis by CEX-UPLC (%)	Région 1	34.3	34.2	34.2	32.9	32.8	34.1
Région 2	62.1	62.2	62.2	64.0	64.0	62.2
Région 3	3.6	3.6	3.6	3.1	3.1	3.6
Relative Potency (%)	ADCC assay	92	NR	NR	99	NR	91

CEX, cation exchange; FDS, fonnuiated drug substance; FDG, Formulation Development Group; HDPE, high-density polyethylene; HMW, high molecular weight; LEFVP, liquid essentially free from visible particulates; LMW, low molecular weight; MCE, microchip capillary electrophoresis; NGHC, Non-glycosylated Heavy Chain; NR, not required per protocol; OD, optical density; RP, reversed-phase; SE, size-exclusion; UPLC, ultra performance liquid chromatography; ADCC, Antibody-dépendent cellular cytotoxicity

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Table 58: Research Stability of 100 mg/mL H1H17139P C2P1 Formulated Drug Substance Stored at -30 °C

Formulation	100 mg/mL H1H17139P, 10 mM L-histidinc, 10% (w/v) sucrose, 0.1 % (w/v) polysorbate 80, pH 6.0
Container/Closure	5 mL gamma-irradiated polycarbonate vial with HDPE closure
Assay	Length of Storage at-30 °C (months)
0	1	3	6	9	12
Physical form ! Condition	LEFVP	LEFVP	LEFVP	LEFVP	LEFVP	LEFVP
Clarity	<6 NTU	<6 NTU	<6 NTU	<6 NTU	<6 NTU	<6 NTU
Col or	<BY4	<BY4	< BY4	<BY4	< BY4	<BY4
pH	6.0	6.0	6.1	6.0	6.0	6.0
Total Protein Content by RPUPLC (mg/mL)	94.4	94.2	96.4	95.9	96.2	97.4
Non-reduced MCE (%)	Purity	95.0	NR	NR	94.7	NR	94.9
LMW	4.8	NR	NR	5.0	NR	4.9
Reduced MCE (%)	Purity	95.6	NR	NR	95.8	NR	96.0
NGHC	3.4	NR	NR	3.3	NR	3.3
LMW	0.2	NR	NR	0.2	NR	0.1
Purity by SEUPLC (%)	Main	99.3	99.3	99.3	99.3	99.3	99.3
LMW	0.1	0.1	0.1	0.1	0.1	0.1
HMW	0.6	0.6	0.6	0.6	0.6	0.6
Charge Variant Analysis by CEX-UPLC (%)	Région 1	34.3	34.2	34.2	33.1	32.8	34.2
Région 2	62.1	62.2	62.2	63.9	64.1	62.1
Région 3	3.6	3.6	3.6	3.0	3.1	3.8
Relative Potency (%)	ADCC assay	92	NR	NR	79	NR	94

CEX, cation exchange; FDS, formulated drug substance; FDG, Formulation Development Group; HDPE, high-density polyethylene; HMW, high molecular weight; LEFVP, liquid essentially free from visible particulates; LMW, low molecular weight; MCE, microchip capillary electrophoresis; NGHC, Non-glycosylated Heavy Chain; NR, not required per protocol; OD, optical density; RP, reversed-phase; SE, size-exclusion; UPLC, ultra performance liquid chromatography; ADCC, Antibody-dependent cellular cytotoxîcity

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Table 59: Research Stability of 100 mg/mL H1H17139P C2P1 Formulated Drug Substance — Effect of Accelerated Conditions at -20 °C

Formulation	100 mg/mL H1H17139P, 10 mM L-histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Container/Closure	5 mL gamma-irradiated polycarbonate vial with FIDPE closure
Assay	Length of Storage at -20 °C (months)
0	1	2	3
Physical form ! Condition	LEFVP	LEFVP	LEFVP	LEFVP
Oarity	< 6 NTU	<6 NTU	<6 NTU	<6 NTU
Color	<BY4	< BY4	< BY4	<BY4
pH	6.0	6.0	6.0	6.1
Total Protein Content by RPUPLC (mg/mL)	94.4	94.7	94.4	96.8
Nonreduced MCE (%)	Purity	95.0	NR	NR	95.1
LMW	4.8	NR	NR	4.8
HMW	0.2	NR	NR	0.2
Reduced MCE (%)	Purity	95.6	NR	NR	95.7
NGHC	3.4	NR	NR	3.4
LMW	0.2	NR	NR	0.1
Purity by SE-UPLC (%)	Main	99.3	99.3	99.3	99.3
LMW	0.1	0.1	0.1	0.1
HMW	0.6	0.6	0.6	0.6
CEX-UPLC (%)	Région 1	34.3	34.2	34.3	34.2
Région 2	62.1	62.2	62.1	62.2
Région 3	3.6	3.6	3.6	3.6
Relative Potency (%)	ADCC Assay	92	NR	NR	107

CEX, cation exchange; FDS, formulated drug substance; FDG, Formulation Development Group; HDPE, high-density polyethylene; HMW, high molecular weight; LEFVP, liquid essentially free from visible particulates; LMW, low molecular weight; MCE, mîcrochip capillary electrophoresis; NGHC, Non-glycosylated Heavy Chain; NR, not required per protocol; OD, optical density; RP, reversed-phase; SE, size exclusion; UPLC, ultra performance liquid chromatography; ADCC, Antibody-Dépendent Cellular Cytotoxicity

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Table 60: Research Stability of 100 mg/mL H1H17139P C2P1 Formulated Drug Substance — Effect of Accelerated Conditions

Formulation	100 mg/mL H1H17139P, 10 mM L-histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Container/Closure	5 mL gamma-irradiated polycarbonate vial with HDPE closure
Assay	t=0	5°C Storage (days)	25°C/60%RH Storage (days)
14	28	56	7	14	28
Physical form / Condition	LEFVP	LEFVP	LEFVP	LEFVP	LEFVP	LEFVP	LEFVP
Clarîty	<6 NTU	<6 NTU	<6 NTL)	< 6 NTU	<6 NTU	<6 NTU	<6 NTU
Color	< BY4	<BY4	< BY4	< BY4	< BY4	< BY4	< BY4
pH	6.0	5.9	6.1	6.0	6.1	6.0	6.0
Total Protein Content by RPUPLC (mg/mL)	94.4	94.2	94.7	99.5	93.7	94.7	94.9
Non-reduced MCE (%)	Purity	95.0	NR	NR	94.9	NR	NR	94.8
LMW	4.8	NR	NR	4.8	NR	NR	5.1
Reduced MCE (%)	Purity	95.6	NR	NR	95.9	NR	NR	95.7
NGHC	3.4	NR	NR	3.2	NR	NR	3.4
LMW	0.2	NR	NR	0.1	NR	NR	0.2
Purity by SEHPLC (%)	Main	99.3	99.3	99.3	99.2	99.2	99.1	99.0
LMW	0.1	0.1	0.1	0.1	0.1	0.1	0.1
HMW	0.6	0.6	0.7	0.7	0.7	0.8	0.9
CEX-UPLC (%)	Région 1	34.3	34.1	34.1	34.1	33.9	34.2	34.7
Région 2	62.1	62.2	62.2	62.2	62.2	61.7	61.1
Région 3	3.6	3.7	3.7	3.8	3.9	4.1	4.3
Relative Potency (%)	ADCC Assay	92	NR	NR	113	NR	NR	100

CEX, cation exchange; FDS, formulated drug substance; FDG, Formulation Development Group; HDPE, high-density polyethylene; HMW, high molecular weight; LEFVP, liquid essentially free from visible particulates; LMW, low molecular weight; MCE, microchip capillary electrophoresis; NGHC, Non-glycosylated Heavy Chain; NR, not required per protocol; OD, optical density; RP, rev ers ed-phase; SE, size-exclusion; HPLC, ultra performance liquid chromatography; ADCC, Antibody-dépendent cellular cytotoxicity

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Table 61: Research Stability of 100 mg/mL H1H17I39P C2P1 Formulated Drug Substance - Effects of Stress Conditions

Formulation	100 mg/mL HIH17139P, 10 mM L-histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Conta iner/Closure	5 mL gamma-irradiated polycarbonate vial with HDPE closure
Assay	T = 0	Length of storage at 40 °C/75%RH (days)
7	14	28
Physical form / Condition	LEFVP	LEFVP	LEFVP	LEFVP
Clarity	<6NTU	< 6 NTU	<6 NTU	<6 NTU
Color	<BY4	< BY4	< BY4	< BY4
pH	6.0	6.0	6.0	6.0
Total Protein Content by RPUPLC (mg/mL)	94.4	95.3	95.4	96.7
Non-reduced MCE (%)	Purity	95.0	NR	NR	92.3
LMW	4.8	NR	NR	6.8
Reduced MCE (%)	Purity	95.6	NR	NR	94.7
NGHC	3.4	NR	NR	3.4
LMW	0.2	NR	NR	0.7
Purity by SEUPLC (%)	Main	99.3	98.8	98.5	98.0
LMW	0.1	0.2	0.3	0.5
HMW	0.6	1.0	1.2	1.5
CEX-UPLC (%)	Région 1	34.3	36.3	39.3	45.4
Région 2	62.1	59.0	55.6	49.2
Région 3	3.6	4.7	5.1	5.5
Relative Potency (%)	ADCC Assay	92	NR	NR	97

CEX, cation exchange; FDS, formulated drug substance; FDG, Formulation Development Group; HDPE, high-density polyethylene; HMW, high molecular weight; LEFVP, liquid essentially free from visible particulates; LMW, low molecular weight; MCE, microchîp capillary electrophoresis; NGHC, Non-glycosylated Heavy Chain; NR, not requîred per protocol; OD, optîcal density; RP, reversed-phase; SE, size-exclusion; UPLC, ultra performance liquid chromatography; ADCC, Antibody-dépendent cellular cytotoxicity

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Table 62: Research Stability of 100 mg/mL H1H17139P C2P1 Formulation Drug Substance Effect of Agitation and Freezing and Thawing

Formulation	100 mg/mL HIH17139P, 10 mM L-hîstidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Conta iner/Closure	5 mL gamma-irradiated polycarbonate vial with HDPE closure
Assay	t-0	Ag ita tio n (m in ut es)	Frccze/Thaw (cycles)
60	120	4	8
Physical form / Condition	LEFVP	LEFVP	LEFVP	LEFVP	LEFVP
Clarity	< 6 NTU	<6 NTU	<6 NTU	<6 NTU	<6 NTU
Col or	<BY4	<BY4	< BY4	< BY4	<BY4
pH	6.0	6.0	6.0	6.0	6.0
Total Protein Content by RP-UPLC (mg/mL)	94.4	94.0	94.4	94.4	94.9
Nonreduced MCE (%)	Purity	95.0	NR	95.0	NR	94.9
LMW	4.8	NR	4.9	NR	4.8
Reduced MCE (%)	Purity	95.6	NR	95.9	NR	95.8
NGHC	3.4	NR	3.3	NR	3.2
LMW	0.2	NR	0.1	NR	0.2
Purity by SE-UPLC (%)	Main	99.3	99.3	99.3	99.3	99.4
LMW	0.1	0.1	0.1	0.1	0.1
HMW	0.6	0.6	0.6	0.6	0.6
CEX-UPLC (%)	Région 1	34.3	34.3	34.2	34.1	34.3
Région 2	62.1	62.1	62.2	62.2	62.1
Région 3	3.6	3.6	3.7	3.7	3.6
Relative Potency (%)	ADCC Assay	92	NR	120	NR	92

CEX, cation exchange; FDS, formulated drug substance; FDG, Formulation Development Group; HDPE, high-density polyethylene; HMW, high molecular weight; LEFVP, liquid essentially free from visible particulates; LMW, low molecular weight; MCE, microchip capîllary electrophoresis; NGHC, Non-glycosylated Heavy Chain; NR, not requîred per protocol; OD, optical density; RP, reversed-phase; SE, size exclusion; UPLC, ultra performance liquid chromatography; ADCC, Antibody-dépendent cellular cytotoxicity

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Table 63: Research Stability of 100 mg/mL H1H17161P C2P1 Formulated Drug

Substance Stored at -80 °C

Formulation	100 mg/mL H1H17161P, 10 mM L-histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Container/CIosure	5 mL gamma-irradiated polycarbonate vial with HDPE closure
Assay	Length of Storage at -80 °C (months)
0	1	3	6	9	12
Physical form / Condition	LEFVP	LEFVP	LEFVP	LEFVP	LEFVP	LEFVP
Ciarity	<6 NTU	<6 NTU	<6 NTU	<6 NTU	<6 NTU	<6 NTU
Color	<BY3	<BY3	<BY3	< BY3	< BY3	<BY3
pH	6.0	6.0	6.1	6.0	6.0	6.0
Total Protein Content by RPUPLC (mg/mL)	95.8	95.8	95.8	97.0	99.1	97.3
Nonreduced MCE (%)	Purity	95.7	NR	NR	95.7	NR	95.6
LMW	3.9	NR	NR	3.9	NR	3.9
Reduced MCE (%)	Purity	96.0	NR	NR	96.2	NR	96.2
NGHC	3.5	NR	NR	3.3	NR	3.5
LMW	0.0	NR	NR	0.0	NR	0.0
Purity by SE-UPLC (%)	Main	98.8	98.8	98.8	98.7	98.5	98.8
LMW	0.1	0.2	0.1	0.2	0.3	0.1
HMW	1.1	l.l	1.1	1.1	1.2	1.1
Charge Variant Analysis by CEX-UPLC (%)	Région 1	48.2	47.9	47.7	47.7	48.2	48,7
Région 2	45.2	45.5	46.1	46.9	45.3	45.3
Région 3	6.7	6.6	6.2	5.4	6.6	6.1
Relative Potency (%)	Pseudovirus Neutralization assay	110	NR	NR	137	NR	112

CEX, cation exchange; FDS, formulated drug substance; FDG, Formulation Development Group; HDPE, high-density polyethylene; HMW, high molecular weight; LEFVP, liquid essentially free from visible particulates; LMW, low molecular weight; MCE, microchip capillary electrophoresis; NGHC, Non-glycosylated Heavy Chain; NR, not requîred per protocol; OD, optical density; RP, reverscd-phase; SE, size-exclusion; UPLC, ultra performance liquid chromatography

144

Table 64: Research Stability of 100 mg/mL H1H17161P C2P1 Formulated Drug Substance Stored at -30 °C

Formulation	100 mg/mL H1H17161P, 10 mM L-histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Conta iner/Closure	5 mL gamma-irradiated polycarbonate vial with HDPE closure
Assay	Length of Storage at -30 °C (months)
0	1	3	6	9	12
Physical form / Condition	LEFVP	LEFVP	LEFVP	LEFVP	LEFVP	LEFVP
Clarity	< 6 N TU	£6 NTU	<6 NTU	< 6 NTU	<6 NTU	<6 NTU
Color	<BY3	< BY3	< BY3	< BY3	< BY3	< BY3
pH	6.0	6.0	6.1	6.0	6.0	6.Û
Total Protein Content by RPUPLC (mg/mL)	95.8	95.8	95.8	96.8	99.4	97.5
Nonreduced MCE (%)	Purity	95.7	NR	NR	95.7	NR	95.7
LMW	3.9	NR	NR	3.9	NR	3.9
Reduced MCE (%)	Purity	96.0	NR	NR	96.1	NR	96.2
NGHC	3.5	NR	NR	3.4	NR	3.3
LMW	0.0	NR	NR	0.0	NR	0.0
Purîty by SE-UPLC (%)	Main	98.8	98.8	98.8	98.7	98.5	98.8
LMW	0.1	0.1	0.!	0.2	0.2	0.2
HMW	1.1	l.l	1.1	1.1	1.2	1.1
Charge Variant Analysis by CEX-UPLC (%)	Région 1	48.2	48.0	47.7	47.6	48.3	48.9
Région 2	45.2	45.4	46.2	47.1	45.1	45.1
Région 3	6.7	6.6	6.2	5.3	6.6	6.0
Relative Potency (%)	Pseudovirus Neutralization Assay	110	NR	NR	132	NR	106

CEX, cation exchange; FDS, formulated drug substance; FDG, Formulation Development Group; HDPE, high-density polyethylene; HMW, high molecular weight; LEFVP, liquid essentially free from visible particulates; LMW, low molecular weight; MCE, microchip capillary electrophoresis; NGHC, Non-glycosylated Heavy Chain; NR, not required per protocol; OD, optîcal density; RP, reversed-phase; SE, size-exclusion; UPLC, ultra performance liquid chromatography

145

Table 65: Research Stability of 100 mg/mL H1H17161P C2P1 Formulated Drug Substance — Effect of Accelerated Conditions at -20 °C

Formulation	100 mg/mL H1H17161P, 10 mM L-histidîne, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Container/Closure	5 mL gamma-irradiated polycarbonate vial wîth HDPE closure
Assay	Length of Storage at -20 °C (months)
0	l	2	3
Physical form ! Condition	LEFVP	LEFVP	LEFVP	LEFVP
Clarity	< 6 NTU	<6 NTU	<6 NTU	<6 NTU
Color	< BY3	< BY3	£BY3	< BY3
pH	6.0	6.0	6.0	6.1
Total Protein Content by RP-UPLC (mg/mL)	95.8	96.3	95.9	95.6
Non-reduced MCE (%)	Purity	95.7	NR	NR	95.6
LMW	3.9	NR	NR	3.9
Reduced MCE (%)	Purity	96.0	NR	NR	95.9
NGHC	3.5	NR	NR	3.7
LMW	0.0	NR	NR	0.0
Purity by SEUPLC (%)	Main	98.8	98.8	98.7	98.8
LMW	0.1	0.1	0.2	0.1
HMW	1.1	1.1	1.1	1.1
CEX-UPLC (%)	Région 1	48.2	47.8	47.7	47.8
Région 2	45.2	45.5	46.1	46.0
Région 3	6.6	6.7	6.2	6.2
Relative Potency (%)	Pseudovirus Neutralization Assay	110	NR	NR	126

CEX, cation exchange; FDS, formulated drug substance; FDG, Formulation Development Group; HDPE, high-density polyethylene; HMW, high molecuiar weight; LEFVP, liquid essentially free from visible particulates; LMW, low molecular weight; MCE, microchip capîllary electrophoresis; NGHC, Non-glycosylated Heavy Chain; NR, not required per protocol; OD, optical density; RP, reversed-phase; SE, size-exclusion; UPLC, ultra performance liquid chromatography

146

Table 66: Research Stability of 100 mg/mL H1H17161P C2P1 Formulated Drug Substance — Effect of Accelerated Conditions

Formulation	100 mg/mL H1H17161 P, 10 mM L-histidine, 10% (w/v) sucrose, 0,1% (w/v) polysorbate 80, pH 6.0
Contaîner/Closure	5 mL gamma-irradiated polycarbonate vial with HDPE closure
Assay	t=0	5°C Storage (days)	25°C/60%RH Storage (days)
14	28	56	7	14	28
Physical form / Condition	LEFVP	LEFVP	LEFVP	LEFVP	LEFVP	LEFVP	LEFVP
Ciarity	<6 NTU	< 6 NTU	<6 NTU	<6 NTU	<6 NTU	<6 NTU	<6 NTU
Color	<BYÎ	< BY3	< BY3	< BYS	< BYÎ	< BY3	< BY3
pH	6.0	6.0	6.0	6.0	6.0	6.0	6.0
Total Protein Content by RPUPLC (mg/mL)	95.8	97.2	97.1	96.9	95.1	97.2	96.7
Non-reduced MCE (%)	Purity	95.7	NR	NR	95.5	NR	NR	95.1
LMW	3.9	NR	NR	3.9	NR	NR	4.0
Reduced MCE (%)	Purity	96.0	NR	NR	96.1	NR	NR	95.7
NGHC	3.5	NR	NR	3.4	NR	NR	3.5
LMW	0.0	NR	NR	0.0	NR	NR	0.1
Purity by SEUPLC (%)	Main	98.8	98.8	98.7	98.5	98.6	98.5	98.3
LMW	0.1	0.1	0.2	0.2	0.2	0.2	0.2
HMW	1.1	1.1	1.2	1.3	1.2	1.4	1.5
CEX-UPLC (%)	Région 1	48.2	48.1	48.4	48.0	49.0	49.3	50.1
Région 2	45.2	45.3	44.9	45.6	44.3	43.6	42.8
Région 3	6.6	6.7	6.8	6.4	6.6	7.0	7.1
Relative Potency (%)	Pseu do virus Neutralization Assay	Π0	NR	NR	108	NR	NR	111

CEX, cation exchange; FDS, formulated drug substance; FDG, Formulation Development Group; HDPE, high-density polyethylene; HMW, high molecular weight; LEFVP, liquid essentially free from visible particulates; LMW, low molecular weight; MCE, microchip capillary electropho resis; NGHC, Non-glycosylated Heavy Chain; NR, not required per protocol; OD, optical density; RP, reversed-phase; SE, size-exclusion; UPLC, ultra performance liquid chromatography

147

Table 67: Research Stability of 100 mg/mL H1H17161P C2P1 Formulated Drug Substance - Effects of Stress Conditions

Formulation	100 mg/mL H1H17161P, 10 mM L-histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Conta iner/Closure	5 mL gamma-irradiated polycarbonate vial with HDPE closure
Assay	T = 0	Length of storage at 40 °C/75%RH (days)
7	14	28
Physîcal form / Condition	LEFVP	LEFVP	LEFVP	LEFVP
Clarity	<6 NTU	<6 NTU	<6 NTU	<6 NTU
Color	< BY3	< BY3	<BY3	<BY3
pH	6.0	6.0	6.0	6.0
Total P rote in Content by RPUPLC (mg/mL)	95.8	97.0	96.4	97.4
Non-reduced MCE (%)	Purity	95.7	NR	NR	93.0
LMW	3.9	NR	NR	5.7
Reduced MCE (%)	Purity	96.0	NR	NR	95.0
NGHC	3.5	NR	NR	3.5
LMW	0.0	NR	NR	0.4
Purity by SEUPLC (%)	Main	98.8	98.2	97.9	97.4
LMW	0.1	0.2	0.3	0.5
HMW	l.l	1.5	1.8	2.1
CEX-UPLC (%)	Région 1	48.2	52.1	56.2	62.6
Région 2	45.2	40.5	36.4	30.3
Région 3	6.6	7.4	7.4	7.1
Relative Potency (%)	Pseudovirus Neutralization Assay	110	NR	NR	114

CEX, cation exchange; FDS, formulated drug substance; FDG, Formulation Development Group; HDPE, high-density polyethylene; HMW, high molecular weight; LEFVP, liquid essentially free from visible particulates; LMW, low molecular weight; MCE, microchip capillary electrophoresis; NGHC, Non-glycosylated Heavy Chain; NR, not required per protocol; OD, optical density; RP, reversed-phase; SE, size-exclusion; UPLC, ultra performance liquid chromatography

148

Table 68: Research Stability' of 100 mg/mL H1H17161P C2P1 Formulation Drug Substance - Effect of Agitation, and Freezing and Thawing

Formulation	100 mg/mL ΗΠΠ7161Ρ, 10 mM L-histidine, 10% (w/v) sucrose, 0.1% (w/v) polysorbate 80, pH 6.0
Container/Closure	5 mL gamma-irradiated polycarbonate vial with HDPE closure
Assay	t-0	Agitation (minutes)	Freeze/Thaw (cycles)
60	120	4	8
Physical form / Condition	0	0	0	0	0
Clarity	<6 NTU	SâNTU	<6 NTU	<6 NTU	<6 NTU
Color	<BY3	< BY3	<BY3	< BY3	< BY3
pH	6.0	6.0	6.0	6.0	5.9
Total Protein Content by RPUPLC (mg/mL)	95.8	96.5	94.0	96.2	96.2
Non-reduced MCE (%)	Purity	95.7	NR	95.8	NR	95.7
LMW	3.9	NR	3.8	NR	3.8
Reduced MCE (%)	Purity	96.0	NR	96.2	NR	96.1
NGHC	3.5	NR	3.4	NR	3.4
LMW	0.0	NR	0.0	NR	0.0
Purîty by SEUPLC (%)	Main	98.8	98.8	98.8	98.8	98.8
LMW	0.1	0.2	0.2	0.1	0.1
HMW	1.1	1.1	l.l	1.1	l.l
CEX-UPLC (%)	Région 1	48.2	48.7	48.6	48.6	48.6
Région 2	45.2	44.9	44.9	44.9	44.8
Région 3	6.6	6.5	6.5	6.6	6.6
Relative Potency (%)	Pseudovirus Neutralization Assay	110	NR	114	NR	115

CEX, cation exchange; FDS, formulated drug substance; FDG, Formulation Development Group; HDPE, high-density polyethylene; HMW, high molecular weight; LEFVP, liquid essentially free from visible particulates; LMW, low molecular weight; MCE, microchip capillary electrophoresis; NGHC, Non-glycosylated Heavy Chain; NR, not required per protocol; RP, reversed-phase; SE, size-exclusion; UPLC, ultra performance liquid chromatography

Example 11: Formulated Drug Substance Research Stability Studies for Co-Formulated H1H17203P, H1H17139P, and H1H17161P C2P1 DP

[000249] Research stability studies were perfbrmed to evaluate the long-term storage, accelerated, and stress conditions for the Combination C2PI DP manufactured for research and developmental use. Six months of research stability data are avaîlable at the long-term storage condition of 5 °C, 6 months at the accelerated condition of 25 °C/60% RH, Studies examining the stress conditions of 3 months at 40 °C/75% RH, agitation, and freezing and thawing are complété.

149

[000250] Table 69 describes ail stabilîty studies examining the Combination C2P1 DP. The analysis plan, preliminary acceptance criteria, and sampling plan for the stabilîty sampies are provided in Table 70.

The stabilîty studies will continue for the entire duration of the stabilîty protocol as presented in Table 69. Sampies were analyzed foliowing the analysis plan outlined in Table 70.

Table 69: Summary of Combination Drug Product Stabilîty Studies

Study Type	Concentration (mg/mL)	Container Closure	Storage Conditions	Study Duration	Available Data
Research	100	20 mL USP/EP glass vial with FluroTec-coated butyl stopper and Flip-Off seai	5 °C	84 months	6 months
25 °C/60% RH	12 months	6 months
40 °C/75% RH	3 months	3 months
Agitation	120 minutes	120 minutes
Freezing and Thawing	8 cycles	8 cycles

DP, drug product; USP, United States Pharmacopeia; EP, European Pharmacopoeia; RH, relative humîdity

Table 70: Analysis Plan for Drug Product Research Stabilîty Studies

Assay	Research Sampies to be Analyzed
Physical form / Condition	Ail sampies
Ciarity	AH sampies
Color	Ali sampies
pH	Al! sampies
Total Protein Content (RP-UPLC)	Al) sampies
Purity by Reduced MCE a. % Purity b. % NGFIC c. % LMW	T = 0, 6, 12, 24, 36, 48, 60, 72 and 84 months at 5 °C; 3 and 6 months at 25 °C/60% RH; 1 and 3 months at 40 °C/75% RH Agitation and Freeze/Thaw sampies
Purity by Non-reduced MCE a. % Purity b. % LMW c. % HMW	T = 0, 6, 12, 24, 36, 48, 60, 72 and 84 months at 5 °C; 3 and 6 months at 25 °C/60% RH; 1 and 3 months at 40 °C/75% RH Agitation and Freeze/Thaw sampies
Purity by SE-UPLC a. % Main peak purity b. % LMW c. % HMW	AH sampies

150

Assay	Research Samples to be Analyzed
Charge Variant Analysis by CEX-UPLC a. % Région le b. % Région 2c c, % Région 3c d. %Main Peak H1H17203P e. %Main Peak H1H17139P f. %Maîn Peak H1H17161P	Al! samples
Potency: ADCC Assay	T = 0, 6, 12, 24, 36, 48, 60, 72 and 84 months at 5 °C; 3 and 6 months at 25 °C/60% RH; 1 and 3 months at 40 °C/75% RH Agitation and Freeze/Thaw samples
Potency: Pseudovirus Neutralization Assay	T = 0, 6, 12, 24, 36, 48, 60, 72 and 84 months at 5 °C; 3 and 6 months at 25 °C/60% RH; 1 and 3 months at 40 °C/75% RH Agitation and Freeze/Thaw samples
Particulate Matter (light obscuration)	T = 0, 6, 12, 24, 36, 48, 60, 72 and 84 months at 5 °C; 3 and 6 months at 25 °C/60% RH; 1 and 3 months at 40 °C/75% RH Agitation and Freeze/Thaw samples
Particulate Matter (MFI) 2 pm < x < 10 pm	T = 0, 6, 12, 24, 36, 48, 60, 72 and 84 months at 5 °C; 3 and 6 months at 25 °C/60% RH; 1 and 3 months at 40 °C/75% RH Agitation and Freeze/Thaw samples
Polysorbate 80	T = 0, 6, 12, 24, 36, 48,60, 72 and 84 months at 5 °C; 3 and 6 months at 25 °C/60% RH; 1 and 3 months at 40 °C/75% RH Agitation and Freeze/Thaw samples

A₂èo, absorbance at 280 nm; CEX, cation-exchange chromatography; EU, endotoxin units; HC, heavy chain; HMW, high molecular weight; LC, light chain; LMW, low molecular weight; MCE, microchip capillary electrophoresis; MFI, Micro-Flow Imaging'*’; N/A, Not applicable; NGHC, non-glycosylated heavy chain; Ph. Eur., European Pharmacopeia; RH, relative humidity; SE-UPLC, size-exclusîon ultra high-performance liquid chromatography; USP, United States Pharmacopeia

Long-term Stability Study Results

[000251] In the research long-term stability study, the Combination DP was physically and Chemically stable when stored at 5 °C throughout the assessment period (Table 71), No appréciable change in the physîcal or Chemical stability was detected in any of the monitored attributes after 6 months at 5 °C. The research stability study examining DP under the long-term storage condition will continue through 84 months.

Accelerated Stability Study Results

[000252] Research stability study results from the analysis ofDP under accelerated condition of 25°C /60% RH are provided in Table 72. Throughout the 6 month assessment period, increases of 0.9% in HMW species and 0.3% ίη LMW were observed by SE-UPLC. Réduction of 2.0%, 3.1%, and 5.1% in main peaks corresponding to the H1H17203P, H1H17I39P and H1H17161P, respectively, were observed by CEX-UPLC. The DP maintained potency following incubation at

151

25°C/ 60% RH for 6 months. Sub-visible partîcle level as determined by HIAC was within the acceptance criteria. No meaningful change in other monitored attributes was observed. Research studies examining DP under the accelerated storage condition of 25 °C/60% RH are complété.

Stress Stability Study Results

[000253] Research stability study results from the analysis of DP under stress conditions of 40 °C/75% RH are provided in Table 72. Throughout the 3 month assessment perîod, increases of 3.0% in HMW and 1.3% in LMW were observed by SE-UPLC; réductions in purity of 3.8% or 7.8% and increases in LMW species of 1.8% or 6.4% were observed by reduced or non-reduced MCE, respectively; and réduction of 9.3%, 11.5%, and 11.4% in main peaks corresponding to the H1H17203P, H1H17I39P and H1H17161P, respectively, were observed by CEX-UPLC. The DP maintained potency as determined by the pseudovirus neutralization assay. The DP maintained potency following the incubation at 40°C/75% RH for 28 days but showed reduced potency after incubation for 3 months as determined by the ADCC assay. Sub-visible particle level as determined by HIAC was within the acceptance criteria. No meaningful change in other monitored attributes was observed. Research studies examining DP under the stress storage condition of 40 °C/75% RH are complété.

[000254] Research stability results from the analysis of DP following agitation and freeze/thaw conditions are provided in Table 73. DP was physically and chemically stable when agitated (vortexed at ambient température) for 120 minutes or when subjected to 4 freeze/thaw cycles (freezing at -30 °C and thawing at room température). No meaningful change in the physical or Chemical stability of the DP was observed in any of the monitored attributes. Research studies examining DP under agitation and freeze/thaw conditions are complété.

Stability Conclusions

[000255] The recommended storage for the Combination DP is 2°C to 8 °C. Data from DP stability studies demonstrate that the product will remain stable when stored at 2 °C to 8 °C.

Table 71: Research Stability of H1H17203P- H1H17139P-H1H17161P Co-Formulated Drug Product 100 mg/mL, Stored at 5 °C

152

Formulation	33.3 mg/mL H1H17203P, 33.3 mg/mL H1H17139P, and 33,3 mg/mL H1H17161P recombinant proteins, in an aqueous buffered solution, pH 6.0, containing 10 mM L-histidine, 10% (w/v) sucrose, and 0.1% (w/v) polysorbate 80
Container Closure	20 mL USP/Ph. Eur. Type 1 borosilicate glass vial; 20 mm FluroTec®coated butvl single-vent stopper; 20 mm Fiip-Off ® seal
Storage Condition	5 °C
Assay	Length of Storage (months)
T = 0	1	3	6
Physical form ! Condition	LEFVP	LEFVP	LEFVP	LEFVP
Clarîty	<6 NTU	<6 NTU	<6 NTU	<6 NTU
Coior	<BY4	<BY4	<BY4	<BY4
pH	6.0	6.0	6.0	6.0
Total Protein Content by RP-UPLC (mg/mL)	98.5	98.4	97.3	96.6
Polysorbate 80 (%w/v)	0.09	NR	NR	0.09
% Relative Potency by Bio assay	ADCC	89	NR	NR	95
Pseudovirus Neutralization	105	NR	NR	120
Reduced MCE (%)	Purity	94.4	NR	NR	94.7
NGHC	4.7	NR	NR	4.5
LMW	0.1	NR	NR	0.2
Non-reduced MCE (%)	Purity	95.4	NR	NR	95.6
LMW	4.1	NR	NR	4.0
SE-UPLC (%)	Main	99.1	99.0	98.8	98.8
LMW	0.1	0.1	0.1	0.1
HMW	0.9	0.9	1.2	1.1
Charge Variant Analysis by CEXUPLC (%)	Région IC	10.9	10.8	11.0	11.5
Région 2C	13.3	13.2	13.3	13.5
Région 3C	18.4	18.4	18.0	18.6
H1H17203P Main	19.3	19.4	19.4	19.2
H1H17139P Main	21.1	21.2	21.1	20.9
H1H17161P Main	17.0	16.9	17.2	16.4
Particulate Matter (light obscuration) (particles/container)	> lOgm	39	NR	NR	5
> 25gm	15	NR	NR	0
Particulate Matter (MFI) (partic!es/mL)	2 to 10 gm	195	NR	NR	90

HMW, high molecular weight; LEFVP, liquid essentially free from visible particulates; LMW, low molecular weight; MCE, microchip capillary electrophoresis; MFI, Micro-Flow Imaging™; NGHC, non-glycosylated heavy chain; SE, Size-exclusion; UPLC, Ultra-high pressure liquid chromatography; CEX, Cation exchange chromatography; RP, reversed-phase; ADCC, Antibody-dépendent cellular cytotoxicity; NR, Not required

153

Table 72: Research Stability of H1H17203P-H1H17139P-H1H17161P Co-Formulated Drug

Product 100 mg/mL, Stored at 25 °C/60%RH and 40 °C/75% RH

Formulation 33.3 mg/mL H1H17203P, 33.3 mg/mL H1H17139P, and 33.3 mg/mL H1H17161P recombinant proteins, in an aqueous buffered solution, pH 6.0, containing 10 mM Lhistidine, 10% (w/v) sucrose, and 0.1 % (w/v) polysorbate 80

Container 20 mL USP/Ph. Eur. Type I borosilicate glass vial; 20 mm FluroTec®-coated butyl single

Closure vent stopper; 20 mm Flip-Off ® seal

Assay	T = 0	25 °C/60% RH Storage (months)	40 °C/75% RH Storage (months)
0.5	1	3	6	0.25	0.5	1	3
Physical form / Condition	LEFVP	LEFV P	LEFVP	LEFV P	LEFV P	LEFV P	LEFV P	LEFV P	LEF VP
Clarity	<6 NTU	<6 NTU	<6 NTU	<6 NTU	<6 NTU	< 6 NTU	<6 NTU	<6 NTU	<6 NTU
Color	<BY4	< BY4	<BY4	<BY4	< BY4	BY4	BY4	<BY4	BY4
pH	6.0	6.0	6.0	6.0	6.0	6.0	6.0	6.0	6.0
Total Protein Content by RPUPLC (mg/mL)	98.5	98.7	98.2	96.9	96.1	98.2	98.3	98.8	96.8
Polysorbate 80 (%w/v)	0.09	NR	NR	0.09	0.09	NR	NR	0.09	0.09
% Relative Potency by Bioassay	ADCC	89	NR	NR	93	82	NR	NR	83	45
Pseudovîrus Neutralizatîo n	105	NR	NR	112	124	NR	NR	101	99
Reduced MCE (%)	Purity	94.4	NR	NR	93.2	93.7	NR	NR	93.7	90.6
NGHC	4.7	NR	NR	4.4	4.6	NR	NR	4.6	5.2
LMW	0.1	NR	NR	0.3	0.7	NR	NR	0.5	1.9
Non-reduced MCE (%)	Purity	95.4	NR	NR	94.2	93.4	NR	NR	93.1	87.6
LMW	4.1	NR	NR	4.9	5.5	NR	NR	6.0	10.5
SE-UPLC (%)	Main	99.1	98.9	98.7	98.2	97.8	98.6	98.3	97.7	94.7
LMW	0.1	0.1	0.2	0.3	0.4	0.2	0.3	0.5	1.4
HMW	0.9	1.1	1.2	1.6	1.8	1.3	1.4	1.8	3.9
Charge Variant Analysis by CEX-UPLC (%)	Région IC	10.9	10.8	11.0	12.2	14.1	11.7	12.6	14.7	20.9
Région 2C	13.3	13.3	13.7	15.1	16.8	14.5	15.7	18.1	25.0
Région 3C	18.4	18.6	19.0	19.8	22.0	19.6	20,7	23.1	28.9
H1H17203P Main	19.3	19.5	19.4	18.7	17.3	18.8	18.0	15.9	10.0
HIHÎ7139P Main	21.1	21.2	20.9	19.6	18.0	20.0	19.0	16.5	9.6
H1H17161P Main	17.0	16.5	16.0	14.7	11.9	15.4	14.1	11.7	5.6
	> ΙΟμτη	39	NR	NR	10	10	NR	NR	131	121

154

Formulation	33.3 mg/mL HIH17203P, 33.3 mg/mL H1H17139P, and 33.3 mg/mL H1H17161P recombinant proteins, in an aqueous buffered solution, pH 6.0, containing 10 mM Lhistidine, 10% (w/v) sucrose, and 0.1% (w/v) polysorbate 80
Container Closure	20 mL USP/Ph. Eur. Type 1 borosilicate glass vial; 20 mm FluroTec®-coated butyl singlevent stopper; 20 mm Flip-Off® seal
Assay	T = 0	25 °C/60% RTI Storage (months)	40 °C/75% RH Storage (months)
		0.5	1	3	6	0.25	0.5	1	3
Particulate Matter (light obscuration) (parti cl es /container)	> 25pm	15	NR	NR	0	0	NR	NR	0	5
Particulate Matter (MFI) (parti cles/mL)	2 to 10 pm	195	NR	NR	450	275	NR	NR	637	409

HMW, high molecular weight; LEFVP, lîquid essentially free from visible parti cul aies; LMW, low molecular weight; MCE, microchip capîllary electrophoresis; MF1, Micro-Flow Imaging™; NGHC, non-glycosyiated heavy chain; SE,

Size-exclusion; UPLC, Ultra-high pressure liquid chromatography; CEX, Cation exchange chromatography; ADCC, Antibody-dependent cellular cytotoxicity; NR, Not required

Table 73: Research Stability of H1H17203P-H1H17139P-H1H17161P Co-Formulated Drug Product - Effect of Agitation, and Freezing and Thawing

Formulation	33.3 mg/mL H1H17203P, 33.3 mg/mL HIH17139P, and 33.3 mg/mL H1H17161P recombinant proteins, in an aqueous buffered solution, pH 6.0, containing 10 mM L-histidine, 10% (w/v) sucrose, and 0.1% (w/v) polysorbate 80
Container/Closure	20 mL USP/Ph. Eur. Type 1 borosilicate glass vial; 20 mm FIuroTec®coated butyl single-vent stopper; 20 mm Flip-Off® seal
Assay	T = 0	Agitation (minutes)	Freezing/Thawing (cycles)
60	120	4	8
Physical form / Condition	LEFVP	LEFVP	LEFVP	LEFVP	LEFVP
Clarity	<6 NTU	<6 NTU	<6 NTU	<6 NTU	<6 NTU
Color	<BY4	<BY4	<BY4	<BY4	<BY4
pH	6.0	6.0	6.0	6.0	6.0
Total Protein Content by RP- UPLC (mg/mL)	98.5	98.4	98.6	98.8	97.6
Polysorbate 80 (%w/v)	0.09	NR	0.09	0.09	0.09
% Relative Potency by Bîoassay	ADCC	89	NR	102	85	87
Ps eu do virus Neutralization	105	NR	119	123	119
Reduced MCE (%)	Purity	94.4	NR	94.9	95.0	94.5
NGHC	4.7	NR	4.3	4.2	4.7
LMW	0.1	NR	0.2	0.2	0.1

155

Formulation	33.3 mg/mL HÏH17203P, 33.3 mg/mL II1H17139P, and 33.3 mg/mL H1H17161P recombinant proteins, in an aqueous buffered solution, pH 6.0, containing 10 mM L-histidine, 10% (w/v) sucrose, and 0.1% (w/v) polysorbate 80
Container/CIosure	20 mL USP/Ph. Eur, Type 1 borosilicate glass vial; 20 mm FluroTec®coated butyl single-vent stopper; 20 mm Flip-Off ® seai
Assay	T = 0	Agitation (minutes)	Freezîng/Thawing (cycles)
60	120	4	8
Non-reduced MCE (%)	Purity	95.4	NR	95.4	95.4	95.4
LMW	4.1	NR	4.2	4.2	4.2
Purity by SEUPLC (%)	Main	99. i	99.1	99.1	99.1	99.0
LMW	0.1	0.1	0.1	0.1	0.1
HMW	0.9	0.9	0.9	0.9	0.9
Charge Variant Analysis by CEX-UPLC (%)	Région IC	10.9	10.8	10.9	10.9	10.4
Région 2C	13.3	13.2	13.2	13.3	13.3
Région 3C	18.4	18.4	18.4	18.5	18.4
HIH17203P Main	19.3	19.4	19.4	19.4	19.4
H1H17139P Main	21.1	21.2	21.2	21.2	21.3
H1H17161P Main	17.0	16.9	17.0	16.7	17.2
Particu late Matter (light obscuration) (parti cl es /container)	> 10pm	39	NR	102	39	53
> 25pm	15	NR	5	0	0
Particu late Matter (MFI) (particles/mL)	2 to 10 pm	195	NR	372	534	494

HMW, high molecular weight; LEFVP, liquid essentially free from visible particulates; LMW, low molecular weight; MCE, microchip capîllary electrophoresis; MFI, Micro-Flow Imaging™; NGHC, non-glycosylated heavy chain; SE, Size-exclusion; UPLC, Uitra-high pressure liquid chromatography; CEX, Cation exchange chromatography; ADCC, Antibody-dépendent cellular cytotoxicity; NR, Not required

Antibody Sequences

[000256] Table 74 sets forth the amino acid sequence identifiers of the heavy and light chaîn variable régions and CDRs of selected anti-Ebola virus antibodies. Table 75 provides sequence identifiers for full length heavy and light chain amino acid sequences.

156

Table 74: Amino Acid Sequence Identifiers

	SEQ ID NOs:
Antibody Désignation	HCVR	HCDR1	HCDR2	HCDR3	LCVR	LCDR1	LCDR2	LCDR3
H1H17203P	2	4	6	8	10	12	14	16
H1H17139P	20	22	24	26	28	30	32	34
H1H17161P	38	40	42	44	46	48	50	52

Table 75: Sequence Identifiers for Full Length Heavy and Light Chain Sequences

	SEQ ID NOs:
Antibody Désignation	Full length Heavv Chain	Full length Light Chain
Amino Acid	Amino Acid
H1H17203P	17	18
H1H17139P	35	36
H1H17161P	53	54

[000257] The présent disclosure is not to be iimited in scope by the spécifie embodiments describcd herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope ofthe appended daims.

Claims (46)

1. A stable liquid pharmaceuticaî formulation comprising:

(a) a stabilizer;

(b) a buffer comprising histidine;

(c) an organic cosolvent comprising polysorbate; and (d) at least one antibody which binds specifically to Ebola virus (EBOV) and comprises three heavy chain complementarity determining régions (CDRs) (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDRl, LCDR2 and LCDR3) contained in a heavy chain variable region/light chain variable région (HCVR/LCVR) amino acid sequence pair selected from the group consisting of (i) SEQ ID NOs: 2/10, (ii) SEQ ID NOs: 20/28, and (iii) SEQ ID NOs: 38/46;

wherein the formulation comprises the following: (i), (ii), (iii), (i)+(ii), (i)+(iii), (ΐΐ)+(ϋΐ), or (i)+(ii)+(iii); and wherein the formulation has a pH of 6.0 ± 0.3.

2. The pharmaceuticaî formulation of claim 1, wherein:

(a) the total antibody concentration is from 5 mg/mL ±0.75 mg/mL to 250mg/mL±37.5 mg/mL; optionally wherein:

(i) the total antibody concentration is 25 mg/mL ±3.75 mg/mL; and/or (îi) the total antibody concentration is 50 mg/mL ±7.5 mg/mL; and/or (iii) the total antibody concentration is 100 mg/mL ± 15.0 mg/mL; and/or (îv) the total antibody concentration is 150 mg/mL ±22.5 mg/mL; and/or (b) the histidine buffer concentration is from 5 mM ± 1 mM to 20 mM ± 4 mM; optionally wherein the histidine buffer concentration is 10 mM ± 2 mM; and/or (c) the polysorbate concentration is from 0.01% ± 0.005% to 0.5% ± 0.25% w/v; optionally wherein:

(i) the polysorbate concentration is 0.1% ± 0.05% w/v; and/or (ii) the polysorbate concentration is 0.2% ± 0.1% w/v; and/or

158 (iii) the polysorbate is polysorbate 80; and/or (d) the stabilizer is sucrose and the sucrose concentration is from 0% to 20% ± 4% w/v.; optionally wherein:

(i) the sucrose concentration is from 5% ± 1% to 15% ± 3% w/v; and/or (ii) the sucrose concentration is 10% ± 2% w/v.

3. The pharmaceutical formulation of claim l, comprising:

(a) (i) + (ii); or (b) (i) + (iii); or (c) (ii) + (iii); or (d) (i) + (ii) + (iii); optionally in a ratio of 1:1:1.

4. The pharmaceutical formulation of claim 3 comprising:

(a) from 5% ± 1 % to 15% ± 3% w/v sucrose, (b) from 5 mM ± 1 mM to 20 mM ± 4 mM histidine buffer, (c) from 0.01% ± 0.005% to 0.5% ± 0.25% w/v polysorbate, and

I I

I

I I

I (d) 50 mg/mL ± 7.5 mg/mL total antibody, at pH 6.0 ±0.3.

5. The pharmaceutical formulation of claim 3 comprising:

(a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1 % ± 0.05% w/v polysorbate, and (d) 50 mg/mL ± 7.5 mg/mL total antibody, atpH6.0±0.3.

6. The pharmaceutical formulation of claim 1 comprising:

(a) 10% ± 2% w/v sucrose, (b) ÎOmM ± 2mM histidine buffer,

159 (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ± 7.5 mg/mL total antibody, at pH 6.0 ±0.3;

wherein the antibody comprises three heavy chain CDRs (HCDRI, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pairof (i) SEQ ID NOs: 2/10.

7. The pharmaceutical formulation of claim 1 comprisîng:

(a) 10% ± 2% w/v sucrose, (b) lOmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ±7.5 mg/mL total antibody, atpH6.0±0.3;

wherein the antibody comprises three heavy chain CDRs (HCDRI, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28.

8. The pharmaceutical formulation of claim 1 comprisîng:

(a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ± 7.5 mg/mL total antibody, atpH6.0±0.3;

wherein the antibody comprises three heavy chain CDRs (HCDRI, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46.

9. The pharmaceutical formulation of claim 1 comprisîng:

(a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer.

(c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ± 7.5 mg/mL total antibody, atpH6.0±0.3;

160 wherein a first antibody comprises three heavy chain CDRs (HCDRl, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10, and a second antibody comprises three heavy chain CDRs (HCDRl, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28.

10. The pharmaceutical formulation of claîm 1 comprising:

(a) 10% ± 2% w/v sucrose, (b) lOmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ± 7.5 mg/mL total antibody, at pH 6.0 ± 0.3;

wherein a first antibody comprises three heavy chain CDRs (HCDRl, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10, and a second antibody comprises three heavy chain CDRs (HCDRl, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46.

11. The pharmaceutical formulation of claim 1 comprising:

(a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ±7.5 mg/mL total antibody, atpH6.0±0.3;

wherein a first antibody comprises three heavy chain CDRs (HCDRl, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28, and a second antibody comprises three heavy chain CDRs (HCDRl, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ni) SEQ ID NOs: 38/46,

161

12. The pharmaceutical formulation of claim 1 comprising:

(a) 10% ± 2% w/v sucrose, (b) lOmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 50 mg/mL ± 7.5 mg/mL total antibody, at pH 6.0 ± 0.3;

wherein a first antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10, a second antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28, and a third antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained În the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46.

13. The pharmaceutical formulation of claim 3 comprising:

(a) from 5% ± 1% to 15% ± 3% w/v sucrose, (b) from 5 mM ± 1 mM to 20 mM + 4 mM histidine buffer, (c) from 0.01% ± 0.005% to 0.5% ± 0.25% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total antibody, at pH 6.0 ± 0.3.

14. The pharmaceutical formulation of claim 3 comprising:

(a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total antibody, at pH 6.0 ±0.3.

15. The pharmaceutical formulation of claim 1 comprising:

(a) 10% ± 2% w/v sucrose, (b) lOmM + 2mM histidine buffer,

162 (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total antibody, at pH 6.0 ± 0.3;

wherein the antibody comprises three heavy chain CDRs (HCDRI, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10.

16. The pharmaceutical formulation of claim 1 comprising:

(a) 10% + 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total antibody, at pH 6.0 ± 0.3;

wherein the antibody comprises three heavy chain CDRs (HCDRI, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs; 20/28.

17. The pharmaceutical formulation of claim 1 comprising:

(a) 10% ± 2% w/v sucrose, (b) lOmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total antibody, at pH 6.0 ± 0.3;

wherein the antibody comprises three heavy chain CDRs (HCDRI, HCDR2 and HCDR3) and three light chain CDRs (LCDRI, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46.

18. The pharmaceutical formulation of claim 1 comprising;

(a) 10% ± 2% w/v sucrose, (b) 10mM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total antibody, at pH 6.0 ± 0.3;

163 wherein a First antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10, and a second antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28.

19. The pharmaceutical formulation of claim 1 comprising:

(a) 10% ± 2% w/v sucrose, (b) IOmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total antibody, at pH 6.0 ±0.3;

wherein a first antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10 and a second antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46.

20. The pharmaceutical formulation of claim 1 comprising:

(a) 10% ± 2% w/v sucrose, (b) IOmM ± 2mM histidine buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total antibody, at pH 6.0 ± 0.3;

wherein a first antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28, and a second antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46.

164

21. The pharmaceutical formulation of claim 1 comprising:

(a) 10% ± 2% w/v sucrose, (b) lOmM ± 2mM histidîne buffer, (c) 0.1% ± 0.05% w/v polysorbate, and (d) 100 mg/mL ± 15 mg/mL total antibody, at pH 6.0 ± 0.3;

wherein a first antibody comprises three heavy chain CDRs (HCDRl, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10, a second antibody comprises three heavy chain CDRs (HCDRl, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28, and a third antibody comprises three heavy chain CDRs (HCDRl, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46.

22. The pharmaceutical formulation of any one of daims 1-21, wherein the formulation has viscosity of less than 10 cP.

23. The pharmaceutical formulation of any one of daims 13-21, wherein the formulation has a viscosity of less than 5 cP.

24. The pharmaceutical formulation of any one of daims 4 - 12, wherein the formulation has a viscosity of less than about 2.5.

25. The pharmaceutical formulation of any one of daims 1 - 24, wherein:

(a) at least 90% of the antibody is the native species after 28 days at 45°C; and/or (b) at least 18% of the antibody is the main charge variant of the antibody after 28 days at 45°C; and/or (c) at least 96% of the antibody is the native species after three months at 25°C; and/or (d) at least 30% of the antibody is the main charge variant of the antibody after three months at 25°C; and/or

165 (e) at least 96% of the antibody is the native species after 12 months at 5°C; and/or (f) at least 34% of the antibody is the main charge variant of the antibody after 12 months at 5°C; and/or (g) at least 97% of the antibody is the native species after 120 minutes agitation; and/or (h) at least 35% of the antibody is the main charge variant of the antibody after 120 minutes agitation; and/or (i) at least 97% of the antibody is the native species after 8 freeze thaw cycles; and/or (j) at least 35% of the antibody is the main charge variant of the antibody after 8 freeze thaw cycles.

26. The pharmaceutical formulation of any one of daims 1, 2, and 13-21, wherein:

(a) the formulation maintains ADCC potency of at least about 90%, or at least about 95%, in an ADCC bioassay after storage at 5°C for 6 months, relative to the same formulation prior to storage at 5°C for 6 months; and/or (b) the formulation maintains pseudovirus neutralization activity of at least about 95% after storage at 5°C for 6 months, relative to the same formulation prior to storage at 5°C for 6 months; and/or (c) the formulation maintains ADCC potency of at least about 80%, or at least about 85%, in an ADCC bioassay after storage at 25°C/60% RH for 6 months, relative to the same formulation prior to storage at 25°C/60% RH for 6 months; and/or (d) the formulation maintains pseudovirus neutralization activity of at least about 95% after storage at 25°C/60% RH for 6 months, relative to the same formulation prior to storage at 25°C/60% RH for 6 months; and/or (e) the formulation maintains pseudovirus neutralization activity of at least about 95% after storage at 40°C/75% RH for 6 months, relative to the same formulation prior to storage at 40°C/75% RH for 6 months; and/or

166 (f) the formulation maintains ADCC potency of at Ieast about 95% in an ADCC bioassay after agitation for 120 minutes, relative to the same formulation prior to agitation for 120 minutes; and/or (g) the formulation maintains ADCC potency of at Ieast about 85% in an ADCC bioassay after 8 freeze/thaw cycles, relative to the same formulation prior to 8 freeze/thaw cycles; and/or (h) the formulation maintains pseudovirus neutralization activity of at Ieast about 95% after agitation for 120 minutes, relative to the same formulation prior to agitation for 120 minutes; and/or (i) the formulation maintains pseudovirus neutralization actîvity of at Ieast about 95% after 8 freeze/thaw cycles, relative to the saine formulation prior 8 freeze thaw cycles.

27. The pharmaceutical formulation of any one of daims 1 - 26, wherein an antibody within the formulation has an attribute selected from the group consisting of:

(i) the antibody retains ADCC activity of at Ieast about 90% after storage at -80°C for 12 months relative to the activity of the same antibody prior to storage;

(ii) the antibody retains ADCC activity of at Ieast about 80%, or at ieast about 90%, after storage at -30°C for 12 months relative to the activity of the same antibody prior to storage;

(iii) the antibody retains ADCC activity of at Ieast about 90%, or at Ieast about 95%, after storage at -20°C for 3 months relative to the activity of the same antibody prior to storage;

(iv) the antibody retains ADCC activity of at Ieast about 90%, or at Ieast about 95%, after storage at 5°C for 56 days relative to the activity of the same antibody prior to storage;

(v) the antibody retains ADCC activity of at Ieast about 90%, or at Ieast about 95%, after storage at 25°C/60% relative humidity (RH) for 28 days relative to the activity of the same antibody prior to storage;

(vi) the antibody retains ADCC activity of at Ieast about 90%, or at Ieast about 95%, after storage at 40°C/75%RH for 28 days relative to the activity of the same antibody prior to storage; and (vii) the antibody retains ADCC activity of at ieast about 90%, or at Ieast about 95%, after agitation for 120 minutes, or 8 freeze/thaw cycles, relative to the activity of the same antibody prior to agitation or freeze/thaw, respectively.

28. The pharmaceutical formulation of any one of daims 1 - 27, wherein an antibody within the formulation has an attribute selected from the group consisting of:

(i) the antibody retains pseudovirus neutralization activity of at Ieast about 90%, or at Ieast about 95%, after storage at -80°C for 12 months relative to the activity of the same antibody prior to

167 storage;

(ii) the antibody retains pseudovirus neutralization activity of at least about 90%, or at least about 95%, after storage at -30°C for 12 months relative to the activity of the same antibody prior to storage;

(iii) the antibody retains pseudovirus neutralization activity of at least about 90%, or at least about 95%, after storage at -20°C for 3 months relative to the activity of the same antibody prior to storage;

(iv) the antibody retains pseudovirus neutralization activity of at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, after storage at 5°C for 56 days relative to the activity of the same antibody prior to storage;

(v) the antibody retains pseudovirus neutralization activity of at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, after storage at 25°C/60% relative humidity (RH) for 28 days relative to the activity of the same antibody prior to storage;

(vi) the antibody retains pseudovirus neutralization activity of at least about 80%, orat least about 85%, or at least about 90%, or at least about 95%, after storage at 40°C/75%RH for 28 days relative to the activity of the same antibody prior to storage; and (vîi) the antibody retains pseudovirus neutralization activity of at least about 90%, or at least about 95%, after agitation for 120 minutes, or 8 freeze/thaw cycles, relative to the activity ofthe same antibody prior to agitation or freeze/thaw, respectively.

29. A stable liquid pharmaceutical formulation comprising:

(a) at least one antibody that binds specîfically to EBOV, wherein the at least one antibody comprises a heavy chain variable region/light chain variable région (HCVR/LCVR) amino acid sequence pair selected from the group consisting of (i) SEQ ID NOs: 2/10, (ii) SEQ ID NOs: 20/28, and (iii) SEQ ID NOs: 38/46, and wherein the total antibody comprises 50 mg/mL ± 7.5 mg/mL, (b) 10 mM ± 2 mM histidine buffer, pH 6.0 ± 0.3, (c) 0.1% + 0.05% w/v polysorbate 80, and (d) 10% ± 2% w/v sucrose; wherein:

(i) at least 96% of the antibody is the native species after 12 months at 5°C;

(îî) at least 97% of the antibody is the native species after 120 minutes agitation; or (iii) at least 97% of the antibody is the native species after 8 freeze thaw cycles;

168 optionally wherein the pharmaceuticaî formulation consists of 50 mg/mL ±7.5 mg/mL total antibody, 10 mM ± 2 mM histidine buffer, 0.1% ± 0.05% w/v polysorbate 80, and 10% ± 2% w/v sucrose, in water at pH 6.0 ± 0.3.

30. A stable liquid pharmaceuticaî formulation comprising:

(a) at least two antibodies that bind specifically to EBOV, wherein the at least two antibodies comprise a heavy chain variable region/light chain variable région (HCVR/LCVR) amino acid sequence pair selected from the group consisting of (i) SEQ ID NOs: 2/10, (ii) SEQ ID NOs: 20/28, and (iii) SEQ ID NOs: 38/46, and wherein the total antibody comprises 50 mg/mL ± 7.5 mg/mL, (b) 10 mM ± 2 mM histidine buffer, pH 6.0 ± 0.3, (c) 0.1% ± 0.05% w/v polysorbate 80, and (d) 10% ± 2% w/v sucrose; wherein:

(i) at least 96% of the antibody is the native species after 12 months at 5°C;

(ii) at least 97% of the antibody is the native species after 120 minutes agitation; and (iii) at least 97% of the antibody is the native species after 8 freeze thaw cycles;

optionally wherein the pharmaceuticaî formulation consîsts of 50 mg/mL ±7.5 mg/mL total antibody, 10 mM ± 2 mM histidine buffer, 0.1% ± 0.05% w/v polysorbate 80, and 10% ±2% w/v sucrose, in water at pH 6.0 ± 0.3.

31. A stable liquid pharmaceuticaî formulation comprising:

(a) a combination of three antibodies that bind specifically to EBOV, wherein the three antibodies comprise a heavy chain variable region/light chain variable région (HCVR/LCVR) amino acid sequence pair of (i) SEQ ID NOs: 2/10, (ii) SEQ ID NOs: 20/28, and (iii) SEQ ID NOs: 38/46, respectively, and wherein the total antibody comprises 50 mg/mL ± 7.5 mg/mL, (b) 10 mM ± 2 mM histidine buffer, pH 6.0 ± 0.3, (c) 0.1% ± 0.05% w/v polysorbate 80, and (d) 10% ± 2% w/v sucrose; wherein:

(i) at least 96% of the antibody is the native species after 12 months at 5°C;

(ii) at least 97% ofthe antibody is the native species after 120 minutes agitation; and (iii) at least 97% of the antibody is the native species after 8 freeze thaw cycles;

169 optionally wherein the pharmaceutical formulation consists of 50 mg/mL ±7.5 mg/mL total antibody, 10 mM ± 2 mM histidine buffer, 0.1% ± 0.05% w/v polysorbate 80, and 10% ±2% w/v sucrose, in water at pH 6.0 ± 0.3.

32. A stable liquid pharmaceutical formulation comprising:

(a) at least one antibody that binds specifically to EBOV, wherein the at least one antibody comprises a heavy chain variable region/light chain variable région (HCVR/LCVR) amino acid sequence pair selected from the group consisting of (i) SEQ ID NOs: 2/10, (ii) SEQ ID NOs: 20/28, and (iii) SEQ ID NOs: 38/46, and wherein the total antibody comprises 100 mg/mL ± 15 mg/mL, (b) 10 mM ± 2 mM histidine buffer, pH 6.0 ± 0.3, (c) 0.1% ± 0.05% w/v polysorbate 80, and (d) 10% ± 2% w/v sucrose; wherein:

(î) at least 96% of the antibody is the native species after 12 months at 5°C;

(ii) at least 97% of the antibody is the native species after 120 minutes agitation; and (iii) at least 97% of the antibody is the native species after 8 freeze thaw cycles;

optionally wherein the pharmaceutical formulation consists of 100 mg/mL ± 15 mg/mL total antibody, 10 mM ± 2 mM histidine buffer, 0.1% ± 0.05% w/v polysorbate 80, and 10% ± 2% w/v sucrose, in water at pH 6.0 ± 0.3.

33, A stable liquid pharmaceutical formulation comprising:

(a) at least two antibodies that bind specifically to EBOV, wherein the at least two antibodies comprise a heavy chain variable region/light chain variable région (HCVR/LCVR) amino acid sequence pair selected from the group consisting of (i) SEQ ID NOs: 2/10, (ii) SEQ ID NOs: 20/28, and (iii) SEQ ID NOs: 38/46, and wherein the total antibody comprises 100 mg/mL ± 15 mg/mL, (b) 10 mM ± 2 mM histidine buffer, pEI 6.0 ± 0.3, (c) 0.1% ± 0.05% w/v polysorbate 80, and (d) 10% ± 2% w/v sucrose; wherein;

(i) at least 96% of the antibody is the native species after 12 months at 5°C;

(ii) at least 97% of the antibody is the native species after 120 minutes agitation; and (iii) at least 97% of the antibody is the native species after 8 freeze thaw cycles;

170 optionally wherein the pharmaceutical formulation consists of 100 mg/mL ± 15 mg/mL total antibody, 10 mM ± 2 mM histidine buffer, 0.1% ± 0.05% w/v polysorbate 80, and 10% ± 2% w/v sucrose, in water at pH 6.0 ± 0.3.

34. A stable liquid pharmaceutical formulation comprising:

(a) a combination of three antibodies that bind specifically to EBOV, wherein the three antibodies comprise a heavy chain variable region/light chain variable région (HCVR/LCVR) amino acid sequence pair of (î) SEQ ID NOs: 2/10, (ii) SEQ IDNOs: 20/28, and (iii) SEQ ID NOs: 38/46, respectively, and wherein the total antibody comprises 100 mg/mL ± 15 mg/mL, (b) 10 mM ± 2 mM histidine buffer, pH 6.0 ± 0.3, (c) 0.1% ± 0.05% w/v polysorbate 80, and (d) 10% ± 2% w/v sucrose; wherein:

(i) at least 96% of the antibody is the native species after 12 months at 5°C;

(ii) at least 97% of the antibody is the native species after 120 minutes agitation; and (iii) at least 97% of the antibody is the native species after 8 freeze thaw cycles;

optionally wherein the pharmaceutical formulation consists of 100 mg/mL ± 15 mg/mL total antibody, 10 mM ± 2 mM histidine buffer, 0.1% ± 0.05% w/v polysorbate 80, and 10% ± 2% w/v sucrose, in water at pH 6.0 ± 0.3.

35. The pharmaceutical formulation of either of daims 1 or 2, wherein:

(a) the antibody comprises a HCDR1 of SEQ ID NO: 4, a HCDR2 of SEQ ID NO: 6, a HCDR3 ofSEQIDNO: 8, aLCDRl ofSEQ ID NO: 12, a LCDR2 of SEQ IDNO: 14, and a LCDR3 of SEQ ID NO: 16; and/or (b) the antibody comprises a HCVR ofSEQ ID NO: 2 and a LCVR ofSEQ ID NO: 10.

36. The pharmaceutical formulation of either of daims 1 or 2, wherein:

(a) the antibody comprises a HCVR having 90% sequence identity to SEQ ID NO: 2; and/or (b) the antibody comprises a LCVR having 90% sequence identity to SEQ ID NO: 10; and/or

171 (c) the antibody comprises a HCVR having 90% sequence identity to SEQ ID NO: 2 and a LCVR having 90% sequence identity to SEQ ID NO: 10.

37. The pharmaceutical formulation of either of daims 1 or 2, wherein:

(a) the antibody comprises a heavy chain and light chaîn, wherein the heavy chain comprises an amino acid sequence of SEQ ID NO: 17; and/or (b) the antibody comprises a heavy chain and light chain, wherein the light chain comprises the amino acid sequence of SEQ ID NO: 18; and/or (c) the antibody comprises a heavy chain/light chain comprising amino acid sequences of SEQ IDNOs: 17/18.

38. The pharmaceutical formulation of either of daims 1 or 2, wherein the antibody comprises a HCDRl ofSEQ ID NO: 22, a HCDR2 ofSEQ ID NO: 24, a HCDR3 ofSEQ ID NO: 26, a LCDR1 ofSEQ IDNO: 30, a LCDR2 ofSEQ ID NO: 32, and a LCDR3 ofSEQ ID NO: 34;

optionally wherein the antibody comprises a HCVR of SEQ ID NO: 20 and a LCVR ofSEQ ID NO: 28.

39. The pharmaceutical formulation of either of daims 1 or 2, wherein:

(a) the antibody comprises a HCVR having 90% sequence identity to SEQ ID NO: 20; and/or (b) the antibody comprises a LCVR having 90% sequence identity to SEQ ID NO: 28; and/or (c) the antibody comprises a HCVR having 90% sequence identity to SEQ ID NO: 20 and a LCVR having 90% sequence identity to SEQ ID NO: 28.

40. The pharmaceutical formulation of either of daims i or 2, wherein:

(a) the antibody comprises a heavy chain and light chain, wherein the heavy chain comprises an amino acid sequence of SEQ ID NO: 35; and/or (b) the antibody comprises a heavy chain and light chain, wherein the light chaîn comprises the amino acid sequence of SEQ ID NO: 36; and/or

172 (c) the antibody comprises a heavy chain/light chain comprising amino acid sequences of SEQ ID NOs: 35/36,

41, The pharmaceutical formulation of either of claims 1 or 2, wherein the antibody comprises a HCDR1 ofSEQ ID NO: 40, a HCDR2 ofSEQ IDNO: 42, a HCDR3 ofSEQ ID NO: 44, a LCDRl of SEQ ID NO: 48, a LCDR2 ofSEQ ID NO: 50, and a LCDR3 ofSEQ ID NO: 52;

optionally wherein the antibody comprises a HCVR ofSEQ ID NO: 38 and a LCVR ofSEQ ID NO: 46.

42. The pharmaceutical formulation of either of claims I or 2, wherein:

(a) the antibody comprises a HCVR having 90% sequence identity to SEQ ID NO: 38; and/or (b) the antibody comprises a LCVR having 90% sequence identity to SEQ ID NO: 46; and/or (c) the antibody comprises a HCVR having 90% sequence identity to SEQ ID NO: 38 and a LCVR having 90% sequence identity to SEQ ID NO: 46.

43, The pharmaceutical formulation of either of claims 1 or 2, wherein:

(a) the antibody comprises a heavy chaîn and light chain, wherein the heavy chain comprises an amino acid sequence ofSEQ ID NO: 53; and/or (b) the antibody comprises a heavy chain and light chain, wherein the light chain comprises the amino acid sequence of SEQ ID NO: 54; and/or (c) the antibody comprises a heavy chain/light chain comprising amino acid sequences of SEQ ID NOs: 53/54.

44. A pharmaceutical formulation of any one of claims 1 - 39, wherein said formulation is contained in a container; optionally wherein (a) the container is a vial; and/or (b) the container is a 10 mL Type I clear glass vial; and/or (c) the container is a syringe; and/or

173 (d) the container is a low-tungsten glass syringe; and/or (e) the container is a prefilled syringe; and/or (f) the container is an autoinjector.

45. A kit comprising a pharmaceutical formulation of any one of daims 1 - 43, a container, and instructions; optionally wherein (a) the container is a glass vial; and/or (b) the container is a prefilled syringe; and/or (c) the container is an autoinjector.

46. The pharmaceutical formulation of any one of daims 1 to 43, formulated for intravenous administration, intramuscular administration, subcutaneous administration, intraperitoneal administration, percutaneous administration, mucosal administration, nasal administration, pulmonary administration, or oral administration.