TW202144007A - Use of an anti-pd-1 antibody in the preparation of a medicament for the treatment of acral melanoma - Google Patents

Abstract

The disclosure relates to the use of an anti-PD-1 antibody in the preparation of a medicament for the treatment of acral melanoma. Specifically, it provides an anti-PD-1 antibody and apatinib in the preparation of a medicament for the treatment of acral melanoma This program has a disease control rate of 72.2% for acral melanoma, and an objective disease remission rate of 22.2%. Compared with single-drug PD-1, it significantly improves the objective disease remission rate and improves the safety and effectiveness of patient medication. On the other hand, the disclosure also provides the use of an anti-PD-1 antibody, apatinib and temozolomide in the preparation of a medicine for treating melanoma.

Description

Use of an anti-PD-1 antibody in the preparation of a drug for the treatment of acral melanoma

The present disclosure relates to the use of an anti-PD-1 antibody or an antigen-binding fragment thereof in combination with a VEGFR inhibitor in the preparation of a medicament for treating acral melanoma.

Early clinical trials have shown that specific binding to anti-programmed death receptors (anti-PD-1), such as nivolumab and pembrolizumab, can significantly improve outcomes in patients with advanced melanoma ( N Engl J Med 2015;372:320-30 and N Engl J Med 2015;372:2521-32). However, most of these studies are mainly based on the efficacy data of anti-PD-1 drugs in the Caucasian population. different.

ANShoushtari et al. ( Cancer. 2016, 122(21): 3354. doi: 10.1002/cncr. 30259) investigated the efficacy of the anti-PD-1 antibody pembrolizumab in acral and mucosal melanoma, and they found that the acral melanoma group The ORR was 32% in the mucosal melanoma group and 23% in the mucosal melanoma group, a result comparable to earlier clinical data.

T. Maeda et al. ( Br J Dermatol . 2018 Nov 17. doi: 10.1111/bjd.17434) reported that nivolumab in different clinical subtypes of melanoma (eg acral melanoma, mucosal melanoma and cutaneous melanoma) According to the clinical study data of Asian patients, among 68 patients, the ORR was 29.4%, of which 2 patients had completed responses, 18 patients had partial responses, 11 patients had stable disease, and 37 patients had progressive disease. Among the subtypes, the ORR in the cutaneous melanoma group was 42.9%, the ORR in the mucosal melanoma group was 20.7%, and the ORR in the acral melanoma group was 18.8%. The ORR was 41.7%, compared with 17.6% in the mucosal melanoma group and 7.7% in the acral melanoma group. The acral melanoma group exhibited a poor ORR (7.7% vs 17.6% vs 41.7%) regardless of subdivision metastatic. Therefore, there are still many uncertainties in the use of PD-1 antibody monotherapy for the treatment of acral melanoma.

Combining more than one anti-tumor drug with different but related targets can give full play to the advantages of each component, which can not only improve the anti-tumor activity of a single drug but also reduce the drug toxicity. It is a generally accepted anti-tumor therapy.

Apatinib is the world's first oral anti-angiogenic drug for advanced gastric cancer, which is highly selective for VEGFR-2 and potently anti-angiogenic. In a multicenter, randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with metastatic gastric/gastroesophageal junction cancer after second-line treatment, the results showed that apatinib monotherapy compared with placebo It can prolong the median overall survival by 1.8 months and the median progression-free survival by 0.8 months, and the adverse events are controllable. The structural formula of apatinib is shown in formula (I).

At present, a number of PD-1 antibodies and VEGFR inhibitors (such as sunitinib, sorafenib, etc.) are in clinical phase II/III, and the indications are malignant liver cancer (sorafenib and PD-1 antibodies). combination) and metastatic renal cell carcinoma (sunitinib combined with PD-1 antibody), preliminary results show that both The effect of drug combination is better than that of single drug, but the combination of PD-1 antibody and VEGF inhibitor has many uncertainties, which is worthy of further study. Report. On the other hand, it is uncertain whether the combination of PD-1 antibody, VEGF inhibitor and alkylating agent such as temozolomide can achieve better efficacy, and it is worthy of further study.

The disclosure provides the use of an anti-PD-1 antibody and a VEGFR inhibitor in combination in the preparation of a medicament for the treatment of acral melanoma (melanoma).

PD-1 antibodies are known, and in some alternative embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is selected from the group consisting of: AMP-224, GLS-010, IBI-308, REGN-2810, PDR-001 , BGB-A317, Pidilizumab, PF-06801591, Genolimzumab, CA-170, MEDI-0680, JS-001, TSR-042, Cemiplimab ), Camrelizumab, Pembrolizumab, Toripalimab, Sintilimab, Tislelizumab, LZM-009, AK-103 and Nivolumab.

In some embodiments, the light chain variable region of the PD-1 antibody comprises LCDR1, LCDR2 and LCDR3 as set forth in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, respectively.

The heavy chain variable region of the PD-1 antibody comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively.

In some embodiments, the CDR sequences in the light/heavy chain of the PD-1 antibody or antigen-binding fragment are shown in the following table:

In alternative embodiments, the PD-1 antibody is a humanized antibody.

In some alternative embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments.

Immunoglobulins can be derived from any commonly known isotype, including but not limited to IgA, secretory IgA, IgG, and IgM. IgG subclasses are also well known to those of skill in the art and include, but are not limited to, IgGl, IgG2, IgG3, and IgG4. "Isotype" refers to the class or subclass of Ab encoded by the heavy chain constant region gene (eg, IgM or IgGl). In some alternative embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof in the present application comprises a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 isotype, preferably a heavy chain of IgG1 or IgG4 isotype chain constant region.

In other alternative embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a kappa or lambda light chain constant region.

In some embodiments, the PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region as set forth in SEQ ID NO: 10 or a variant thereof, preferably the variant as set forth in SEQ ID NO: 10 There are 0-10 amino acid changes in the light chain variable region sequence, more preferably A43S amino acid changes; and the heavy chain variable region as shown in SEQ ID NO: 9 or a variant thereof, the variant is more Preferably, there are 0-10 amino acid changes in the heavy chain variable region sequence shown in SEQ ID NO: 9, more preferably G44R amino acid changes.

The variable region sequences of the heavy and light chains of the aforementioned PD-1 antibody or its antigen-binding fragment are as follows:

heavy chain variable region

SEQ ID NO: 9

light chain variable region DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIK

SEQ ID NO: 10

In an alternative embodiment, the humanized antibody light chain sequence is the sequence shown in SEQ ID NO: 8 or a variant thereof; the variant preferably has 0-10 amino acids in the light chain variable region change; more preferably amino acid change of A43S. The heavy chain sequence of the humanized antibody is the sequence shown in SEQ ID NO: 7 or a variant thereof; the variant preferably has 0-10 amino acid changes in the variable region of the heavy chain; more preferably G44R Amino acid changes.

In some embodiments, the light chain sequence of the humanized antibody is the sequence set forth in SEQ ID NO:8 and the heavy chain sequence is the sequence set forth in SEQ ID NO:7.

The sequences of the humanized antibody heavy and light chains are as follows:

heavy chain

SEQ ID NO: 7

light chain

SEQ ID NO: 8

On the other hand, PD-1 (programmed death 1), the programmed death receptor 1, is an important immunosuppressive molecule. When the switch of PD-1 is turned on, it initiates a series of responses that inhibit T cell activity. Tumor cells use PD-L1 to combine with PD-1 of T cells, "trick" T cells, evade the recognition of T cells, and continue to run rampant in the body. The PD-L1/PD-1 antibody can help T cells uncover the hypocrisy of tumor cells and restore their recognition and killing of tumor cells. In some alternative combination embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is cemiplimab. In some alternative combination embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is Toripalimab. In some alternative combination embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is sintilimab. In some optional combination embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is Tislelizumab.

In another aspect, in some embodiments, wherein the VEGFR inhibitor is a VEGFR-2 inhibitor.

In some embodiments, wherein the VEGFR inhibitor is selected from apatinib, anlotinib, tavitinib, famitinib, sorafenib or a pharmaceutically acceptable salt thereof, preferably apatinib or a pharmaceutically acceptable salt thereof.

The pharmaceutically acceptable salt of the present disclosure is selected from the group consisting of mesylate, maleate, tartrate, succinate, acetate, difluoroacetate, fumarate, citrate, citrate, benzene Sulfonate, benzoate, naphthalene sulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate, and phosphate. In some embodiments, the pharmaceutically acceptable salt of apatinib is selected from mesylate. In some embodiments, the pharmaceutically acceptable salt of anlotinib is selected from hydrochloric acid. The combined anti-PD-1 antibody and VEGFR inhibitor described in the present disclosure have synergistic pharmacodynamic effects.

Further, the patients described in this disclosure are selected from recurrent, unresectable or metastatic.

In some embodiments, the recurrence is postoperative recurrence.

In alternative embodiments, the patient is selected from postoperative recurrence

In an alternative embodiment, the patient is selected from inoperable.

On the other hand, the aforementioned anti-PD-1 antibody and VEGFR inhibitor regimen further includes an alkylating agent.

In some embodiments, the use further comprises temozolomide or a pharmaceutically acceptable salt thereof.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered in a dose (by patient weight) in a human subject selected from the group consisting of 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4mg/kg, 0.5mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1.0mg/kg, 1.2mg/kg, 1.4mg/kg, 1.6mg/kg, 1.8mg/kg, 2.0mg/kg, 2.2mg/kg, 2.4mg/kg, 2.6mg/kg, 2.8mg/kg, 3.0mg/kg, 3.2mg/kg, 3.4mg/kg, 3.6mg/kg, 3.8mg/kg, 4.0mg/kg, 4.2mg/kg, 4.4mg/kg, 4.6mg/kg, 4.8mg/kg, 5.0mg/kg, 5.2mg/kg, 5.4mg/kg, 5.6mg/kg, 5.8mg/kg, 6.0mg/kg, 6.2mg/kg, 6.4mg/kg, 6.6mg/kg, 6.8mg/kg, 7.0mg/kg, 7.2mg/kg, 7.4mg/kg, 7.6mg/kg, 7.8mg/kg, 8.0mg/kg, 8.2mg/kg, 8.4mg/kg, 8.6mg/kg, 8.8mg/kg, 9.0mg/kg, 9.2mg/kg, 9.4mg/kg, 9.6mg/kg, 9.8mg/kg, 10.0mg/kg or any value between any two values, preferably 3mg/kg.

In another embodiment, the dose of the PD-1 antibody or its antigen-binding fragment in a human subject is 1-600 mg, preferably 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, 2.0 mg mg, 2.2mg, 2.4mg, 2.6mg, 2.8mg, 3.0mg, 3.2mg, 3.4mg, 3.6mg, 3.8mg, 4.0mg, 4.2mg, 4.4mg, 4.6mg, 4.8mg, 5.0mg, 5.2mg, 5.4mg, 5.6mg, 5.8mg, 6.0mg, 6.2mg, 6.4mg, 6.6mg, 6.8mg, 7.0mg, 7.2mg, 7.4mg, 7.6mg, 7.8mg, 8.0mg, 8.2mg, 8.4mg, 8.6mg , 8.8mg, 9.0mg, 9.2mg, 9.4mg, 9.6mg, 9.8mg, 10.0mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg 365mg, 370mg, 375mg, 380mg, 385mg, 390mg, 395mg, 400mg, 405mg, 410mg, 415mg, 420mg, 425mg, 430mg, 435mg, 440mg, 445mg, 450mg, 455mg, 460mg, 465mg, 470mg, 475mg, 480mg, 485mg 490mg, 495mg, 500mg, 505mg, 510mg, 515mg, 520mg, 525mg, 530mg, 535mg, 540mg, 545mg, 550mg, 555mg, 560mg, 565mg, 570mg, 575mg, 580mg, 585mg, 590mg, 595mg, 600mg or any two values in between Any value, preferably 200 mg.

The administration frequency of the anti-PD-1 antibody or its antigen-binding fragment described in the present disclosure is once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, and once every three days. Once a week, every four weeks, or once a month.

In some embodiments, the administration dose of the anti-PD-1 antibody or antigen-binding fragment thereof of the present disclosure in a human subject is 50-600 mg/2-3 weeks, more preferably 200 mg/2-3 weeks .

In other embodiments, the administration dose of the VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof in a human subject is selected from 0.1-500 mg, and can be 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg , 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 12.5mg, 15mg, 17.5mg, 20mg, 22.5mg, 25mg, 30mg, 45mg, 50mg, 60mg, 70mg, 75mg, 80mg, 90mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 375mg, 400mg, 500mg, more preferably 0.25mg, 0.5mg, 1mg, 2mg, 3mg, 4mg, 10mg, 15mg, 20mg, 30mg, 45mg, 50mg, 60mg, 75mg, 100mg, 125mg, 150mg, 175mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg or any value in between , preferably 250mg or 375mg.

For the purposes described in the present disclosure, the administration frequency of the VEGFR inhibitor such as apatinib is once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, and once a week. Three days, once a day, four days a week, once a day, five days a week, once a day.

In some embodiments, the PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose selected from 60 to 600 mg, intravenous infusion, once every to three weeks; a VEGFR inhibitor such as apatibate mesylate The doses of nisin administered in human subjects are selected from 250 mg to 500 mg, orally, once every to two days.

In some embodiments, the PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose selected from 1-5 mg/kg, intravenous infusion, once every to three weeks; a VEGFR inhibitor such as Patinib is administered in a human subject at a dose selected from 250 mg to 500 mg orally once every to two days.

In some embodiments, the PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose selected from 200 mg, intravenous infusion, once every two weeks; a VEGFR inhibitor such as apatinib mesylate in humans The administered dose in the subject is selected from 250 mg orally once daily.

In some embodiments, the PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose selected from 3 mg/kg, intravenous infusion, once every two weeks; a VEGFR inhibitor such as apatinib mesylate The dose administered in human subjects is selected from 250 mg orally once daily.

In some embodiments, the PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose selected from 200 mg, intravenous infusion, once every two weeks; a VEGFR inhibitor such as apatinib mesylate in humans The administered dose in the subject is selected from 375 mg orally once daily.

Further, the VEGFR inhibitor described in the present disclosure is administered after meals, for example, within 30 minutes after meals.

On the other hand, in another optional embodiment, the administered dose of the alkylating agent such as temozolomide in a human subject (administered by body surface area) is selected from 50 mg/m ² to 300 mg/m ² , including 50 mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg or Any value between any two values, preferably 150 mg/m ² or 200 mg/m ² .

The alkylating agent of the present disclosure, such as temozolomide, is administered at a frequency of once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, and once every four weeks or once a month.

In some embodiments, such as for the alkylating agent temozolomide administered at a dose in a human subject selected from 150mg / m ² or 200mg / m ^2, orally, once daily.

In some embodiments, the alkylating agent such as temozolomide is administered in a human subject at a dose selected from 150 mg/m ² or 200 mg/m ² orally once daily for 5 days.

In some embodiments, the alkylating agent such as temozolomide is administered in a human subject at a dose selected from 150 mg/m ² or 200 mg/m ² orally once daily for 5 days followed by 23 days off.

In other embodiments, wherein the PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose selected from 60 to 600 mg, intravenous infusion, once every to three weeks; a VEGFR inhibitor such as Pa erlotinib in human subjects administered dose is selected from 250mg to 500mg, orally, once every one to two days; the alkylating agent temozolomide is administered as a dose in a human subject selected from 150mg / m ² or 200mg/m ² , orally, once a day.

In other embodiments, wherein the PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose selected from 200 mg, intravenous infusion, once every two weeks; a VEGFR inhibitor such as apatinib mesylate administered dose in human subjects selected 250mg, orally, once daily; as for the alkylating agent temozolomide administered at a dose in a human subject selected from 200mg / m ^2, administered orally, once a day 5 sky.

Another aspect of the present disclosure also provides the use of an anti-PD-1 antibody, a VEGFR inhibitor combined with temozolomide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating melanoma.

In some embodiments, wherein the PD-1 antibody or antigen-binding fragment thereof is administered in a dose of 60 to 600 mg in a human subject; VEGFR inhibitor such as apatinib mesylate in a human subject The administered dose is selected from 0.1 mg to 500 mg; the administered dose of the alkylating agent such as temozolomide in a human subject is selected from 50 mg/m ² to 200 mg/m ² .

In other embodiments, wherein the PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose selected from 60 to 600 mg, intravenous infusion, once every to three weeks; a VEGFR inhibitor such as Pa erlotinib in human subjects administered dose is selected from 0.1 to 500mg, orally, once every one to two days; administered as the alkylating agent temozolomide in human subjects selected dose 50mg / m ² to 200mg/m ² , orally, once a day.

In other embodiments, wherein the PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dose selected from 200 mg, intravenous infusion, once every two weeks; a VEGFR inhibitor such as apatinib mesylate administered dose in human subjects selected 250mg, orally, once daily; as for the alkylating agent temozolomide administered at a dose in a human subject selected from 200mg / m ^2, administered orally, once a day 5 sky.

The present disclosure also provides the use of an anti-PD-1 antibody in combination with a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of mucosal melanoma (mucosal melanoma), further comprising an alkyl group The alkylating agent is preferably temozolomide or a pharmaceutically acceptable salt thereof.

The present disclosure provides the above-mentioned anti-PD-1 antibody in combination with a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof as a treatment for preparing a drug for the treatment of acral melanoma, further comprising an alkylating agent, and the alkylating agent is preferably Temozolomide or a pharmaceutically acceptable salt thereof.

The present disclosure also provides an anti-PD-1 antibody for the treatment of melanoma, such as acral melanoma, wherein the anti-PD-1 antibody is administered in combination with a VEGFR inhibitor. In some embodiments, an alkylating agent is also included, preferably temozolomide or a pharmaceutically acceptable salt thereof.

In addition, the present disclosure also provides a VEGFR inhibitor for the treatment of melanoma (eg, acral melanoma), wherein the VEGFR inhibitor is administered in combination with an anti-PD-1 antibody. In some embodiments, an alkylating agent is also included, preferably temozolomide or a pharmaceutically acceptable salt thereof.

The present disclosure also provides an alkylation inhibitor such as temozolomide or a pharmaceutically acceptable salt thereof for treating melanoma (eg, acral melanoma), wherein the alkylation inhibitor is combined with an anti-PD-1 antibody and a VEGFR inhibitor apply. The present disclosure provides the above-mentioned anti-PD-1 antibody in combination with a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof as a drug for reducing adverse drug reactions. In some embodiments, the adverse drug reaction is selected from an anti-PD-1 antibody or a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof.

In another aspect, the present disclosure provides the above-mentioned anti-PD-1 antibody, VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof in combination with temozolomide or a pharmaceutically acceptable salt thereof as a drug for reducing adverse drug reactions. In some embodiments, the adverse drug reaction is selected from an anti-PD-1 antibody or a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof, or temozolomide or a pharmaceutically acceptable salt thereof.

The present disclosure provides the above-mentioned anti-PD-1 antibody in combination with a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof as a dose reduction for the single administration of the anti-PD-1 antibody and/or a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof The salt is administered alone in doses of the drug.

The present disclosure provides a method for treating acral melanoma, comprising administering to a patient an effective amount of the above anti-PD-1 antibody and a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof, and further administering to the patient an effective amount of an anti-PD-1 antibody and a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof Alkylating agents such as temozolomide or a pharmaceutically acceptable salt thereof.

The present disclosure also provides a combination for the treatment of acral melanoma. In some embodiments, the combination comprises an anti-PD-1 antibody and a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof. In other embodiments, the aforementioned combinations further comprise an alkylating agent such as temozolomide or a pharmaceutically acceptable salt thereof.

In another aspect, the present disclosure also provides an anti-PD-1 antibody, a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof, and an alkylating agent such as temozolomide or a pharmaceutically acceptable salt thereof for the treatment of melanoma A combination of salt. The combination contains an effective dose of an anti-PD-1 antibody, a VEGFR inhibitor or an alkylating agent. In some embodiments, the melanoma comprises mucosal melanoma or acral melanoma.

The present disclosure also provides a method for reducing the dose of an anti-PD-1 antibody administered alone and/or a dose of a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof alone, comprising administering the above-mentioned anti-PD-1 antibody in combination with VEGFR to a patient Inhibitors such as apatinib or a pharmaceutically acceptable salt thereof, are further administered to the patient an effective dose of an alkylating agent, preferably temozolomide or a pharmaceutically acceptable salt thereof.

In some embodiments, when used in combination with PD-1, the dose of the VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof is 10%-100% of the dose administered alone, preferably 10%-100% 75%, better 75%, 50%, 25%, 12.5%. In some embodiments, when used in combination with PD-1, the alkylating agent such as temozolomide or a pharmaceutically acceptable salt thereof is administered at a dose of 10% to 100%, preferably 10% to 75% of the dose administered alone , better 75%, 50%, 25%, 12.5%.

In some embodiments, when used in combination with a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof, the dose of anti-PD-1 antibody is 10% to 100% of the dose of anti-PD-1 antibody administered alone, preferably 10% %~50%. In some embodiments, when used in combination with a VEGFR inhibitor, the alkylating agent such as temozolomide or a pharmaceutically acceptable salt thereof is administered at a dose of 10% to 100%, preferably 10% to 75% of the dose administered alone , better 75%, 50%, 25%, 12.5%.

In an embodiment of the present disclosure, when the PD-1 antibody is used in combination with a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof or/and an alkylating agent such as temozolomide or a pharmaceutically acceptable salt thereof, the reduction of the anti-PD-1 antibody PD-1 antibody and/or immune-mediated adverse drug reactions; preferably, the adverse reactions are selected from vascular-related adverse reactions, hypogonadism, skin adverse reactions, respiratory system adverse reactions, liver-related adverse reactions, and endocrine-related adverse reactions Adverse reactions, digestive system adverse reactions, kidney-related adverse reactions, fatigue, fever; the preferred vascular-related adverse reactions are selected from hemangioma, vasculitis, lymphangioma, and the hypothyroidism is selected from hypothyroidism, parathyroidism Adrenal insufficiency, pancreatic insufficiency, and prostate insufficiency; the skin adverse reactions are selected from pruritus, urticaria, rash, and toxic epidermal necrosis; the respiratory system adverse reactions are selected from pneumonia, bronchitis, chronic obstructive pulmonary disease, and pulmonary fibrosis The liver-related adverse reactions are selected from hepatitis and abnormal liver function; the endocrine-related adverse reactions are selected from type I diabetes, type II diabetes, and hypoglycemia; the kidney-related adverse reactions are selected from nephritis and renal failure; the digestive system adverse reactions Selected from diarrhea, nausea, vomiting, enteritis, constipation; more preferably, the adverse drug reaction is selected from hemangioma, hypothyroidism, hypoparathyroidism, pruritus, pneumonia, hepatitis, abnormal liver function, type I diabetes , nephritis, renal failure.

The present disclosure also provides a pharmaceutical combination comprising a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof, and an anti-PD-1 antibody or an antigen-binding fragment thereof, further comprising an alkylating agent, the alkylating agent is selected from temozolomide or a pharmaceutically acceptable salt thereof.

In the disclosed embodiment, the PD-1 antibody is administered by injection, such as subcutaneous or intravenous injection, and the PD-1 antibody needs to be formulated into an injectable form before injection. A particularly preferred injectable form of the PD-1 antibody is an injectable solution or a lyophilized powder, which contains the PD-1 antibody, a buffer, a stabilizer, and optionally a surfactant. The buffer can be selected from one or more of acetate, citrate, succinate, and phosphate. Stabilizers may be selected from sugars or amino acids, preferably disaccharides such as sucrose, lactose, trehalose, maltose. Surfactant is selected from polyoxyethylene hydrogenated castor oil, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, preferably the polyoxyethylene sorbitan fatty acid ester is polysorbate 20, 40, 60 or 80, the best polysorbate 20. The most preferred injectable forms of PD-1 antibody comprise PD-1 antibody, acetate buffer, trehalose and polysorbate 20.

The combination scheme of the present disclosure optionally further includes other components, including but not limited to other anti-tumor drugs and the like.

Unless explained to the contrary, the terms in this disclosure have the following meanings:

In the present disclosure, "combination" is a mode of administration, which refers to the administration of at least one dose of a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof and at least one dose of PD-1 antibody or its antigen within a certain period of time Binding fragments in which both substances exhibit pharmacological effects. The time period can be within one dosing cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours. The VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof and the PD-1 antibody or antigen-binding fragment thereof can be administered simultaneously or sequentially. This term includes treatment in which a VEGFR inhibitor such as apatinib or a pharmaceutically acceptable salt thereof and a PD-1 antibody or antigen-binding fragment thereof are administered by the same route of administration or by different routes of administration. The modes of administration of the combinations described herein are selected from simultaneous administration, separate formulation and co-administration, or separate formulation and sequential administration. In other embodiments, "combination" of the present disclosure refers to the administration of three different drugs, such as a VEGFR inhibitor, a PD-1 antibody, and an alkylating agent, such as temozolomide, for a period of time as described above.

An "effective amount" or "effective dose" as used in this disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

The term "humanized antibody", also known as CDR-grafted antibody, refers to the grafting of mouse CDR sequences into a human antibody variable region framework, ie a different type of human germline Antibody produced in antibody framework sequences. can overcome chimeric antibodies due to carrying A large number of mouse protein components, thereby inducing strong antibody-variable antibody responses. Such framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences. For example, the germline DNA sequences of human heavy and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the Internet at www.mrccpe.com.ac.uk/vbase), and in Kabat, EA, et al. Human, 1991 Sequences of Proteins of Immunological Interest, 5th ed. In a preferred embodiment of the present application, the CDR sequences of the PD-1 humanized antibody are selected from SEQ ID NOs: 1, 2, 3, 4, 5, and 6.

The term "antigen-binding fragment" refers to Fab fragments, Fab' fragments, F(ab')2 fragments with antigen-binding activity, and Fv fragments sFv fragments that bind to human PD-1; comprising the antibody of the present application selected from the group consisting of SEQ One or more CDR regions of ID NO:1 to SEQ ID NO:6. Fv fragments contain antibody heavy and light chain variable regions, but no constant regions, and are the smallest antibody fragments with all antigen-binding sites. Typically, Fv antibodies also contain a polypeptide linker between the VH and VL domains and are capable of forming the structure required for antigen binding. Different linkers can also be used to link the two antibody variable regions into a single polypeptide chain, called a single chain antibody or single chain Fv (sFv). The term "binding to PD-1" in the present application refers to the ability to interact with human PD-1. The term "antigen-binding site" in the present application refers to a discrete three-dimensional space site on an antigen that is recognized by the antibody or antigen-binding fragment of the present application.

Progression-Free Survival (PFS): Time from randomization to the date of first recording of objective tumor progression or to death from any cause, whichever occurs first.

Overall survival (OS) refers to the period from randomization to death from any cause. For subjects who were still alive at the last follow-up, their OS was censored at the time of the last follow-up. For subjects lost to follow-up, their OS was censored by the last confirmed survival time before the loss to follow-up. Data-censored OS was defined as the time from randomization to censoring.

Objective response rate (ORR) refers to the proportion of patients whose tumor shrinkage reaches a certain level and maintains it for a certain period of time, including cases of CR and PR. Objective tumor response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST 1.1 criteria). Subjects must have measurable According to the RECIST 1.1 criteria, the efficacy evaluation criteria are divided into complete remission (CR), partial remission (PR), stable (SD), and progressive (PD).

8週)病例數在可評價療效患者中的百分比。 Disease Control Rate (DCR) refers to confirmed complete remission, partial remission and stable disease (

8 weeks) number of cases in percent of patients evaluable for efficacy.

Complete remission (CR): All target lesions disappeared, and the short diameter of all pathological lymph nodes (including target and non-target nodules) must be reduced to <10mm.

Partial remission (PR): At least 30% reduction in the sum of target lesion diameters from baseline.

Disease progression (PD): At least 20% relative increase in diameter and relative increase in diameter and relative increase of at least 20% with reference to the minimum value of the sum of all measured target lesion diameters during the entire experimental study (reference to baseline value if the baseline measurement value is the smallest); otherwise In addition, the absolute value of the sum of the diameters must increase by at least 5 mm (the appearance of one or more new lesions is also considered as disease progression).

Stable disease (SD): The degree of reduction of target lesions does not reach the PR level, and the degree of increase does not reach the level of PD. Between the two, the minimum sum of diameters can be used as a reference in the study.

The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

Example 1: Study of anti-PD-1 antibody combined with apatinib mesylate in the treatment of acral melanoma

Compound A: PD-1 antibody was prepared according to the method in patent application WO2017054646A, and the sequences of its heavy and light chains were as shown in SEQ ID NO: 7 and SEQ ID NO: 8 in the present disclosure. 200 mg/bottle, 20 mg/ml for use.

Compound B: apatinib mesylate, which can be prepared according to the method in patent application WO2010031266A1.

Inclusion criteria: (1) Patients with recurrent, unresectable or metastatic acral melanoma confirmed by histopathology after surgery; (2) 3. Have not received any systemic antitumor drug treatment before

Method of administration:

PD-1 antibody: fixed dose of 200 mg, intravenous infusion (no preventive medication required), or 3 mg/kg for subjects with baseline body weight < 50 kg, once every 2 weeks for a 4-week cycle;

Apatinib: 250 mg/tablet, orally, once a day, one tablet at a time, after meals.

in conclusion:

A total of 20 subjects were enrolled. Of the 18 evaluable subjects, 4 patients had a reduction in the sum of the target lesion diameters by at least 30% from the baseline level, 9 subjects had stable disease (SD), and 5 patients had stable disease (SD). It is manifested as disease progression, the overall disease control rate is 72.2%, and the disease remission rate is 22.2%, while the single-agent PD-1 disease remission rate is 15%, which significantly improves the safety and efficacy of patients' medication.

Example 2: Anti-PD-1 antibody combined with apatinib mesylate in the treatment of acral melanoma

Compound A: PD-1 antibody was prepared according to the method in patent application WO2017054646A, and the sequences of its heavy and light chains were as shown in SEQ ID NO: 7 and SEQ ID NO: 8 in the present disclosure. 200 mg/bottle, 20 mg/ml for use.

Compound B: apatinib mesylate, which can be prepared according to the method in patent application WO2010031266A1.

Compound C: temozolomide, temozolomide for injection (powder injection, Shanghai Hengrui) or temozolomide capsule (Merck & Co.).

Inclusion criteria: (1) Patients with recurrent, unresectable or metastatic melanoma (including acral ones) confirmed by histopathology after surgery; (2) 3. Have not received any systemic antitumor drug treatment before.

Method of administration:

PD-1 antibody: fixed dose of 200 mg, intravenous infusion (no preventive medication required), or 3 mg/kg for subjects with baseline body weight < 50 kg, once every 2 weeks for a 4-week cycle;

Apatinib: 250 mg/tablet, orally, once a day, one tablet at a time, after meals, every 28 days as a cycle;

Temozolomide: 200 mg/m ² , orally or intravenously, once a day, for 5 consecutive days, with a cycle every 28 days.

in conclusion:

Among the 23 evaluable subjects, 1 patient disappeared all target lesions, no new lesions appeared, and the tumor markers were normal (CR), and the sum of the target lesion diameters in 11 patients decreased by at least 30% compared with the baseline level (PR), Ten patients showed stable disease (SD), 1 patient was discharged from the group, the disease control rate was 96.65% (22 cases), and the objective response rate was 52.17% (12 cases). Compared with other treatment modalities, such as two-drug (ORR22.2%, DCR72.2%) or single-drug PD-1 (15%), it has obvious advantages.

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Claims (20)

Use of an anti-PD-1 antibody in combination with a VEGFR inhibitor in the preparation of a medicament for treating acral melanoma. The use according to claim 1, wherein the VEGFR inhibitor is selected from apatinib, anlotinib, tafitinib, famitinib, sorafenib or a pharmaceutically acceptable salt thereof, preferably a Patinib or a pharmaceutically acceptable salt thereof. The use according to claim 1 or 2, wherein the PD-1 antibody or its antigen-binding fragment is selected from the group consisting of: AMP-224, GLS-010, IBI-308, REGN-2810, PDR-001, BGB-A317, Pidilizumab, PF-06801591, Genolimzumab, CA-170, MEDI-0680, JS-001, TSR-042, Cemiplimab, Carrilizumab Camrelizumab, Pembrolizumab, Toripalimab, Sintilimab, Tislelizumab, LZM-009, AK- 103 and Nivolumab. The use of claim 1, wherein the light chain variable region of the PD-1 antibody or antigen-binding fragment thereof comprises LCDR1 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively , LCDR2 and LCDR3, the heavy chain variable region of the PD-1 antibody comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively. The use according to claim 4, wherein the PD-1 antibody is selected from humanized antibodies or antigen-binding fragments thereof. The use according to claim 4 or 5, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 isotype, preferably IgG1 or IgG4 isotype Heavy chain constant region. The use of any one of claims 4 to 6, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain constant region of kappa or lambda. The use according to any one of claims 4 to 6, wherein the light chain variable region sequence of the humanized antibody is the sequence shown in SEQ ID NO: 8 or a variant thereof, preferably the variant is The light chain variable region has 0-10 amino acid changes, more preferably A43S amino acid changes; the heavy chain variable region sequence is the sequence shown in SEQ ID NO: 7 or a variant thereof, the variant Preferably there are 0-10 amino acid changes in the heavy chain variable region, more preferably G44R amino acid changes. The use according to any one of claims 4 to 6, wherein the PD-1 antibody or antigen-binding fragment thereof comprises a light chain shown in SEQ ID NO:8, and a heavy chain shown in SEQ ID NO:7. The use according to any one of claims 1 to 9, wherein the patient is selected from recurrent, unresectable or metastatic, preferably recurrent after surgery. The use according to any one of claims 1 to 10, wherein the dose of the PD-1 antibody or antigen-binding fragment thereof is selected from 1-10 mg/kg, such as 3 mg/kg. The use according to any one of claims 1 to 10, wherein the dose of the PD-1 antibody or antigen-binding fragment thereof is selected from 50-600 mg, such as 200 mg. The use of any one of claims 1 to 12, wherein the VEGFR inhibitor dose is selected from 0.1-500 mg, eg 250 mg or 375 mg. The use according to any one of claims 1 to 13, further comprising an alkylating agent, preferably temozolomide or a pharmaceutically acceptable salt thereof. The use of claim 14, wherein the temozolomide dose is selected from 50 mg/m ² to 300 mg/m ² , such as 150 mg/m ² or 200 mg/m ² . The use according to any one of claims 2 to 15, wherein the pharmaceutically acceptable salt of apatinib is selected from the group consisting of mesylate, maleate, tartrate, succinate, acetate, difluoroacetic acid salt, rich Maleate, citrate, citrate, benzenesulfonate, benzoate, naphthalenesulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate and phosphate, The mesylate salts are preferred. Use of an anti-PD-1 antibody, a VEGFR inhibitor combined with temozolomide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating melanoma. An anti-PD-1 antibody for treating melanoma, wherein the anti-PD-1 antibody is administered in combination with a VEGFR inhibitor, further comprising an alkylating agent, preferably temozolomide or a pharmaceutically acceptable salt thereof. A VEGFR inhibitor for treating melanoma, wherein the VEGFR inhibitor is administered in combination with an anti-PD-1 antibody, further comprising an alkylating agent, preferably temozolomide or a pharmaceutically acceptable salt thereof. A pharmaceutical combination comprising an effective therapeutic amount of a PD-1 antibody or an antigen-binding fragment thereof and a VEGFR inhibitor, further comprising an alkylating agent, preferably temozolomide or a pharmaceutically acceptable salt thereof.