WO2024243355A1

WO2024243355A1 - Human monoclonal antibodies that target the rh5 complex of blood-stage plasmodium falciparum

Info

Publication number: WO2024243355A1
Application number: PCT/US2024/030637
Authority: WO
Inventors: Joshua Hoong Yu TAN; Lawrence Tsuchun WANG; Andrew Cooper
Original assignee: The United States Of America, As Represented By The Secretary, Department Of Health And Human Services
Priority date: 2023-05-24
Filing date: 2024-05-22
Publication date: 2024-11-28

Abstract

Antibodies and antigen binding fragments that specifically bind to P. falciparum circumsporozoite protein are disclosed. Nucleic acids encoding these antibodies, vectors and host cells are also provided. The disclosed antibodies, antigen binding fragments, nucleic acids and vectors can be used, for example, to inhibit a P. falciparum infection.

Description

HUMAN MONOCLONAL ANTIBODIES THAT TARGET THE RH5 COMPLEX OF BLOODSTAGE PLASMODIUM FALCIPARUM

CROSS REFERENCE TO RELATED APPLICATION

This claims the benefit of U.S. Provisional Application No. 63/468,740, filed May 24, 2023, which is incorporated herein by reference.

FIELD OF THE DISCLOSURE

This relates to monoclonal antibodies and antigen binding fragments that specifically bind to Plasmodium falciparum (P. falciparum), specifically to the reticulocyte binding protein homolog (RH)5 of P. falciparum, and their use, for example, in methods of inhibiting P. falciparum infection in a subject.

SEQUENCE LISTING

The Sequence Listing is submitted as an XML file in the form of the file named “Sequence.xml” (226, 087 bytes), which was created on April 1, 2024, which is incorporated by reference herein.

BACKGROUND

Malaria ranks as one of the world’s deadliest infectious diseases, with approximately 300 million cases per year. Malaria in humans is caused by five species of the Plasmodium parasite: P. falciparum, P. vivax, P. ovale, P. knowlesi and P. malariae. P. falciparum causes the most severe form of malaria disease, leading to the death of about - 500,000 people annually, most of whom are young children.

Each of the Plasmodium species that infect humans is transmitted through the bite of an infected female Anopheles mosquito, which introduces Plasmodium sporozoites into the bloodstream of the human host. The sporozoites rapidly reach the liver where they are sequestered by hepatocytes and undergo asexual expansion. One week later, the infected hepatocytes rupture and release mature parasites, the merozoites. These then begin the erythrocytic phase of malaria by attaching to and invading red blood cells, or erythrocytes. The invasion of the erythrocytes by the malarial parasites leads to malarial pathogenesis and clinical infection.

While there is no FDA approved vaccine for malaria, the World Health Organization (WHO) recently approved the RTS,S vaccine, which has modest efficacy against malaria. Moreover, malarial parasites are increasingly becoming resistant to antimalarial drugs used to treat the disease. Therefore, interventions to inhibit malaria infection, such as antibodies, are urgently needed for limiting morbidity, mortality, and ultimately eliminating malaria.

SUMMARY OF THE DISCLOSURE

This disclosure provides monoclonal antibodies and antigen binding fragments directed against RH5. In some aspects, disclosed is an isolated monoclonal antibody or antigen binding fragment thereof, comprising a heavy chain variable (VH) region and a light chain variable region (VL) comprising a heavy chain complementarity determining region (HCDR)l, a HCDR2, and a HCDR3, and a light chain complementarity determining region (LCDR)l, a LCDR2, and a LCDR3 of the VH and VL set forth as any one of: a) SEQ ID NOs: 1 and 5, respectively (MAD8-502); b) SEQ ID NOs: 9 and 13, respectively (MAD8-151); c) SEQ ID NOs: 17 and 21, respectively (MAD10-192); d) SEQ ID NOs: 25 and 29, respectively (MAD10-219); e) SEQ ID NOs: 33 and 37, respectively (MAD10-255); f) SEQ ID NOs: 49 and 53, respectively (MAD10-466); g) SEQ ID NOs: 41 and 45, respectively (MAD 10-437) ;h) SEQ ID NOs: 57 and 61, respectively (MAD10-291); i) SEQ ID NOs: 65 and 69, respectively (MAD10-349); j) SEQ ID NOs: 73 and 77, respectively (MAD10-439); k) SEQ ID NOs: 81 and 85, respectively (MAD10-30); I) SEQ ID NOs: 89 and 93, respectively (MAD10-447); m) SEQ ID NOs: 97 and 101, respectively (MAD10-378): n) SEQ ID NOs: 105 and 109, respectively (MAD10-137); o) SEQ ID NOs: 113 and 117, respectively (MAD10-434); p) SEQ ID NOs: 121 and 125, respectively (MAD10-410); q) SEQ ID NOs: 129 and 133, respectively (MAD10-371); r) SEQ ID NOs: 137 and 141, respectively (MAD1O-313); s) SEQ ID NOs: 145 and 149, respectively (MAD10-479); t) SEQ ID NOs: 153 and 157, respectively (MAD10-326): u) SEQ ID NOs: 161 and 165, respectively (MAD10-216); v) SEQ ID NOs: 169 and 173, respectively (MAD10-385); w) SEQ ID NOs: 177 and 181, respectively (MAD10-494); x) SEQ ID NOs: 185 and 189, respectively (MAD10-485); y) SEQ ID NOs: 193 and 197, respectively (MAD10-416); z) SEQ ID NOs: 201 and 205, respectively (MAD10-458); aa) SEQ ID NOs: 209 and 213, respectively (MAD10-409); bb) SEQ ID NOs: 217 and 221, respectively (MAD10-412); cc) SEQ ID NOs: 225 and 229, respectively (MAD10-435); dd) SEQ ID NOs: 233 and 237, respectively (MAD10-81); ee) SEQ ID NOs: 241 and 245, respectively (MAD10-429); ff) SEQ ID NOs: 249 and 253, respectively (MAD10-407); gg) SEQ ID NOs: 257 and 261, respectively (MAD10-432); hh) SEQ ID NOs: 265 and 269, respectively(MAD10-50); or ii) SEQ ID NOs: 273 and 277, respectively (MAD10-370), wherein the monoclonal antibody specifically binds to P. falciparum RH5 molecule and neutralizes P. falciparum.

Also disclosed are compositions including the antibodies and antigen binding fragments, nucleic acids encoding the antibodies and antigen binding fragments, expression vectors comprising the nucleic acids, and isolated host cells that comprise the nucleic acids. In several aspects, the nucleic acid molecule encoding a disclosed antibody or antigen binding fragment can be a cDNA or RNA molecule that encodes the antibody or antigen binding fragment. In additional aspects, the nucleic acid molecule can be a bicistronic expression construct encoding the Vu and VL of the antibody or antigen binding fragment.

The disclosed antibodies and antigen binding fragments can inhibit blood stage P. falciparum and can be used in vivo. Accordingly, a method is disclosed for inhibiting P. falciparum infection in a subject. Methods are provided for both treating and preventing a P. falciparum infection. The method comprises administering an effective amount (that is, an amount effective to inhibit P. falciparum infection in a subject) of one or more of the disclosed antibodies, antigen binding fragments, nucleic acid molecules, vectors, or compositions, to the subject, such as a subject at risk of or having a P. falciparum infection.

The antibodies, antigen binding fragments, nucleic acid molecules, vectors, and compositions disclosed herein can be used for a variety of additional purposes, such as for diagnosing P. falciparum infection in a subject, or detecting P. falciparum in a sample.

The foregoing and other features and advantages of this disclosure will become more apparent from the following detailed description of several aspects, which proceeds with reference to the accompanying figures.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1E. Rare, potent anti-RH5 antibodies are elicited by malaria exposure. (A) RH5- positive wells per 10⁵ IgG⁺ B cells, comparing infected with vaccinated donors. Four individuals with high RH5-specific polyclonal IgG and five malaria-naive individuals vaccinated with recombinant RH5/AS01B were selected and screened for RH5-specific memory B cells. (B) Somatic mutation frequencies of monoclonal antibody (mAb) VH, comparing infected with vaccinated donors. (C) RH5 binding of mAbs, comparing infected with vaccinated donors. mAbs were titrated against RH5-coated beads, and results calculated as AUC. Negative control mAb, VRC01-LS, is indicated by the dotted line. (D) Growth inhibition activity (GIA) of mAbs isolated from infected versus vaccinated donors. All mAbs were tested for in vitro inhibition of blood-stage malaria at 1 mg/mL. (E) 50% growth inhibition (ICso) values from titrations of the 35 most potent mAbs. All mAbs were tested for in vitro inhibition of blood-stage malaria at multiple titrations, and 50% inhibition of blood-stage malaria was calculated. Each point represents an independent experiment.

FIGS. 2A-2F. Natural infection primarily raises mAbs targeting non- neutralizing RH5 epitopes. (A) Heat map showing binding competition between a panel of mAbs targeting RH5. Competing mAb combinations are marked grey. Non-competing mAb combinations are marked white. Bin designations I to VI (based on published reference RH5 mAbs R5.004 - R.016) are indicated. (B) RH5 structure, with binding partners and bins indicated. Reference mAbs were used to mark the binding locations of bins as follows: Bin I (R5.004, PDB 6RCU), II (R5.016, PDB 6RCU), IV (R5.011, PDB 6RCV), V (R5.015, PDB 7PHU). The basigin receptor (PDB 4U0Q) and its Plasmodium binding partner CyRPA (PDB 6MPV) are also shown. (C) mAb GIA scores subdivided by epitope bin. All adjunct bins (e.g. bin I_a) are included in main epitope bins (e.g. bin I_a in bin I). mAbs derived from natural infection are indicated by black outlines. (D) Epitope bins of the 35 RH5-specific mAbs with highest potency determined by GIA titration. The six most potent mAbs are named. (E) Bin frequencies for mAbs from natural infection and vaccination. (F) mAbs scored by proximity of binding site to the basigin-binding site of RH5. Data are calculated as geometric means from two independent experiments. Greyscale is used to indicate GIA score at 1 mg/mL.

FIGS. 3A-3C. Binding strength correlates with neutralization potency only for mAbs targeting epitope bins I and II. (A) Bin I and II correlation scores (Spearman correlation) for GIA score and a number of binding and sequence parameters. Circle size and coloration intensity are proportional to the correlation r value. KD, equilibrium dissociation constant; K_a, association rate constant; Kd, dissociation rate constant. KD and Ka were inverted to allow a direct comparison of positive correlations. (B) Correlation score (Spearman correlation) between growth inhibition and RH5 binding affinity (all mAbs from major epitope bins, I-V). Outer bounds of band indicate 95% confidence interval. (C) Correlation score (Spearman correlation) between growth inhibition and RH5 binding affinity, divided into Bins I-V. Outer bounds of band indicate 95% confidence interval.

SEQUENCES

The nucleic and amino acid sequences listed in the accompanying sequence listing are shown using standard letter abbreviations for nucleotide bases, and three letter code for amino acids, as defined in 37 C.F.R. 1.822. Only one strand of each nucleic acid sequence is shown, but the complementary strand is understood as included by any reference to the displayed strand. a. MAD8-502

Vi,:

QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAINWVRQAPGQGPEWLGGnPlLDRVNYAQKFQG RVTITADELGGTAYMELTSLRSEDTAMYYCARLADGPFDYWGQGTQVIVSS (SEQ ID NO: 1) HCDR1: GGTFSSYA (SEQ ID NO: 2)

HCDR2: IIPILDRV (SEQ ID NO: 3)

HCDR3: ARLADGPFDY (SEQ ID NO: 4)

V_L:

NIVMTQTPLSLSVSPGQPASISCKSSQSLLHSDGQTYMYWYLQKPGQSPQLLISEVSSRFSGVPDRFS GSGSGTTFTLKISRVEAEDVGVYYCMQAKDPYSFGQGTKLEIK (SEQ ID NO: 5)

LCDR1: QSLLHSDGQTY (SEQ ID NO: 6)

LCDR2: EVS (SEQ ID NO: 7)

LCDR3: MQAKDPYS (SEQ ID NO: 8) b. MAD8-151

V_H:

QVQLQESGPGLVKPSETLSLTCTVSGGPISSYYWNWIRQPPGKGLEWIGHFYHSGSTNYNPSLKSRV TISVDTSKNQFYLNLSSVTAADSAVYFCARQVTMIQGLIDSWGQGMLVTVSS (SEQ ID NO: 9) HCDR1: GGPISSYY (SEQ ID NO: 10)

HCDR2: FYHSGST (SEQ ID NO: 11)

HCDR3: ARQVTMIQGLIDS (SEQ ID NO: 12)

V_L:

DIQMTQSPSSLSASVGDRVTITCQASQDINNSLNWYQQKPGKALKLLIYDVSNLETGVPSRFSGEGS GTDFSLIISSLQPEDIATYYCQQYEALPLTFGGGTKVEIK (SEQ ID NO: 13)

LCDR1: QDINNS (SEQ ID NO: 14)

LCDR2: DVS (SEQ ID NO: 15)

LCDR3: QQYEALPLT (SEQ ID NO: 16) c. MAD10-192

V_H:

EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRLAPGKGLEWVSGISWNSDNIDYADSV KGRFTISRDNAKNSLYLQMNSLGAEDTAFYYCARGTYSSVVMGYFDLWGRGTLVTVSS (SEQ ID NO: 17)

HCDR1: GFTFDDYA (SEQ ID NO: 18)

HCDR2: ISWNSDNI (SEQ ID NO: 19)

HCDR3: ARGTYSSVVMGYFDL (SEQ ID NO:20) V_L:

SYEVTQSPSVSVSPGQTASITCSGDKLGDKYACWYQLKPGQSPVLVIYQDSKRPSGIPERFSGSNSG

NTATLTISGTQAMDEADYYCQAWDSSTGVFGGGTKLTVL (SEQ ID NO: 21)

LCDR1: KLGDKY (SEQ ID NO: 22)

LCDR2: QDS (SEQ ID NO: 23)

LCDR3: QAWDSSTGV (SEQ ID NO: 24) d. MAD 10-219

V_H:

QVQLVESGGGVVQPGRSLRLSCAASGSTFSIYGMHWVRQAPGKGLEWVAIISFDGSNKYYADSVK

GRFTVSRDNSRDRVYLQMNSLRADDTAVYYCAKDDCENCRLQYFDWLSNHAFDIWGQGTMVTV

SS (SEQ ID NO: 25)

HCDR1: GSTFSIYG (SEQ ID NO:26)

HCDR2: ISFDGSNK (SEQ ID NO: 27)

HCDR3: AKDDCENCRLQYFDWLSNHAFDI (SEQ ID NO: 28)

V_L:

DIHMTQSPSSLSASVGDRVTITCRASQSISTYLNWYQQKLGKAPKLLIYAASSLHSGVPSRFSGGGSG

TDFTLTINSLQPEDFATYYCQQSYSMPPTFGQGTRLEIR (SEQ ID NO: 29)

LCDR1: QSISTY (SEQ ID NO: 30)

LCDR2: AAS (SEQ ID NO: 31)

LCDR3: QQSYSMPPT (SEQ ID NO: 32) e. MAD10-255

V_H:

QVQLQESGPGLVKPSETLSLTCTVSGGSISTYYWSWIRQPPGKGLEWLGYIYHSGSTDYNPSLESRV

TISVDTSRTRFSLRLRSVTAADTAVYYCARSTTMIQQYFDYWGRGTLVTVSS (SEQ ID NO:33)

HCDR1: GGSISTYY (SEQ ID NO: 34)

HCDR2: IYHSGST (SEQ ID NO: 35)

HCDR3: ARSTTMIQQYFDY (SEQ ID NO: 36)

V_L:

DIQMTQSPSSLSASLGDRVTITCQASQGISNSLNWYQQKPGKAPKVLIYDASNLETGVPSRFSGSGS

GTDFTFTITSLQPEDIATYYCQQYHYLPLTFGGGTKLEIK (SEQ ID NO: 37)

LCDR1: QGISNS (SEQ ID NO: 38)

LCDR2: DAS (SEQ ID NO: 39)

LCDR3: QQYHYLPLT (SEQ ID NO: 40) f. MAD 10-466

V_H:

QVQLVQSGAEVKKPGSSVKVSCKVSGGTFRSYAINWVRQAPGQGLEWMGRIIPIFGTANYAQKFQ

GRVTITADESTSTAYMELSSLRSEDTAVYYCARHGYSSGLDIWGQGTMVTVSS (SEQ ID NO: 41)

HCDR1: GGTFRSYA (SEQ ID NO: 42)

HCDR2: IIPIFGTA (SEQ ID NO: 43)

HCDR3: ARHGYSSGLDI (SEQ ID NO: 44)

Vi.:

DIQMTQSPSSLSASVGDRVTITCQASQDIRDSLNWYQHKPGKAPNLLISDASNLETGVPSRFSGSGSG

THFTFTISSLQPEDIATYYCQHYDNLPSYTFGQGTKLEIK (SEQ ID NO: 45)

LCDR1: QDIRDS (SEQ ID NO: 46)

LCDR2: DAS (SEQ ID NO: 47)

LCDR3: QHYDNLPSYT (SEQ ID NO: 48) g. MAD 10-437

V_H

QVQLVQSGAEVKKPGSSVKVSCKTSGGTFSIYAISWVRQAPGQGLEWMGGIIPILGSAKYAQKFQG RVTITADESTSTAYMELSSLRSEDTAAYYCARGWLAAARDAFDIWGQGTMVIVSS (SEQ ID NO: 49)

HCDR1: GGTFSIYA (SEQ ID NO: 50)

HCDR2: IIPILGSA (SEQ ID NO: 51)

HCDR3: ARGWLAAARDAFDI (SEQ ID NO: 52)

V_L:

DVVMTQSPLSLPVTLGQPASISCRSSQSLVYSDGNTYLNWFQQRPGQSPRRLIYEVSNRDSGVPDRF

SGSGSGTDFTLKISRVEAEDVGIYYCMQNTHWPLTFGGGTKVEIK (SEQ ID NO: 53)

LCDR1: QSLVYSDGNTY (SEQ ID NO: 54)

LCDR2: EVS (SEQ ID NO:55)

LCDR3: MQNTHWPLT (SEQ ID NO: 56) h. MAD 10-291

V_H:

QVQVVQSGAEVKKPGASVKVSCKVSGYTLTELSMHWVRQAPGKGLEWMGGFDPEDGKTIYAQK

FQGRVSMTEDTSTDTAYMELSSLRSEDTAVYYCAAVWRISMFRGVLEYWGQGTLVSVSS (SEQ ID

NO: 57)

HCDR1: GYTLTELS (SEQ ID NO: 58)

HCDR2: FDPEDGKT (SEQ ID NO: 59)

HCDR3: AAVWRISMFRGVLEY (SEQ ID NO: 60)

V_L:

EIVLTQSPGTLSLSPGERATLSCRASQSVRSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGS

GTDFTLTISRLEPEDFAVYYCQQYGSSPPLTFGGGTKVEIK (SEQ ID NO: 61)

LCDR1: QSVRSSY (SEQ ID NO: 62)

LCDR2: DAS (SEQ ID NO: 63)

LCDR3: QQYGSSPPLT (SEQ ID NO: 64) i. MAD10-349

V_H:

QLQLQESGPGLVKPSETLSLTCTVSGGSISSKGYYWGWIRQPPGKGLEWIGSIYYSGSTYYNPSLRSR

VTISADTSKNQVSLKLSSVTAADTAVYYCAKMGIAYYMDVWGKGTTVTVSS (SEQ ID NO: 65)

HCDR1: GGSISSKGYY (SEQ ID NO: 66)

HCDR2: IYYSGST (SEQ ID NO: 67)

HCDR3: AKMGIAYYMDV (SEQ ID NO: 68)

V_L:

EIVMTQSPATLSVSPGERATLSCRASQTISNSLAWYQQKPGQAPRLLIYDASTRATGFPARFSGSGSG

TEFTLTISSLQSEDFAVYFCQQYVSWPTFGQGTKVEIK (SEQ ID NO: 69)

LCDR1: QTISNS (SEQ ID NO: 70)

LCDR2: DAS (SEQ ID NO: 71)

LCDR3: QQYVSWPT (SEQ ID NO: 72) j. MAD 10-439

V_H:

QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQLPGKGLECVGFIYHSGSTHYNPSLES

RVIISLDTSKNQFSLKLTSVTAADTAVYYCARDNFFLSAIDYWGQGTLVTVSS (SEQ ID NO: 73)

HCDR1: GGSISSGGYY (SEQ ID NO: 74)

HCDR2: IYHSGST (SEQ ID NO: 75)

HCDR3: ARDNFFLSAIDY (SEQ ID NO: 76)

V_L:

EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS

GTDFTLTVSRLEPEDFAVYYCQHYGSSPRGTFGQGTKVEIK (SEQ ID NO:77) LCDR1: QSVSSSY (SEQ ID NO: 78)

LCDR2: GAS (SEQ ID NO: 79)

LCDR3: QHYGSSPRGT (SEQ ID NO: 80) k. MAD 10-30

Vi,:

QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLQWMGGIIPMFGTANNAQKFQ

GRVTITADESTSTAYMELSSLRSEDTAVYYCARVGYYDSSGPYVAAFDIWGQGTMVTVSS (SEQ ID

NO: 81)

HCDR1: GGTFSSYA (SEQ ID NO: 82)

HCDR2: IIPMFGTA (SEQ ID NO: 83)

HCDR3: ARVGYYDSSGPYVAAFDI (SEQ ID NO: 84)

V_L:

EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS

GTDFTLTISRLEPEDFAVYSCQQYGSSPVTFGPGTKVDIK (SEQ ID NO: 85)

LCDR1: QSVSSSY (SEQ ID NO: 86)

LCDR2: GAS (SEQ ID NO: 87)

LCDR3: QQYGSSPVT (SEQ ID NO: 88) l. MAD 10-447

V_H:

EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMHWVRQATGKGLEWVSGITTSGDTYYPGSVKG

RFTISRENAKNSLYLQMNSLRAGDTAVYYCARAAWDIVVVSAATKNYFYSYYMDVWGKGTTVT

VSS (SEQ ID NO: 89)

HCDR1: GFTFSSYD (SEQ ID NO: 90)

HCDR2: ITTSGDT (SEQ ID NO: 91)

HCDR3: ARAAWDIVVVSAATKNYFYSYYMDV (SEQ ID NO: 92)

V_L:

DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSG

TDFTLTISSLQPEDFATYYCQQSYSTLMYTFGQGTKLEIK (SEQ ID NO: 93)

LCDR1: QSISSY (SEQ ID NO: 94)

LCDR2: AAS (SEQ ID NO: 95)

LCDR3: QQSYSTLMYT (SEQ ID NO: 96) m. MAD10-378

V_H:

QVQLQESGPGLVKPSQTLSLTCTVSGGSISSRGSYWSWIRQHPGKGLEWIGYIYYSGSTYYNPSLTS

RSTISVDTSKNQFSLKLSSVTAADTAVYYCARALEYSYGSGNYGMDVWGQGTTVTVSS (SEQ ID

NO: 97)

HCDR1: GGSISSRGSY (SEQ ID NO: 98)

HCDR2: IYYSGST (SEQ ID NO: 99)

HCDR3: ARALEYSYGSGNYGMDV (SEQ ID NO: 100)

V_L:

EIVLTQSPATLSLSPGERATLSCRASQSVSNYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSG

TDFTLTISSLEPEDFAVYYCQQRSHWPTFGQGTRLEIK (SEQ ID NO: 101)

LCDR1: QSVSNY (SEQ ID NO: 102)

LCDR2: DAS (SEQ ID NO: 103)

LCDR3: QQRSHWPT (SEQ ID NO: 104) n. MAD 10- 137

V_H:

QVQLQESGPGLVKPSQTLSLTCSVSGGSINSGGFYWSWIRQHPGKGLEW1GYIYYSGSTHYNPSLKS

RVTISIDTSKNQFSLRLSSVTAADTAVYYCARTLRGGIWFDPWGQGTLVTVSS (SEQ ID NO: 105) HCDR1: GGSINSGGFY (SEQ ID NO: 106)

HCDR2: IYYSGST (SEQ ID NO: 107)

HCDR3: ARTLRGGIWFDP (SEQ ID NO: 108)

V_L:

EIVLTQSPATLSLSPGERVTLSCRASQSVSNYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSG

TDFTLTISSLEPEDFAVYYCQQHTNWITFGQGTRLEIK (SEQ ID NO: 109)

LCDR1: QSVSNY (SEQ ID NO: 110)

LCDR2: DAS (SEQ ID NO: 111)

LCDR3: QQHTNWIT (SEQ ID NO: 112) o. MAD 10-434

V_H:

QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGSANYAQKFQG

RVTITADESTSTVYMELSSLTSEDTAVYYCAREVKWADEADYWGQGTLVTVSS (SEQ ID NO: 113)

HCDR1: GGTFSSYA (SEQ ID NO: 114)

HCDR2: IIPIFGSA (SEQ ID NO: 115)

HCDR3: AREVKWADEADY (SEQ ID NO: 116)

V_L:

EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLTWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS

GTDFTLTISRLEPEDFAVYYCQQYGSSPPWTFGQGTKVEIK (SEQ ID NO: 117)

LCDR1: QSVSSSY (SEQ ID NO: 118)

LCDR2: GAS (SEQ ID NO: 119)

LCDR3: QQYGSSPPWT (SEQ ID NO: 120) p. MAD 10-410

V_H:

QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWTWIRQHPGKGLEWLGYIYYSGSTHYNPSLTS

RVSMSVDTSKNQFSLKLSSVTAADTAVYFCARVDKSKYGYGNLGLFDYWGQGTLVTVSS (SEQ ID

NO: 121)

HCDR1: GGSISSGGYY (SEQ ID NO: 122)

HCDR2: IYYSGST (SEQ ID NO: 123)

HCDR3: ARVDKSKYGYGNLGLFDY (SEQ ID NO: 124)

V_L:

DIQMTQSPSSLSASVGDRVTITCQASQDISNSLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGS

GTDFTFTISSLQPEDIATYYCQQYANLPSFGQGTKLEIK (SEQ ID NO: 125)

LCDR1: QDISNS (SEQ ID NO: 126)

LCDR2: DAS (SEQ ID NO: 127)

LCDR3: QQYANLPS (SEQ ID NO: 128) q. MAD 10-371

V_H:

QVQLQESGPGLVKPSQTLSLTCTVSGGSISSSGYYWSWIRQYPGKGLEWIGYIYYTGSAYYNPSLES

RVTISVDTSKNQFSLKLSSVTAADTAVYYSARFSSGYHTIPDAFDIWGQGTMVTVSS (SEQ ID

NO: 129)

HCDR1: GGSISSSGYY (SEQ ID NO: 130)

HCDR2: IYYTGSA (SEQ ID NO: 131)

HCDR3: ARFSSGYHTIPDAFDI (SEQ ID NO: 132)

V_L:

EIVMTQSPGTLSVSPGERATLSCRASQTVGNNLAWYQQKFGQAPRLLIYGASTRATGIPARFSGSGS

GTEFTLTISSLQSEDFAVYYCQQYHNWPTFGQGTKVEIK (SEQ ID NO: 133)

LCDR1: QTVGNN (SEQ ID NO: 134)

LCDR2: GAS (SEQ ID NO: 135)

LCDR3: QQYHNWPT (SEQ ID NO: 136) r. MAD 10-313

V_H:

QVQLQESGPGLVKPSQTLSLTCSVSGGSINSGGYYWNWIRQHPGKGLEWIGCIYYSGSTYYNPSLKS

RVTISVETAKNQFSLKLSSVTAADTAVYYCARSLPWMTFDYWGQGTLVTVSS (SEQ ID NO: 137)

HCDR1: GGSINSGGYY (SEQ ID NO: 138)

HCDR2: IYYSGST (SEQ ID NO: 139)

HCDR3: ARSLPWMTFDY (SEQ ID NO: 140)

V_L:

DIQLTQSPSFLSASVGDRVTITCRASQGISNFLAWYQQKPGKAPNLLIYSASTLQSGVPSRFSGSGSG

TEFTLTISSLQPEDFATYYCQQLNSYPTFGGGTKVEIK (SEQ ID NO: 141)

LCDR1: QGISNF (SEQ ID NO: 142)

LCDR2: SAS (SEQ ID NO: 143)

LCDR3: QQLNSYPT (SEQ ID NO: 144) s. MAD 10-479

V_H:

QVQLQESGPGLVKPSQTLSLTCTVSGGSISSAGYYWSWIRQHPGKGLEWIGYIYYSGSTYYNPSLKS

RVTISVDTSKNQFSLKLSSVTAADTAVYYCARVTVRGDWAFDIWGQGTMVTVSS (SEQ ID

NO: 145)

HCDR1: GGSISSAGYY (SEQ ID NO: 146)

HCDR2: IYYSGST (SEQ ID NO: 147)

HCDR3: ARVTVRGDWAFDI (SEQ ID NO: 148)

V_L:

DIQMTQSPSSLSASVGDRVTITCQASQDISNSLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGS

GTDFTFTISSLQPEDIGTYYCQQYDNFPTFGPGTKVDIK (SEQ ID NO: 149)

LCDR1: QDISNS (SEQ ID NO: 150)

LCDR2: DAS (SEQ ID NO: 151)

LCDR3: QQYDNFPT (SEQ ID NO: 152) t. MAD 10-326

V_H:

QLQLQESGPGLLKPSETLSLTCTVSGGSVSSSFYYWGWIRQPPGKGLEWIGSIYYSGSAHYNPSLKS

RVTISVDTSKNHFSLKLSSVTAADTAVYYCARHPPEVYFDYWGQGTLVTVSS (SEQ ID NO: 153)

HCDR1: GGSVSSSFYY (SEQ ID NO: 154)

HCDR2: IYYSGSA (SEQ ID NO: 155)

HCDR3: ARHPPEVYFDY (SEQ ID NO: 156)

V_L:

DIQMTQSPSSLSASVGDRVSITCRASQGISNFLAWYQQKPGKVPKLLIYAASTLQSGVPSRFSGSGSG

TDFTLTISSLQPEDVATYYCQKYDSVPGFGQGTRLEIK (SEQ ID NO: 157)

LCDR1: QGISNF (SEQ ID NO: 158)

LCDR2: AAS (SEQ ID NO: 159)

LCDR3: QKYDSVPG (SEQ ID NO: 160) u. MAD 10-216

V_H:

QVQLVQSGAEVKKPGASVKVSCKASGYKFTGYYMHWVRKAPGHGLEWMGWINLNSGDTNSAQ

KFQGRVTMTRDTSISTAYIEVKRLRTDDTAVYYCTRGEEGLLYGDYGGHAFEIWGQGTLLIVSS

(SEQ ID NO: 161)

HCDR1: GYKFTGYY (SEQ ID NO: 162)

HCDR2: INLNSGDT (SEQ ID NO: 163)

HCDR3: TRGEEGLLYGDYGGHAFE1 (SEQ ID NO: 164) V_L:

EIVMSQSPLSLPVTPGEPASISCRSSQSLLHSIGYNYLDWYVQKPGQSPQLLIYLGSARASGVPDRFS

GSGSGTDFTLKISRVEAEDVGVYYCMQALQTPVTFGQGTKVEIK (SEQ ID NO: 165)

LCDR1: QSLLHSIGYNY (SEQ ID NO: 166)

LCDR2: LGS (SEQ ID NO: 167)

LCDR3: MQALQTPVT (SEQ ID NO: 168) v. MAD10-385

V_H:

QLQLQESGPGLVKPSETLSLTCTVSGASISSSGYYWGWIRQPPGKGLEWIATIYYSGSTYYNPSLKSR

VTISVDTSKNQFSLKLTSVTAADTAVYSCARHLPWGWYFDLWGRGTLVTVSS (SEQ ID NO: 169)

HCDR1: GASISSSGYY (SEQ ID NO: 170)

HCDR2: IYYSGST (SEQ ID NO: 171)

HCDR3: ARHLPWGWYFDL (SEQ ID NO: 172)

V_L:

EIVLTQSPGTLSLSPGERATLSCRASQSLNNNDLAWYQQKPGQAPRLLIHGASSRATGIPDRFSGSGS

GTHFTLTISRLEPEDFAVYYCQQYANSPLTFGGGTKVEIK (SEQ ID NO: 173)

LCDR1: QSLNNND (SEQ ID NO: 174)

LCDR2: GAS (SEQ ID NO: 175)

LCDR3: QQYANSPLT (SEQ ID NO: 176) w. MAD 10-494

V_H:

QLQLQESGPGLVKPSETLSLTCNVSGGSISSSGYYWGWIRQPPGKGLEWIGSIYYSGSTHYNPSLKSR

VTISVDTSKNQFSLKLSSVTAADTAVYYCARQWYEMATLDWGQGTLVTVSS (SEQ ID NO: 177)

HCDR1: GGSISSSGYY (SEQ ID NO: 178)

HCDR2: IYYSGST (SEQ ID NO: 179)

HCDR3: ARQWYEMATLD (SEQ ID NO: 180)

V_L:

EIVMTQSPATLSVSPGERATLSCRASQSVSINLAWYQKKPGQAPRLLIQGASTRATGIPARFSGSGSG

TEFTLTISSLQSEDFAVYYCQQYNNWPTFGQGTKLEIK (SEQ ID NO: 181)

LCDR1: QSVSIN (SEQ ID NO: 182)

LCDR2: GAS (SEQ ID NO: 183)

LCDR3: QQYNNWPT (SEQ ID NO: 184) x. MAD 10-485

V_H:

QVQLVESGGGVVQPGRSLRLSCAAAGFTFSSYAMHWVRQAPGKGLEWVALISFDGSNKYYADSV

KGRFTISRDNSKNTLQLQMNSLRAEDMAVYYCAREQGSLSETYYVDYYGMDVWGQGTTVTVSS

(SEQ ID NO: 185)

HCDR1: GFTFSSYA (SEQ ID NO: 186)

HCDR2: ISFDGSNK (SEQ ID NO: 187)

HCDR3: AREQGSLSETYYVDYYGMDV (SEQ ID NO: 188)

Vi.:

DIQLTQSPSFLSASVGDRVTITCRASQGISSYLVWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSG

PEFTLTISSLQPEDFATYYCQQLNSYQITFGQGTRLEIK (SEQ ID NO: 189)

LCDR1: QGISSY (SEQ ID NO: 190)

LCDR2: AAS (SEQ ID NO: 191)

LCDR3: QQLNSYQIT (SEQ ID NO: 192) y. MAD 10-416

V_H:

EVQLVESGGGLVQPGGSLRLSCAASGFSFSSYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSV KGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARVAWDIVVVVAAPGDYYYYYMDVWGKGTTV

TVSS (SEQ ID NO: 193)

HCDR1: GFSFSSYW (SEQ ID NO: 194)

HCDR2: IKQDGSEK (SEQ ID NO: 195)

HCDR3: ARVAWDIVVVVAAPGDYYYYYMDV (SEQ ID NO: 196)

V_L:

DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSG

TDFTLTISSLQPEDFATYYCQQSYSTLLYTFGQGTKLEIK (SEQ ID NO: 197)

LCDR1: QSISSY (SEQ ID NO: 198)

LCDR2: AAS (SEQ ID NO: 199)

LCDR3: QQSYSTLLYT (SEQ ID NO: 200) z. MAD 10-458

V_H:

QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAGIWSDGSNKYYPDSV

KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGGLYYSSGSPLDYWGQGTLVTVSS (SEQ ID

NO: 201)

HCDR1: GFTFSSYG (SEQ ID NO: 202)

HCDR2: IWSDGSNK (SEQ ID NO: 203)

HCDR3: ARGGLYYSSGSPLDY (SEQ ID NO: 204)

V_L:

DFQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQHKPGKAPKLLIYAASSLQSGVPSRFSGSGSG

TDFTLTISSLQPEDFATYYCQESYSTRTAFGPGTKVDIK (SEQ ID NO: 205)

LCDR1: QSISSY (SEQ ID NO: 206)

LCDR2: AAS (SEQ ID NO: 207)

LCDR3: QESYSTRTA (SEQ ID NO: 208) aa. MAD 10-409

V_H:

QVQLQESGPGLVKPSQTLSLTCIISGGSIGSGGYYWSWIRQHPGKGLEWIGDIYYSGSTYYNPSLKSR

LTISVDTSKNQFSLQLTSVTAADTAVYYCARKGRWELGAFDFWGQGTLVTVSS (SEQ ID NO: 209)

HCDR1: GGSIGSGGYY (SEQ ID NO: 210)

HCDR2: IYYSGST (SEQ ID NO: 211)

HCDR3: ARKGRWELGAFDF (SEQ ID NO: 212)

V_L:

EIVLTQSPGTLSLSPGERATLSCRASQSLTSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS

GTDFTLTISRLEPEDFAVYYCLEYGTSPGTFGQGTKVEIK (SEQ ID NO: 213)

LCDR1: QSLTSSY (SEQ ID NO: 214)

LCDR2: GAS (SEQ ID NO: 215)

LCDR3: LEYGTSPGT (SEQ ID NO: 216) bb. MAD10-412

V_H:

QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLECVAYISRSGNTIYSADSVKG

RFTISRDNAKNSLYLQMNSLRAEDTAVYYCARESGDTFDIWGHGTMVTVSS (SEQ ID NO: 217)

HCDR1: GFTFSDYY (SEQ ID NO:218)

HCDR2: ISRSGNTI (SEQ ID NO: 219)

HCDR3: ARESGDTFDI (SEQ ID NO: 220)

V_L:

QSVLTQPPSVSGAPGQRVTISCTGTSSNIGAGYDVHWYQQLPGTAPKLLIYANSNRPSGVPDRFSGS

KSGSSASLAITGLQAEDEADYYCQSYDSSLSGVLFGGGTKLTVL (SEQ ID NO: 221)

LCDR1: SSNIGAGYD (SEQ ID NO: 222) LCDR2: ANS (SEQ ID NO:223)

LCDR3: QSYDSSLSGVL (SEQ ID NO: 224) cc. MAD 10-435

V_H:

QVQLVQSGAEVKKPGSSVKVSCKASGVTFSTHALSWVRQAPGQGLEWMGGFIPIFGTANYAQKFQ

GRVTITADESTSTAYMEESSERSEDTAVYYCAREYMGNFDYWGQGTEVTVSS (SEQ ID NO: 225)

HCDR1: GVTFSTHA (SEQ ID NO: 226)

HCDR2: FIPIFGTA (SEQ ID NO: 227)

HCDR3: AREYMGNFDY (SEQ ID NO: 228)

V_L:

QSALTQPASVSGSPGQSITISCTGTSSDVGSYNLVSWYQQRPGKAPTLMIYEVTERPSGVSNRFSGSK

SGNTASLTISGLLSEDEADYYCCSYAGSRTSVFGGGTKLTVL (SEQ ID NO: 229)

LCDR1: SSDVGSYNL (SEQ ID NO: 230)

LCDR2: EVT (SEQ ID NO: 231)

LCDR3: CSYAGSRTSV (SEQ ID NO: 232) dd. MAD 10-81

V_H:

QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAAIWYDGSNKYYADS

VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDAAYYSDSGIDYWGQGTLVTVSS (SEQ ID

NO: 233)

HCDR1: GFTFSSYG (SEQ ID NO: 234)

HCDR2: IWYDGSNK (SEQ ID NO: 235)

HCDR3: ARDAAYYSDSGIDY (SEQ ID NO: 236)

V_L:

DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSG

TDFTLTISSLQPEDFATYYCQQSYSSPPSFGGGTKVEIK (SEQ ID NO: 237)

LCDR1: QSISSY (SEQ ID NO: 238)

LCDR2: AAS (SEQ ID NO: 239)

LCDR3: QQSYSSPPS (SEQ ID NO: 240) ee. MAD 10-429

V_H:

EVQLVESGGGLVQPGRSLRLSCAASGFSFDDYAMHWVRQTPGKGLEWISGISWNSGNMDYADSV

KGRFTVSRDNAKNSLYLQMNSLRAEDTALYYCAKDLGSSGWYAPIDFWGQGTLVTVSS (SEQ ID

NO: 241)

HCDR1: GFSFDDYA (SEQ ID NO: 242)

HCDR2: ISWNSGNM (SEQ ID NO: 243)

HCDR3: AKDLGSSGWYAPIDF (SEQ ID NO: 244)

V_L:

EIVLTQSPGTLSLSPGERATLSCRASQSVRIIYLAWYQQKPGQAPRLLIYGPSSRATGIPDRFSASGSG

TDFTLTISRLEPEDFAVYYCQQYGRSPPWTFGQGTKVEIK (SEQ ID NO: 245)

LCDR1: QSVRIIY (SEQ ID NO: 246)

LCDR2: GPS (SEQ ID NO: 247)

LCDR3: QQYGRSPPWT (SEQ ID NO: 248) ff. MAD 10-407

V_H:

QVQLQESGPGLVKPSQTLSLTCTVSGGSVSSGGYYWSWLRQHPGKGLEWIGYIYYSGSTHYNPSLK

SRVTISVDTSKNQFSLKLSSVTAADTAMYYCARGWFDAFDIWGQGTVVTVSS (SEQ ID NO: 249)

HCDR1: GGSVSSGGYY (SEQ ID NO: 250) HCDR2: IYYSGST (SEQ ID NO: 251)

HCDR3: ARGWFDAFDI (SEQ ID NO: 252)

V_L:

EIVLTQSPATLSLSPGERATLSCRASQSVSSFLVWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSG

TDFTLTISSLEPEDFAIYYCQQRSSWLSFGGGTKVEIK (SEQ ID NO: 253)

LCDR1: QSVSSF (SEQ ID NO: 254)

LCDR2: DAS (SEQ ID NO: 255)

LCDR3: QQRSSWLS (SEQ ID NO: 256) gg. MAD10-432

V_H:

QVQLVESGGGVVQPGRSLRLSCAASGFIFSSYGMHWVRQAPGKGLEWVAAIWSDGSNKYYADSV

KGRFTISRDNFKNTLYLQMNSLRAEDTAVYYCAKDHSYYASGSHLDYWGQGTLVTVSS (SEQ ID

NO: 257)

HCDR1: GFIFSSYG (SEQ ID NO: 258)

HCDR2: IWSDGSNK (SEQ ID NO: 259)

HCDR3: AKDHSYYASGSHLDY (SEQ ID NO: 260)

V_L:

DIQMTQSPSSLSAYVGDRVTITCRASQSVSSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGS

GTDFTLTINSLQPEDFATYYCQQSYDTPTFGQGTRLEIK (SEQ ID NO: 261)

LCDR1: QSVSSY (SEQ ID NO: 262)

LCDR2: AAS (SEQ ID NO: 263)

LCDR3: QQSYDTPT (SEQ ID NO: 264) hh. MAD 10-50

V_H:

QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLECIGYIYYSGSTYYNPSLKS

RVTISVDTSKNQFSLKLSSVTAADTAVYYCARDFYDSSGFDYWGQGTLVTVSS (SEQ ID NO: 265)

HCDR1: GGSISSGGYY (SEQ ID NO: 266)

HCDR2: IYYSGST (SEQ ID NO: 267)

HCDR3: ARDFYDSSGFDY (SEQ ID NO: 268)

Light Chain:

EIVMTQSPATLSVSPGERATLSCRASQSVSSDLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGS

GTEFTLTISSLQSEDFAVYYCQQYNNWPRTFGQGTKVEIK (SEQ ID NO: 269)

LCDR1: QSVSSD (SEQ ID NO: 270)

LCDR2: GAS (SEQ ID NO: 271)

LCDR3: QQYNNWPRT (SEQ ID NO:272) ii. MAD10-370

V_H:

QVQLVQSGAEVKKPGSSVKVSCKASGGTFNNYGHSWVRQAPGQGLEWMGRIIPVLDKADYAQKF

QGRVTITADESTSTLYMELSSLRSEDTAVYYCARGGGDGYYFYGMDVWGQGTTVTVSS (SEQ ID

NO: 273)

HCDR1: GGTFNNYG (SEQ ID NO: 274)

HCDR2: IIPVLDKA (SEQ ID NO: 275)

HCDR3: ARGGGDGYYFYGMDV (SEQ ID NO: 276)

V_L:

DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPKKAPKLLIYDASNLQTGVPPRFSGSGS

GTDFTFTISSLQPEDFATYYCLQYDNLPLTFGGGTRVEIK (SEQ ID NO:277)

LCDR1: QDISNY (SEQ ID NO: 278)

LCDR2: DAS (SEQ ID NO:279)

LCDR3: LQYDNLPLT (SEQ ID NO:280) DETAILED DESCRIPTION OF SEVERAL EMBODIMENTS

Malaria is a mosquito-borne parasitic disease that causes high morbidity and mortality, primarily in infants and young children in sub-Saharan Africa. Development of a highly effective vaccine or antibodies that can prevent and ultimately eliminate malaria is urgently needed.

This disclosure provides monoclonal antibodies and antigen binding fragments directed against RH5. The RH5-specific antibodies and antigen binding fragments provided herein can inhibit blood-stage P. falciparum, and are effective for passive prevention of malaria for use in suitable subjects, such as travelers, military personnel, and subjects in elimination campaigns.

I. Summary of Terms

Unless otherwise noted, technical terms are used according to conventional usage. Definitions of many common terms in molecular biology may be found in Krebs et al. (eds.), Lewin ’s genes XII, published by Jones & Bartlett Learning, 2017. As used herein, the singular forms “a,” “an,” and “the,” refer to both the singular as well as plural, unless the context clearly indicates otherwise. For example, the term “an antigen” includes singular or plural antigens and can be considered equivalent to the phrase “at least one antigen.” As used herein, the term “comprises” means “includes.” It is further to be understood that any and all base sizes or amino acid sizes, and all molecular weight or molecular mass values, given for nucleic acids or polypeptides are approximate, and are provided for descriptive purposes, unless otherwise indicated. Although many methods and materials similar or equivalent to those described herein can be used, particular suitable methods and materials are described herein. In case of conflict, the present specification, including explanations of terms, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. To facilitate review of the various embodiments, the following explanations of terms are provided:

Administration: The introduction of a composition into a subject by a chosen route. Administration can be local or systemic. For example, if the chosen route is intravenous, the composition is administered by introducing the composition into a vein of the subject. Exemplary routes of administration include, but are not limited to, oral, injection (such as subcutaneous, intramuscular, intradermal, intraperitoneal, and intravenous), sublingual, rectal, transdermal (for example, topical), intranasal, vaginal, and inhalation routes.

Antibody and Antigen Binding Fragment: An immunoglobulin, antigen-binding fragment, or derivative thereof, that specifically binds and recognizes an analyte (antigen) such as RH5. The term “antibody” is used herein in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antigen binding fragments, so long as they exhibit the desired antigen-binding activity.

Non-limiting examples of antibodies include, for example, intact immunoglobulins and variants and fragments thereof that retain binding affinity for the antigen. Examples of antigen binding fragments include but are not limited to Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g. scFv); and multispecific antibodies formed from antibody fragments. Antibody fragments include antigen binding fragments either produced by the modification of whole antibodies or those synthesized de novo using recombinant DNA methodologies (see, e.g., Kontermann and Diibel (Eds.), Antibody Engineering, Vols. 1-2, 2^nd ed., Spring er- Verlag, 2010).

Antibodies also include genetically engineered forms such as chimeric antibodies (such as humanized murine antibodies) and heteroconjugate antibodies (such as bispecific antibodies).

An antibody may have one or more binding sites. If there is more than one binding site, the binding sites may be identical to one another or may be different. For instance, a naturally -occurring immunoglobulin has two identical binding sites, a single-chain antibody or Fab fragment has one binding site, while a bispecific or bifunctional antibody has two different binding sites.

Typically, a naturally occurring immunoglobulin has heavy (H) chains and light (E) chains interconnected by disulfide bonds. Immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon and mu constant region genes, as well as the myriad immunoglobulin variable domain genes. There are two types of light chain, lambda (X) and kappa (K). There are five main heavy chain classes (or isotypes) which determine the functional activity of an antibody molecule: IgM, IgD, IgG, IgA and IgE.

Each heavy and light chain contains a constant region (or constant domain) and a variable region (or variable domain). In combination, the heavy and the light chain variable regions specifically bind the antigen.

References to “VH” or “VH” refer to the variable region of an antibody heavy chain, including that of an antigen binding fragment, such as Fv, scFv, dsFv or Fab. References to “VL” or “VL” refer to the variable domain of an antibody light chain, including that of an Fv, scFv, dsFv or Fab.

The VH and VL contain a “framework” region interrupted by three hypervariable regions, also called “complementarity-determining regions” or “CDRs” (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest, 5^th ed., NIH Publication No. 91-3242, Public Health Service, National Institutes of Health, U.S. Department of Health and Human Services, 1991). The sequences of the framework regions of different light or heavy chains are relatively conserved within a species. The framework region of an antibody, that is the combined framework regions of the constituent light and heavy chains, serves to position and align the CDRs in three-dimensional space.

The CDRs are primarily responsible for binding to an epitope of an antigen. The amino acid sequence boundaries of a given CDR can be readily determined using any of a number of well-known schemes, including those described by Kabat et al. (Sequences of Proteins of Immunological Interest, 5^th ed., NIH Publication No. 91-3242, Public Health Service, National Institutes of Health, U.S. Department of Health and Human Services, 1991; “Kabat” numbering scheme), Al-Lazikani et al., (“Standard conformations for the canonical structures of immunoglobulins,” J. Mol. Bio., 273(4):927-948, 1997; “Chothia” numbering scheme), and Lefranc et al. (“IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains,” Dev. Comp. Immunol., 27(l):55-77, 2003; “IMGT” numbering scheme). The CDRs of each chain are typically referred to as CDR1, CDR2, and CDR3 (from the N-terminus to C-terminus), and are also typically identified by the chain in which the particular CDR is located. Thus, a VH CDR3 is the CDR3 from the VH of the antibody in which it is found, whereas a VL CDR1 is the CDR1 from the VL of the antibody in which it is found. Light chain CDRs are sometimes referred to as LCDR1, LCDR2, and LCDR3. Heavy chain CDRs are sometimes referred to as HCDR1, HCDR2, and HCDR3.

In some embodiments, a disclosed antibody includes a heterologous constant domain. For example, the antibody includes a constant domain that is different from a native constant domain, such as a constant domain including one or more modifications (such as the “LS” mutations) to increase half-life.

A “monoclonal antibody” is an antibody obtained from a population of substantially homogeneous antibodies, that is, the individual antibodies comprising the population are identical and/or bind the same epitope, except for possible variant antibodies, for example, containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being described herein. In some examples monoclonal antibodies are isolated from a subject. Monoclonal antibodies can have conservative amino acid substitutions which have substantially no effect on antigen binding or other immunoglobulin functions. (See, for example, Greenfield (Ed.), Antibodies: A Laboratory Manual, 2^nd ed. New York: Cold Spring Harbor Laboratory Press, 2014.)

A “humanized” antibody or antigen binding fragment includes a human framework region and one or more CDRs from a non-human (such as a mouse, rat, or synthetic) antibody or antigen binding fragment. The non-human antibody or antigen binding fragment providing the CDRs is termed a “donor,” and the human antibody or antigen binding fragment providing the framework is termed an “acceptor.” In one embodiment, all the CDRs are from the donor immunoglobulin in a humanized immunoglobulin. Constant regions need not be present, but if they are, they can be substantially identical to human immunoglobulin constant regions, such as at least about 85-90%, such as about 95% or more identical. Hence, all parts of a humanized antibody or antigen binding fragment, except possibly the CDRs, are substantially identical to corresponding parts of natural human antibody sequences.

A “chimeric antibody” is an antibody which includes sequences derived from two different antibodies, which typically are of different species. In some examples, a chimeric antibody includes one or more CDRs and/or framework regions from one human antibody and CDRs and/or framework regions from another human antibody.

A “fully human antibody” or “human antibody” is an antibody which includes sequences from (or derived from) the human genome, and does not include sequence from another species. In some embodiments, a human antibody includes CDRs, framework regions, and (if present) an Fc region from (or derived from) the human genome. Human antibodies can be identified and isolated using technologies for creating antibodies based on sequences derived from the human genome, for example by phage display or using transgenic animals (see, e.g., Barbas et al. Phage display: A Laboratory Manuel. 1^st Ed. New York: Cold Spring Harbor Laboratory Press, 2004. Print.; Lonberg, Nat. Biotech., 23: 1117-1125, 2005; Lonenberg, Curr. Opin. Immunol., 20:450-459, 2008).

Antibody or antigen binding fragment that neutralizes P. falciparum'. An antibody or antigen binding fragment that specifically binds to a P. falciparum antigen (such as RH5) in such a way as to inhibit a biological function associated with P. falciparum that inhibits P. falciparum infection. The antibody can neutralize the activity of P. falciparum at various points during the lifecycle of the pathogen. An antibody can inhibit blood stage P. falciparum. For example, an antibody or antigen binding fragment that neutralizes P. falciparum may interfere with infection of erythrocytes. The antibody can inhibit merozoite invasion of red blood cells.

In some aspects, an antibody or antigen binding fragment that specifically binds to RH5 and inhibits blood stage P. falciparum, for example, by at least 50% (such as at least 60%, at least 70%, at least 80%, at least 90%, or more) compared to a control antibody or antigen binding fragment. In some embodiments, an antibody or antigen binding fragment that specifically binds to RH5 and neutralizes P. falciparum inhibits infection of a human subject by P. falciparum, for example, by at least 50% compared to a control antibody or antigen binding fragment.

Biological sample: A sample obtained from a subject. Biological samples include all clinical samples useful for detection of disease or infection (for example, P. falciparum infection) in subjects, including, but not limited to, cells, tissues, and bodily fluids, such as blood, derivatives and fractions of blood (such as serum), cerebrospinal fluid; as well as biopsied or surgically removed tissue, for example tissues that are unfixed, frozen, or fixed in formalin or paraffin. In a particular example, a biological sample is obtained from a subject having or suspected of having a P. falciparum infection.

Bispecific antibody: A recombinant molecule composed of two different antigen binding domains that consequently binds to two different antigenic epitopes. Bispecific antibodies include chemically or genetically linked molecules of two antigen-binding domains. The antigen binding domains can be linked using a linker. The antigen binding domains can be monoclonal antibodies, antigen-binding fragments e.g., Fab, scFv), or combinations thereof. A bispecific antibody can include one or more constant domains, but does not necessarily include a constant domain.

CIS43 Antibody: A monoclonal antibody that specifically binds to an epitope on PfCSP and neutralizes malaria infection. The CIS43 antibody and methods for its production are described, for example, in PCT Pub. No. WO 2018/148660, which is incorporated by reference herein in its entirety. The amino acid sequences of the heavy and light variable regions of the CIS43 antibody are also provided in PCT Publication No. WO 2020/227228, incorporated herein by reference.

Conditions sufficient to form an immune complex: Conditions which allow an antibody or antigen binding fragment to bind to its cognate epitope to a detectably greater degree than, and/or to the substantial exclusion of, binding to substantially all other epitopes. Conditions sufficient to form an immune complex are dependent upon the format of the binding reaction and typically are those utilized in immunoassay protocols or those conditions encountered in vivo. See Greenfield (Ed.), Antibodies: A Laboratory Manual, 2^nd ed. New York: Cold Spring Harbor Laboratory Press, 2014, for a description of immunoassay formats and conditions. The conditions employed in the methods are “physiological conditions” which include reference to conditions (e.g., temperature, osmolarity, pH) that are typical inside a living mammal or a mammalian cell. While it is recognized that some organs are subject to extreme conditions, the intra-organismal and intracellular environment normally lies around pH 7 (e.g., from pH 6.0 to pH 8.0, more typically pH 6.5 to 7.5), contains water as the predominant solvent, and exists at a temperature above 0°C and below 50°C. Osmolarity is within the range that is supportive of cell viability and proliferation.

The formation of an immune complex can be detected through conventional methods, for instance immunohistochemistry (IHC), immunoprecipitation (IP), flow cytometry, immunofluorescence microscopy, ELISA, immunoblotting (for example, Western blot), magnetic resonance imaging (MRI), computed tomography (CT) scans, radiography, and affinity chromatography. Immunological binding properties of selected antibodies may be quantified using known methods.

Conjugate: A complex of two molecules linked together, for example, linked together by a covalent bond. In one embodiment, an antibody is linked to an effector molecule; for example, an antibody that specifically binds to RH5 from P. falciparum covalently linked to an effector molecule. The linkage can be by chemical or recombinant means. In one embodiment, the linkage is chemical, wherein a reaction between the antibody moiety and the effector molecule has produced a covalent bond formed between the two molecules to form one molecule. A peptide linker (short peptide sequence) can optionally be included between the antibody and the effector molecule. Because conjugates can be prepared from two molecules with separate functionalities, such as an antibody and an effector molecule, they are also sometimes referred to as “chimeric molecules.”

Conservative variants: “Conservative” amino acid substitutions are those substitutions that do not substantially affect or decrease a function of a protein, such as the ability of the protein to interact with a target protein. For example, a RH5-specific antibody can include up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10 conservative substitutions compared to a reference antibody sequence and retain specific binding activity for RH5, and/or P. falciparum neutralization activity. The term conservative variation also includes the use of a substituted amino acid in place of an unsubstituted parent amino acid.

Individual substitutions, deletions or additions which alter, add or delete a single amino acid or a small percentage of amino acids (for instance less than 5%, in some embodiments less than 1%) in an encoded sequence are conservative variations where the alterations result in the substitution of an amino acid with a chemically similar amino acid.

The following six groups are examples of amino acids that are considered to be conservative substitutions for one another:

1) Alanine (A), Serine (S), Threonine (T);

2) Aspartic acid (D), Glutamic acid (E);

3) Asparagine (N), Glutamine (Q);

4) Arginine (R), Lysine (K);

5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); and

6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W).

Non-conservative substitutions are those that reduce an activity or function of the RH5 specific antibody, such as the ability to specifically bind to RH5 or neutralize P. falciparum. For instance, if an amino acid residue is essential for a function of the protein, even an otherwise conservative substitution may disrupt that activity. Thus, a conservative substitution does not alter the basic function of a protein of interest.

Contacting: Placement in direct physical association; includes both in solid and liquid form, which can take place either in vivo or in vitro. Contacting includes contact between one molecule and another molecule, for example the amino acid on the surface of one polypeptide, such as an antigen, that contacts another polypeptide, such as an antibody. Contacting can also include contacting a cell for example by placing an antibody in direct physical association with a cell.

Control: A reference standard. In some embodiments, the control is a negative control, such as sample obtained from a healthy patient not infected with P. falciparum. In other embodiments, the control is a positive control, such as a tissue sample obtained from a patient diagnosed with P. falciparum infection. In still other embodiments, the control is a historical control or standard reference value or range of values (such as a previously tested control sample, such as a group of P. falciparum patients with known prognosis or outcome, or group of samples that represent baseline or normal values).

A difference between a test sample and a control can be an increase or conversely a decrease. The difference can be a qualitative difference or a quantitative difference, for example a statistically significant difference. In some examples, a difference is an increase or decrease, relative to a control, of at least about 5%, such as at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 350%, at least about 400%, or at least about 500%.

Detectable marker: A detectable molecule (also known as a label) that is conjugated directly or indirectly to a second molecule, such as an antibody, to facilitate detection of the second molecule. For example, the detectable marker can be capable of detection by ELISA, spectrophotometry, flow cytometry, microscopy or diagnostic imaging techniques (such as CT scans, MRIs, ultrasound, fiberoptic examination, and laparoscopic examination). Specific, non- limiting examples of detectable markers include fluorophores, chemiluminescent agents, enzymatic linkages, radioactive isotopes and heavy metals or compounds (for example super paramagnetic iron oxide nanocrystals for detection by MRI). Methods for using detectable markers and guidance in the choice of detectable markers appropriate for various purposes are discussed for example in Green and Sambrook (Molecular Cloning: A Laboratory Manual, 4^th ed., New York: Cold Spring Harbor Laboratory Press, 2012) and Ausubel et al. (Eds.) (Current Protocols in Molecular Biology, New York: John Wiley and Sons, including supplements, 2017).

Detecting: To identify the existence, presence, or fact of something.

Effective amount: A quantity of a specific substance sufficient to achieve a desired effect in a subject to whom the substance is administered. For instance, this can be the amount necessary to inhibit a P. falciparum infection, such as the amount necessary to inhibit or prevent A P. falciparum infection, or blood stage P. falciparum.

In some embodiments, administration of an effective amount of a disclosed antibody or antigen binding fragment that binds to RH5 can reduce or inhibit a P. falciparum infection (for example, as measured by infection of blood cells, or by number or percentage of subjects infected by the P. falciparum, or by an increase in the survival time of infected subjects, or reduction in symptoms associated with P. falciparum infection) by a desired amount, for example by at least 10%, at least 20%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or even at least 100% (elimination or prevention of detectable P. falciparum infection), as compared to a suitable control.

The effective amount of an antibody or antigen binding fragment that specifically binds RH5 that is administered to a subject to inhibit P. falciparum infection will vary depending upon a number of factors associated with that subject, for example the overall health and/or weight of the subject. An effective amount can be determined by varying the dosage and measuring the resulting response, such as, for example, a reduction in pathogen titer. Effective amounts also can be determined through various in vitro, in vivo or in situ immunoassays.

An effective amount encompasses a fractional dose that contributes in combination with previous or subsequent administrations to attaining an effective response. For example, an effective amount of an agent can be administered in a single dose, or in several doses, for example daily, during a course of treatment lasting several days or weeks. However, the effective amount can depend on the subject being treated, the severity and type of the condition being treated, and the manner of administration. A unit dosage form of the agent can be packaged in an amount, or in multiples of the effective amount, for example, in a vial (e.g., with a pierceable lid) or syringe having sterile components.

Effector molecule: A molecule intended to have or produce a desired effect; for example, a desired effect on a cell to which the effector molecule is targeted. Effector molecules can include, for example, polypeptides and small molecules. In one non-limiting example, the effector molecule is a toxin. Some effector molecules may have or produce more than one desired effect.

Epitope: An antigenic determinant. These are particular chemical groups or peptide sequences on a molecule that are antigenic, i.e. that elicit a specific immune response. An antibody specifically binds a particular antigenic epitope on a polypeptide. In some examples a disclosed antibody specifically binds to an epitope on RH5 from P. falciparum.

Expression: Transcription or translation of a nucleic acid sequence. For example, an encoding nucleic acid sequence (such as a gene) can be expressed when its DNA is transcribed into RNA or an RNA fragment, which in some examples is processed to become mRNA. An encoding nucleic acid sequence (such as a gene) may also be expressed when its mRNA is translated into an amino acid sequence, such as a protein or a protein fragment. In a particular example, a heterologous gene is expressed when it is transcribed into an RNA. In another example, a heterologous gene is expressed when its RNA is translated into an amino acid sequence. Regulation of expression can include controls on transcription, translation, RNA transport and processing, degradation of intermediary molecules such as mRNA, or through activation, inactivation, compartmentalization or degradation of specific protein molecules after they are produced.

Expression Control Sequences: Nucleic acid sequences that regulate the expression of a heterologous nucleic acid sequence to which it is operatively linked. Expression control sequences are operatively linked to a nucleic acid sequence when the expression control sequences control and regulate the transcription and, as appropriate, translation of the nucleic acid sequence. Thus, expression control sequences can include appropriate promoters, enhancers, transcriptional terminators, a start codon (ATG) in front of a protein-encoding gene, splice signals for introns, maintenance of the correct reading frame of that gene to permit proper translation of mRNA, and stop codons. The term “control sequences” is intended to include, at a minimum, components whose presence can influence expression, and can also include additional components whose presence is advantageous, for example, leader sequences and fusion partner sequences. Expression control sequences can include a promoter.

Expression vector: A vector comprising a recombinant polynucleotide comprising expression control sequences operatively linked to a nucleotide sequence to be expressed. An expression vector comprises sufficient cis- acting elements for expression; other elements for expression can be supplied by the host cell or in an in vitro expression system. Non-limiting examples of expression vectors include cosmids, plasmids (e.g., naked or contained in liposomes) and viruses (e.g., lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses) that incorporate the recombinant polynucleotide.

A polynucleotide can be inserted into an expression vector that contains a promoter sequence which facilitates the efficient transcription of the inserted genetic sequence of the host. The expression vector typically contains an origin of replication, a promoter, as well as specific nucleic acid sequences that allow phenotypic selection of the transformed cells.

Fc region: The constant region of an antibody excluding the first heavy chain constant domain. Fc region generally refers to the last two heavy chain constant domains of IgA, IgD, and IgG, and the last three heavy chain constant domains of IgE and IgM. An Fc region may also include part or all of the flexible hinge N-terminal to these domains. For IgA and IgM, an Fc region may or may not include the tailpiece, and may or may not be bound by the J chain. For IgG, the Fc region is typically understood to include immunoglobulin domains Cy2 and Cy3 and optionally the lower part of the hinge between Cyl and Cy2. Although the boundaries of the Fc region may vary, the human IgG heavy chain Fc region is usually defined to include residues following C226 or P230 to the Fc carboxyl-terminus, wherein the numbering is according to Kabat. For IgA, the Fc region includes immunoglobulin domains Ca2 and Ca3 and optionally the lower part of the hinge between Cal and Ca2.

IgA: A polypeptide belonging to the class of antibodies that are substantially encoded by a recognized immunoglobulin alpha gene. In humans, this class or isotype comprises IgAi and IgAz. IgA antibodies can exist as monomers, polymers (referred to as plgA) of predominantly dimeric form, and secretory IgA. The constant chain of wild-type IgA contains an 18-amino-acid extension at its C-terminus called the tail piece (tp). Polymeric IgA is secreted by plasma cells with a 15-kDa peptide called the J chain linking two monomers of IgA through the conserved cysteine residue in the tail piece.

IgG: A polypeptide belonging to the class or isotype of antibodies that are substantially encoded by a recognized immunoglobulin gamma gene. In humans, this class comprises IgGi, IgGz, IgG;, and IgG i.

Immune complex: The binding of antibody or antigen binding fragment (such as a scFv) to a soluble antigen forms an immune complex. The formation of an immune complex can be detected through conventional methods, for instance immunohistochemistry, immunoprecipitation, flow cytometry, immunofluorescence microscopy, ELISA, immunoblotting (for example, Western blot), magnetic resonance imaging, CT scans, radiography, and affinity chromatography.

Inhibiting a disease or condition: Reducing the full development of a disease or condition in a subject, for example, reducing the full development of a P. falciparum infection in a subject who is at risk of a P. falciparum infection. This includes neutralizing, antagonizing, prohibiting, preventing, restraining, slowing, disrupting, stopping, or reversing progression or severity of the disease or condition.

Inhibiting a disease or condition refers to a prophylactic intervention administered before the disease or condition has begun to develop (for example a treatment initiated in a subject at risk of P. falciparum infection, but not infected by P. falciparum) that reduces subsequent development of the disease or condition and/or ameliorates a sign or symptom of the disease or condition following development. The term “ameliorating,” with reference to inhibiting a disease or condition refers to any observable beneficial effect of the prophylactic intervention intended to inhibit the disease or condition. The beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease or condition in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease or condition, a slower progression of the disease or condition, an improvement in the overall health or well-being of the subject, a reduction in infection, inhibition of clinical symptoms of a blood stage infection, or by other parameters known in the art that are specific to the particular disease or condition.

In some embodiments, the disclosed RH5-specific antibodies and antigen binding fragments inhibit the blood stage of Plasmodium falciparum. For example, the disclosed RH5-specific antibodies and antigen binding fragments can inhibit the invasion of Plasmodium falciparum cells by at least 20%, at least 30%, at least 40%, or at least 50%, compared to a suitable control. In some embodiments, the disclosed RH5-specific antibodies and antigen binding fragments inhibit the growth of Plasmodium falciparum in a subject, for example, the antibodies and antigen binding fragments inhibit the multiplication of Plasmodium falciparum in the subject, resulting in a reduction in pathogen load in the subject compared to a relevant control. For example, the disclosed RH5-specific antibodies and antigen binding fragments can inhibit the amount of Plasmodium falciparum merozoites or schizonts in the blood of a subject by at least 20%, at least 30%, at least 40%, or at least 50%, compared to a suitable control.

Isolated: A biological component (such as a nucleic acid, peptide, protein or protein complex, for example an antibody) that has been substantially separated, produced apart from, or purified away from other biological components in the cell of the organism in which the component naturally occurs, that is, other chromosomal and extra-chromosomal DNA and RNA, and proteins. Thus, isolated nucleic acids, peptides and proteins include nucleic acids and proteins purified by standard purification methods. The term also embraces nucleic acids, peptides and proteins prepared by recombinant expression in a host cell, as well as, chemically synthesized nucleic acids. An isolated nucleic acid, peptide or protein, for example an antibody, can be at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% pure.

Kabat position: A position of a residue in an amino acid sequence that follows the numbering convention delineated by Kabat et al. (Sequences of Proteins of Immunological Interest, 5^th Edition, Department of Health and Human Services, Public Health Service, National Institutes of Health, Bethesda, NIH Publication No. 91-3242, 1991).

L9 Antibody: A monoclonal antibody that specifically binds to an epitope on PfCSP and neutralizes malaria infection. The L9 antibody, including the amino acid sequences of the heavy and light variable regions and methods for its production are described, for example, in PCT Pub. No. WO 2020/227228, which is incorporated by reference herein in its entirety.

Linker: A bi-functional molecule that can be used to link two molecules into one contiguous molecule, for example, to link an effector molecule to an antibody. Non-limiting examples of peptide linkers include glycine-serine linkers.

The terms “conjugating,” “joining,” “bonding,” or “linking” can refer to making two molecules into one contiguous molecule; for example, linking two polypeptides into one contiguous polypeptide, or covalently attaching an effector molecule or detectable marker radionuclide or other molecule to a polypeptide, such as an scFv. The linkage can be either by chemical or recombinant means. “Chemical means” refers to a reaction between the antibody moiety and the effector molecule such that there is a covalent bond formed between the two molecules to form one molecule.

Malaria: Malaria is a parasitic infection of humans by the Plasmodium species P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi. Humans become infected following the bite of an infected mosquito, the host of the malarial parasite. Malaria rarely occurs in humans following a blood transfusion or subsequent to needle-sharing. Clinical manifestations of malarial infection which may occur include blackwater fever, cerebral malaria, respiratory failure, hepatic necrosis, occlusion of myocardial capillaries and death. The major protein on the surface of the infecting P. falciparum sporozoites is the circumsporozoite protein (PfCSP).

Infection begins when malaria sporozoites gain access to or are directly injected into the bloodstream of a host by a mosquito. After injection, they migrate to the liver and multiply in hepatocytes for -one week. The sporozoites substantially expand in the liver and differentiate to merozoites which are released from the liver into the blood stream, where they infect erythrocytes and begin the “blood-stage.” When the merozoite matures in the red blood cell, it is known as a trophozoite and, when fully developed, as a schizont. A schizont is the stage when nuclear division occurs to form individual merozoites which are released to invade other red cells. Malaria clinical symptoms appear during the blood-stage. After several schizogonic cycles, some parasites, instead of becoming schizonts through asexual reproduction, develop into large uninucleate parasites, know as gametocytes. These gametocytes are the sexual blood cell stage forms of the parasite.

Sexual development of the malaria parasites involves the female macrogametocyte and the male microgametocyte. If a mosquito feeds on the blood of an infected host, it can ingest gametocytes within the blood. Fertilization and sexual recombination of the parasite occurs in the mosquito's gut. The fertilized parasite, which is known as a zygote, then develops into an ookinete. The ookinete penetrates the midgut wall of the mosquito and develops into an oocyst, within which many small sporozoites form. When the oocyst ruptures, the sporozoites migrate to the salivary gland of the mosquito via the hemolymph. Once in the saliva of the mosquito, the parasite can be injected into a host, repeating the life cycle.

Nucleic acid (molecule or sequence): A deoxyribonucleotide or ribonucleotide polymer or combination thereof including without limitation, cDNA, mRNA, genomic DNA, and synthetic (such as chemically synthesized) DNA or RNA. The nucleic acid can be double stranded (ds) or single stranded (ss). Where single stranded, the nucleic acid can be the sense strand or the antisense strand. Nucleic acids can include natural nucleotides (such as A, T/U, C, and G), and can include analogs of natural nucleotides, such as labeled nucleotides.

“cDNA” refers to a DNA that is complementary or identical to an mRNA, in either single stranded or double stranded form.

“Encoding” refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (i.e., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom. Thus, a gene encodes a protein if transcription and translation of mRNA produced by that gene produces the protein in a cell or other biological system. Both the coding strand, the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings, and non-coding strand, used as the template for transcription, of a gene or cDNA can be referred to as encoding the protein or other product of that gene or cDNA. Unless otherwise specified, a “nucleotide sequence encoding an amino acid sequence” includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. Nucleotide sequences that encode proteins and RNA may include introns.

Operably linked: A first nucleic acid sequence is operably linked with a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence. For instance, a promoter, such as the CMV promoter, is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Generally, operably linked DNA sequences are contiguous and, where necessary to join two protein-coding regions, in the same reading frame.

Pharmaceutically acceptable carriers: The pharmaceutically acceptable carriers of use are conventional. Remington: The Science and Practice of Pharmacy, 22^,ul ed. , London, UK: Pharmaceutical Press, 2013, describes compositions and formulations suitable for pharmaceutical delivery of the disclosed agents.

In general, the nature of the carrier will depend on the particular mode of administration being employed. For instance, parenteral formulations usually include injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle. For solid compositions (e.g., powder, pill, tablet, or capsule forms), conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate. In addition to biologically neutral carriers, pharmaceutical compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, added preservatives (such as non-natural preservatives), and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate. In particular examples, the pharmaceutically acceptable carrier is sterile and suitable for parenteral administration to a subject for example, by injection. In some embodiments, the active agent and pharmaceutically acceptable carrier are provided in a unit dosage form such as a pill or in a selected quantity in a vial. Unit dosage forms can include one dosage or multiple dosages (for example, in a vial from which metered dosages of the agents can selectively be dispensed).

Polypeptide: A polymer in which the monomers are amino acid residues that are joined together through amide bonds. When the amino acids are alpha-amino acids, either the L-optical isomer or the D- optical isomer can be used, the L-isomers being preferred. The terms “polypeptide” or “protein” as used herein are intended to encompass any amino acid sequence and include modified sequences such as glycoproteins. A polypeptide includes both naturally occurring proteins, as well as those that are recombinantly or synthetically produced. A polypeptide has an amino terminal (N-terminal) end and a carboxy-terminal end. In some embodiments, the polypeptide is a disclosed antibody or a fragment thereof.

Purified: The term purified does not require absolute purity; rather, it is intended as a relative term. Thus, for example, a purified peptide preparation is one in which the peptide or protein (such as an antibody) is more enriched than the peptide or protein is in its natural environment within a cell. In one embodiment, a preparation is purified such that the protein or peptide represents at least 50% of the total peptide or protein content of the preparation.

Recombinant: A recombinant nucleic acid is one that has a sequence that is not naturally occurring or has a sequence that is made by an artificial combination of two otherwise separated segments of sequence. This artificial combination can be accomplished by chemical synthesis or, more commonly, by the artificial manipulation of isolated segments of nucleic acids, for example, by genetic engineering techniques. A recombinant protein is one that has a sequence that is not naturally occurring or has a sequence that is made by an artificial combination of two otherwise separated segments of sequence. In several embodiments, a recombinant protein is encoded by a heterologous (for example, recombinant) nucleic acid that has been introduced into a host cell, such as a bacterial or eukaryotic cell. The nucleic acid can be introduced, for example, on an expression vector having signals capable of expressing the protein encoded by the introduced nucleic acid or the nucleic acid can be integrated into the host cell chromosome.

Reticulocyte Binding Protein Homolog (RH)5: A protein that acts as a part of a multi-protein complex with Rh5 interacting protein (Ripr, PF3D7_0323400) (Chen et al., PLoS Pathog.

201 l;7:el002199), cysteine rich protein antigen (CyRPA, PF3D7JJ423800) (Reddy et al., Proc Natl Acad Sci USA. 2015:112: 1179-84) and Pl 13 (PF3D7_1420700) (Galaway et al., Proc Natl Acad Sci USA. 2015; 112: 1179-84). Both CyRPA and PfRIPR are housed within parasite micronemes and are released during merozoite invasion to facilitate entrance into the erythrocyte via their assembly into a trimeric complex with PfRH5. This RH5-CyRPA-Ripr complex binds better to the erythrocyte cell surface than RH5 alone. In vivo, interaction of RH5 with its erythrocyte surface protein receptor, basigin, triggers a transient increase in Ca²⁺ concentration and alters the erythrocyte cytoskeleton. RH5 undergoes proteolytic cleavage, resulting in fragments of approximately 18 kDa and 45 kDa. RH5 binds directly to Pl 13 (via the smaller Rh5 fragment, and CyRPA, while Ripr is associated with Rh5 through its interaction with CyRPA.

Therefore, CyRPA forms the contact sites for RH5 and Ripr. PfRH5-PfCyRPA-PfRipr form the RCR complex.

Sequence identity: The identity between two or more nucleic acid sequences, or two or more amino acid sequences, is expressed in terms of the identity between the sequences. Sequence identity can be measured in terms of percentage identity; the higher the percentage, the more identical the sequences. Homologs and variants of a VL or a VH of an antibody that specifically binds a target antigen are typically characterized by possession of at least about 75% sequence identity, for example at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity counted over the full-length alignment with the amino acid sequence of interest.

Methods of alignment of sequences for comparison are well known in the art. Various programs and alignment algorithms are described in: Smith and Waterman, Adv. AppL Math. 2(4):482-489, 1981; Needleman and Wunsch, J. Mol. Biol. 48(3):443-453, 1970; Pearson and Lipman, Proc. Natl. Acad. Sci. U.S.A. 85(8):2444-2448, 1988; Higgins and Sharp, Gene, 73(l):237-244, 1988; Higgins and Sharp, Bioinformatics. 5(2): 151-3, 1989; Corpet, Nucleic Acids Res. 16(22): 10881-10890, 1988; Huang et al. Bioinformatics. 8(2): 155-165, 1992; and Pearson, Methods Mol. Biol. 24:307-331, 1994. Altschul et al., J. Mol. Biol. 215(3):403-410, 1990, presents a detailed consideration of sequence alignment methods and homology calculations. The NCBI Basic Local Alignment Search Tool (BLAST) (Altschul et al., J. Mol. Biol. 215(3):403-410, 1990) is available from several sources, including the National Center for Biological Information and on the Internet, for use in connection with the sequence analysis programs blastp, blastn, blastx, tblastn, and tblastx. Blastn is used to compare nucleic acid sequences, while blastp is used to compare amino acid sequences. Additional information can be found at the NCBI web site.

Generally, once two sequences are aligned, the number of matches is determined by counting the number of positions where an identical nucleotide or amino acid residue is present in both sequences. The percent sequence identity between the two sequences is determined by dividing the number of matches either by the length of the sequence set forth in the identified sequence, or by an articulated length (such as 100 consecutive nucleotides or amino acid residues from a sequence set forth in an identified sequence), followed by multiplying the resulting value by 100.

Specifically bind: When referring to an antibody or antigen binding fragment, refers to a binding reaction which determines the presence of a target protein in the presence of a heterogeneous population of proteins and other biologies. Thus, under designated conditions, an antibody binds preferentially to a particular target protein, peptide or polysaccharide (such as an antigen present on a pathogen, such as RH5 ) and does not bind in a significant amount to other proteins present in the sample or subject. Specific binding can be determined by standard methods. See Harlow & Lane, Antibodies, A Laboratory Manual, 2^nd ed., Cold Spring Harbor Publications, New York (2013), for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity.

With reference to an antibody-antigen complex, specific binding of the antigen and antibody has a KD of less than about 10'⁷ Molar, such as less than about 10'⁸ Molar, 10'⁹, or even less than about IO ¹⁰ Molar. KD refers to the dissociation constant for a given interaction, such as a polypeptide ligand interaction or an antibody antigen interaction. For example, for the bimolecular interaction of an antibody or antigen binding fragment and an antigen it is the concentration of the individual components of the bimolecular interaction divided by the concentration of the complex.

An antibody that specifically binds to an epitope on RH5 is an antibody that binds substantially to RH5, a cell transformed to express RH5, a substrate to which the RH5 is attached, or RH5 in a biological specimen. It is, of course, recognized that a certain degree of non-specific interaction may occur between an antibody or conjugate including an antibody (such as an antibody that specifically binds RH5 or conjugate including such antibody) and a non-target (such as a cell that does not express RH5). Typically, specific binding results in a much stronger association between the antibody and protein or cells bearing the antigen than between the antibody and protein or cells lacking the antigen. Specific binding typically results in greater than 2-fold, such as greater than 5-fold, greater than 10-fold, or greater than 100-fold increase in amount of bound antibody (per unit time) to a protein including the epitope or cell or tissue expressing the target epitope as compared to a protein or cell or tissue lacking this epitope. Specific binding to a protein under such conditions requires an antibody that is selected for its specificity for a particular protein. A variety of immunoassay formats are appropriate for selecting antibodies or other ligands specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select monoclonal antibodies specifically immunoreactive with a protein.

Subject: Living multi-cellular vertebrate organisms, a category that includes human and nonhuman mammals. In an example, a subject is a human. In an additional example, a subject is selected that is in need of inhibiting a P. falciparum infection. For example, the subject is uninfected and at risk of P. falciparum infection.

Transformed: A transformed cell is a cell into which a nucleic acid molecule has been introduced by molecular biology techniques. As used herein, the term transformed and the like e.g., transformation, transfection, transduction, etc.) encompasses all techniques by which a nucleic acid molecule might be introduced into such a cell, including transduction with viral vectors, transformation with plasmid vectors, and introduction of DNA by electroporation, lipofection, and particle gun acceleration.

Vector: An entity containing a nucleic acid molecule (such as a DNA or RNA molecule) bearing a promoter(s) that is operationally linked to the coding sequence of a protein of interest and can express the coding sequence. Non-limiting examples include a naked or packaged (lipid and/or protein) DNA, a naked or packaged RNA, a subcomponent of a virus or bacterium or other microorganism that may be replicationincompetent, or a virus or bacterium or other microorganism that may be replication-competent. A vector is sometimes referred to as a construct. Recombinant DNA vectors are vectors having recombinant DNA. A vector can include nucleic acid sequences that permit it to replicate in a host cell, such as an origin of replication. A vector can also include one or more selectable marker genes and other genetic elements. Viral vectors are recombinant nucleic acid vectors having at least some nucleic acid sequences derived from one or more viruses. In some embodiments, a viral vector comprises a nucleic acid molecule encoding a disclosed antibody or antigen binding fragment that specifically binds to RH5 and neutralizes P. falciparum. In some embodiments, the viral vector can be an adeno-associated virus (AAV) vector.

II. Description of Several Embodiments

A. Neutralizing Monoclonal Antibodies to RH5 and Antigen Binding Fragments Thereof

Isolated monoclonal antibodies and antigen binding fragments that specifically bind an epitope on RH5 are provided. The antibodies and antigen binding fragments can be fully human. The antibodies and antigen binding fragments can neutralize P. falciparum, for example the disclosed antibodies can inhibit invasion of red blood cells by merozoitesln some embodiments, the use of the disclosed antibodies reduces the amount of merozoites and/or schizonts in the blood. Also disclosed herein are compositions comprising the antibodies and antigen binding fragments and a pharmaceutically acceptable carrier. Nucleic acids encoding the antibodies or antigen binding fragments, expression vectors (such as DNA and RNA vectors for expression and delivery, as well as adeno-associated virus (AAV) viral vectors) comprising these nucleic acids are also provided. The antibodies, antigen binding fragments, nucleic acid molecules, host cells, and compositions can be used for research, diagnostic and prophylactic purposes. For example, the disclosed antibodies and antigen binding fragments can be used to diagnose a subject with a P. falciparum infection, or can be administered prophylactically to inhibit P. falciparum infection in a subject.

1. Exemplary monoclonal antibodies and antigen binding fragments

The discussion of monoclonal antibodies below refers to isolated monoclonal antibodies that include heavy and/or light chain variable domains (or antigen binding fragments thereof) comprising a CDR1, CDR2, and/or CDR3 with reference to the IMGT numbering scheme (unless the context indicates otherwise). Various CDR numbering schemes (such as the Kabat, Chothia or IMGT numbering schemes) can be used to determine CDR positions. The amino acid sequence and the CDR positions (according to the IMGT numbering scheme) of the heavy and light chains of exemplary monoclonal antibodies that bind to RH5 and neutralize P. falciparum are listed above. a. MAD8-502

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD8- 502 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD8-502 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 1, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 5, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 1 and 5, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 2, 3 and 4, respectively, and a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 6, 7, and 8 respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 2, 3 and 4, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 6, 7, and 8, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 1 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 1), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 5 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 2, 3 and 4, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 6, 7, and 8, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 1, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 5, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 1, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 5, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 1 and 5, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. b. MAD8-151

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD8- 151 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD8-151 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 9, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 13, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 9 and 13, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 10, 11 and 12, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 14, 15, and 16 respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 10, 11 and 12, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 14, 15 and 16, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 9 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 9), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 13 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 13) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 10, 11 and 12, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 14, 15 and 16, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 9, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 13, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 9, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 13, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 9 and 13, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. c. MAD10-192

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 10- 192 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-192 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 17, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 21, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 17 and 21, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 18, 19 and 20, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 22, 23 and 24 respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1 , a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 18, 19 and 20, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 22, 23 and 24, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 17 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 17), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 21 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 21) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 18, 19 and 20, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 22, 23 and 24, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 17, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 21, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 17, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 21, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 17 and 21, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. d. MAD10-219

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 10- 219 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to 1MGT, Kabat, or Chothia), of the MAD10-219 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 25, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 29, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a Vn and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 25 and 29, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 26, 27 and 28, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 30, 31 and 32 respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 26, 27 and 28, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 30, 31 and 32, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 25 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 25), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 29 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 29) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 26, 27 and 28, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 30, 31 and 32, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 25, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 29, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 25, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 29, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 25 and 29, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. e. MAD10-255

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 10- 255 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a Vi, and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-255 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 33, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 37, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 33 and 37, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs:34, 35 and 36, respectively, and a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 38, 39 and 40 respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 34, 35 and 36, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 38, 39 and 40, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 33 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 33), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 37 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 37) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 34, 35 and 36, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 38, 39 and 40, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 33, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 37, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 33, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 37, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 33 and 37, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control.

/. MAD10-437

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 10- 437 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-437 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 41, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 45, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 41 and 45, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs:42, 43 and 44, respectively, and a V Comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 46, 47 and 48, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 42, 43 and 44, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 46, 47 and 48, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 41 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 41), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 45 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 45) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 42, 43 and 44, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 46, 47 and 48, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 41, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 45, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 41, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 45, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 41 and 45, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. g. MAD10-466

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 10- 437 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-466 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 49, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 53, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 49 and 53, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 50, 51 and 52, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 54, 55 and 56 respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 50, 51 and 52, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 54, 55 and 56, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 49 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 49), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 53 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 53) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 50, 51 and 52, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 54, 55 and 56, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 49, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 53, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 49, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 53, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 49 and 53, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. h. MAD10-291

In some aspects, the antibody or antigen binding fragment is based on or derived from the M ADI fl- 291 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a Vii an a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-291 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a Vn comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 57, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 61, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 57 and 61, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 58, 59 and 60, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 62, 63 and 64, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 58, 59 and 60, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 62, 63 and 64, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 57 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 57), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 61 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 61) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 58, 59 and 60, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 62, 63 and 64, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 57, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 61, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 57, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a V comprising the amino acid sequence set forth as SEQ ID NO: 61, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 57 and 61, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. i. MAD10-349

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD10- 349 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a Vnand a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-349 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 65, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 69, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 65 and 69, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 66, 67 and 68, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 70, 71 and 72 respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 66, 67 and 68, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 70, 71 and 72, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 65 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 65), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 69 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 69) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 66, 67 and 68, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 70, 71 and 72 respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 65, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 69, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 65, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 69, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 65 and 69, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. j. MAD10-439

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD10- 439 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a Vnand a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-439 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 73, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 77, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 73 and 77, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1 , a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 74, 75 and 76, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 78, 79 and 80 respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a Vn comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 74, 75 and 76, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 78, 79 and 80, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 73 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 73), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 77 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 77) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 74, 75 and 76, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 78, 79 and 80, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 73, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 77, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 73, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 77, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 73 and 77, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. k. MAD 10-30

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 10- 30 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VH and a Vi. comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-30 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 81, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 85, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 81 and 85, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 82, 83 and 84, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 86, 87 and 88, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 82, 83 and 84 respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 86, 87 and 88 respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 81 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 81), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 85 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 85) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs:82, 83 and 84, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 86, 86 and 88 respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 81, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 85, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 81, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 85, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 81 and 85, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

/. MAD10-447

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD10- 447 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a V,, and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-447 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 89, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 93, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 89 and 93, respectively, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 90, 91 and 92, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 94, 95 and 96, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 90, 91 and 92, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 94, 95 and 96 respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 89 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 89), the V comprises an amino acid sequence at least 90% identical to SEQ ID NO: 93 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 93) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs:90, 91 and 92, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 94, 95 and 96, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 89, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 93, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 89, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 93, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 89 and 93, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. m. MAD10-378

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 10- 378 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-378 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 97, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 101, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 97 and 101, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 98, 99 and 100, respectively, and a V comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 102, 103 and 104, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 98, 99 and 100, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 102, 103 and 104, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 97 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 97), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 101 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 101) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs:98, 99 and 100, respectively, a V_L comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 102, 103 and 104, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 97, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 101, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 97, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 101, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 97 and 101, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. n. MAD10-137

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 10- 137 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-137 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 105, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 109, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 105 and 109, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 106, 107 and 108, respectively, and a V_Lcomprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 110, 111 and 112, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 106, 107 and 108, respectively, a VLcomprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 110, 111 and 112, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 105 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 105), the V comprises an amino acid sequence at least 90% identical to SEQ ID NO: 109 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 109) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 106, 107 and 108, respectively, a V comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs 110, 111 and 112, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 105, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 109, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 105, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 109, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 105 and 109, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. o. MAD10-434

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 1 fl- 434 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a Vn and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-434 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 113, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 117, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 113 and 117, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 114, 115 and 116, respectively, and a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 118, 119 and 120, respectively, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 114, 115 and 116, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 118, 119 and 120, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 113 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 113), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 117 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 117) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 114, 115 and 116, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs 118, 119 and 120, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 113, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 117, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 113, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a V comprising the amino acid sequence set forth as SEQ ID NO: 117, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 113 and 117, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. p. MAD10-410

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 10- 410 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-410 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 121, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 125, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 121 and 125, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 122, 123 and 124, respectively, and a V Comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 126, 127 and 128, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 122, 123, and 124, respectively, a VL Comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 126, 127 and 128, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 121 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 121), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 125 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 125) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 122, 123 and 124, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs 126, 127 and 128, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 121, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 125, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 121, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 125, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 121 and 125, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. q. MAD10-371

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 10- 371 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-371 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 129, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 133, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 129 and 133, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 130, 131 and 132, respectively, and a V Comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 134, 135 and 136, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 130, 131 and 132, respectively, a V_Lcomprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 134, 135 and 136, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 129 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 129), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 133 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 133) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 130, 131 and 132, respectively, a VLcomprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs 134, 135 and 136, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 129, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 133, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 129, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 133, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 129 and 133, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. r. MAD10-313

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 10- 313 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1 , the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-313 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 137, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 141, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 137 and 141, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 138, 139 and 140, respectively, and a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 142, 143 and 144, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 138, 139 and 140, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 142, 143 and 144, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 137 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 137), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 141 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 141) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 138, 139 and 140, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs 142, 143 and 144, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 137, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 141, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 137, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 141 , and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 137 and 141, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

5. MAD10-479

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD10- 479 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a Vn nd a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-479 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 145, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 149, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 145 and 149, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 146, 147 and 148, respectively, and a Vi coruprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 150, 151 and 152, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 146, 147 and 148, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 150, 151 and 152, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 145 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 145), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 149 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 149) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 146, 147 and 148, respectively, a Vrcomprising a LCDR1 , a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 150, 151 and 152, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 145, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 149, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 145, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 149, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 145 and 149, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. t. MAD10-326

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 10- 326 antibody, and specifically binds to RH5 and neutralizes P . falciparum. For example, the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-326 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 153, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 157, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 153 and 157, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 154, 155 and 156, respectively, and a Vrcomprising a LCDR1 , a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 158, 159 and 160, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 154, 155 and 156, respectively, a V Comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 158, 159 and 160, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 153 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 153), the V comprises an amino acid sequence at least 90% identical to SEQ ID NO: 157 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 157) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 154, 155 and 156, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 158, 159 and 160, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 153, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 157, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 153, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 157, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 153 and 157, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. u. MAD10-216

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 10- 216 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-216 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 161, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 165, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 161 and 165, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 162, 163 and 164, respectively, and a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 166, 167 and 168, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 162, 163 and 164, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 166, 167 and 168, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 161 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 161), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 165 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 165) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 162, 163 and 164, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs 166, 167 and 168, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 161, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 165, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 161, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 165, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a Vi, comprising the amino acid sequences set forth as SEQ ID NOs: 161 and 165, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. v. MAD10-385

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD10- 385 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a V,, and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-385 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 169, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 173, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 169 and 173, respectively, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 170, 171 and 172, respectively, and a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 174, 175 and 176, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 170, 171 and 172, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 174, 175 and 176, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 169 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 169), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 173 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 173) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 170, 171 and 172, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 174, 175 and 176, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 169, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 173, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 169, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 173, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 169 and 173, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. w. MAD10-494

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 10- 494 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-494 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 177, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 181, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 177 and 181, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 178, 179 and 180, respectively, and a V Comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 182, 183 and 184, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 178, 179 and 180, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 182, 183 and 184, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 177 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 177), the V comprises an amino acid sequence at least 90% identical to SEQ ID NO: 181 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 181) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 178, 179 and 180, respectively, a V_Lcomprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 182, 183 and 184, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 177, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 181, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 177, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 181, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 177 and 181, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. x. MAD10-485

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 10- 485 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-485 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 185, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 189, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 185 and 189, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 186, 187 and 188, respectively, and a V_Lcomprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 190, 191 and 192, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 186, 187 and 188, respectively, a VLcomprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 190, 191 and 192, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 185 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 185), the V comprises an amino acid sequence at least 90% identical to SEQ ID NO: 189 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 189) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 186, 187 and 188, respectively, a VLcomprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs 190, 191 and 192, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 185, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 189, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 185, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 189, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 185 and 189, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. y. MAD10-416

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 10- 416 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a Vn and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-416 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 193, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 197, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 193 and 197, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 194, 195 and 196, respectively, and a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 198, 199 and 200, respectively, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 194, 195 and 196, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 198, 199 and 200, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 193 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 193), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 197 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 197) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 194, 195 and 196, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 198, 199 and 200, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 193, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 197, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 193, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a V comprising the amino acid sequence set forth as SEQ ID NO: 197, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 193 and 197, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. z. MAD10-458

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 10- 458 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-458 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 201, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 205, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 201 and 205, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 202, 203 and 204, respectively, and a V Comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 206, 207 and 208, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 202, 203 and 204, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 206, 207 and 208, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 201 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 201), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 205 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 205) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 202, 203 and 204, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 206, 207 and 208, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 201, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 205, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 201 and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 205, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 201 and 205, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. aa. MAD10-409

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 10- 409 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-409 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 209, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 213, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 209 and 213, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 210, 211 and 212, respectively, and a V Comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 214, 215 and 216, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 210, 211 and 212, respectively, a V_Lcomprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 214, 215 and 216, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 209 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 209), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 213 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 213) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 210, 211 and 212, respectively, a VLcomprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 214, 215 and 216, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 209, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 213, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 209 and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 213, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 209 and 213, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. bb. MAD10-412

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 10- 412 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1 , the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-412 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 217, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 221, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 217 and 221, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 218, 219 and 220, respectively, and a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 222, 223 and 224, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 218, 219 and 220, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 222, 223 and 224, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 217 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 217), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 221 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 221) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 218, 219 and 220, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 222, 223 and 224, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 217, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 221, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 217 and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 221 , and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 217 and 221, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. cc. MAD10-435

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD10- 435 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a Vn nd a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-435 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 225, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 229, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 225 and 229, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 226, 227 and 228, respectively, and a Vi coruprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 230, 231 and 232, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 226, 227 and 228, respectively, a VLeomprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 230, 231 and 232, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 225 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 225), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 229 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 229) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 226, 227 and 228, respectively, a Vrcomprising a LCDR1 , a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 230, 231 and 232, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 225, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 229, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 225 and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 229, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 225 and 229, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. dd. MAD10-81

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 10- 81 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-81 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 233, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 237, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 233 and 237, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 234, 235 and 236, respectively, and a Vrcomprising a LCDR1 , a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 238, 239 and 240, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 234, 235 and 236, respectively, a V Comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 238, 239 and 240, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 233 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 233), the V comprises an amino acid sequence at least 90% identical to SEQ ID NO: 237 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 237) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 234, 235 and 236, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 238, 239 and 240, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 233, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 237, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 233 and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 237, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 233 and 237, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. ee. MAD10-429

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 10- 429 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-429 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 241, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 245, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 241 and 245, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 242, 243 and 244, respectively, and a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 246, 247 and 248, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 242, 243 and 244, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 246, 247 and 248, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 241 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 241), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 245 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 245) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 242, 243 and 244, respectively, a VLeomprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 246, 247 and 248, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 241, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 245, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 241 and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 245, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a Vi, comprising the amino acid sequences set forth as SEQ ID NOs: 241 and 245, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. ff. MAD10-407

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD10- 407 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a V,, and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-407 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 249, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 253, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 249 and 253, respectively, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 250, 251 and 252, respectively, and a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 254, 255 and 256, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 250, 251 and 252, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 254, 255 and 256, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 249 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 249), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 253 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 253) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 250, 251 and 252, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 254, 255 and 256, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 249, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 253, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 249 and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 253, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 249 and 253, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. gg. MAD10-432

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 10- 432 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-432 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 257, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 261, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 257 and 261, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 258, 259 and 260, respectively, and a V comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs:262, 263 and 264, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1 , a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 258, 259 and 260, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 262, 263 and 264, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 257 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 257), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 261 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 261) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 258, 259 and 260, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs 262, 263 and 264, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 257, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 261, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 257 and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 261, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 257 and 261, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. hh. MAD10-50

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 10- 50 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to 1MGT, Kabat, or Chothia), of the MAD10-50 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 265, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 269, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a Vn and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 265 and 269, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 266, 267 and 268, respectively, and a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 270, 271 and 272, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 266, 267 and 268, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 270, 271 and 272, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 265 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 265), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 269 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 269) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 266, 267 and 268, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 270, 271 and 272, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 265, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 269, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 265 and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 269, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 265 and 269, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the disclosed antibodies and antigen binding fragments inhibit blood stage Plasmodium falciparum, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control. ii. MAD10-370

In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD 10- 370 antibody, and specifically binds to RH5 and neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a Vi, and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD10-370 antibody, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as 57 least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 273, and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 277, and specifically binds to RH5 and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 273 and 277, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 274, 275 and 276, respectively, and a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 278, 279 and 280, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 274, 275 and 276, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 278, 279 and 280, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 273 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 273), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 277 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 277) and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In some aspects, the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 274, 275 and 276, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 278, 279 and 280, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth SEQ ID NO: 273, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as SEQ ID NO: 277, and the antibody or antigen binding fragment specifically binds to RH5 and neutralizes P. falciparum.

In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 273 and specifically binds to RH5 and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a V comprising the amino acid sequence set forth as SEQ ID NO: 277, and specifically binds to RH5 and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 273 and 277, respectively, and specifically binds to RH5 and neutralizes P. falciparum.

2. Additional Description of Antibodies and Antigen Binding Fragments

The antibody or antigen binding fragment can be a human antibody or fragment thereof. Chimeric antibodies are also provided. The antibody or antigen binding fragment can include any suitable framework region, such as (but not limited to) a human framework region. Human framework regions, and mutations that can be made in human antibody framework regions, are known (see, for example, in U.S. Patent No. 5,585,089, which is incorporated herein by reference). Alternatively, a heterologous framework region, such as, but not limited to a mouse or monkey framework region, can be included in the heavy or light chain of the antibodies. (See, for example, Jones et al., Nature, 321(6069):522-525, 1986; Riechmann et al., Nature, 332(6162):323-327, 1988; Verhoeyen et al., Science 239(4847):1534-1536, 1988; Carter et al., Proc. Natl. Acad. Sci. U.S.A. 89(10):4285-4289, 1992; Sandhu, Crit. Rev. Biotechnol. 12(5-6) 437 -462, 1992; and Singer et al., J. Immunol.150(7 f 2844-2857 , 1993.) In some aspects, antigen binding fragments of MAD8-502, MAD8-151, MAD10-192, MAD10-219, MAD10-255, MAD10-466, MAD10-437, MAD10-291, MAD10- 349, MAD10-439, MAD10-30, MAD10-447, MAD10-378, MAD10-137, MAD10-434, MAD10-410, MAD10-371, MAD10-313, MAD10-479, MAD10-326, MAD10-216, MAD10-385, MAD10-494, MAD10- 485, MAD10-416, MAD10-458, MAD10-409, MAD10-412, MAD10-435, MAD10-81, MAD10-429, MAD10-407, MAD10-432 , MAD10-50, and MAD10-37 are provided.

The antibody can be of any isotype. The antibody can be, for example, an IgM or an IgG antibody, such as IgGi. IgG₂, IgGs, or IgG4. The class of an antibody that specifically binds RH5 can be switched with another. In one aspect, a nucleic acid molecule encoding VL or VH is isolated such that it does not include any nucleic acid sequences encoding the constant region of the light or heavy chain, respectively. A nucleic acid molecule encoding VL or VH is then operatively linked to a nucleic acid sequence encoding a CL or CH from a different class of immunoglobulin molecule. This can be achieved, for example, using a vector or nucleic acid molecule that comprises a Ci. or CH chain. For example, an antibody that specifically binds RH5, that was originally IgG may be class switched to an IgM. Class switching can be used to convert one IgG subclass to another, such as from IgGi to IgG?, IgGj, or IgG.;.

In some examples, the disclosed antibodies are oligomers of antibodies, such as dimers, trimers, tetramers, pentamers, hexamers, septamers, octomers and so on.

The antibody or antigen binding fragment can be derivatized or linked to another molecule (such as another peptide or protein). In general, the antibody or antigen binding fragment is derivatized such that the binding to P. falciparum is not affected adversely by the derivatization or labeling. For example, the antibody or antigen binding fragment can be functionally linked (by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody (for example, a bi-specific antibody or a diabody), a detectable marker, an effector molecule, or a protein or peptide that can mediate association of the antibody or antibody portion with another molecule (such as a streptavidin core region or a polyhistidine tag).

(a) Binding affinity

In several embodiments, the antibody or antigen binding fragment specifically binds RH5 with an affinity (e.g., measured by KD) of no more than 1.0 x 10’⁸ M, no more than 5.0 x 10’⁸ M, no more than 1.0 x 10⁹ M, no more than 5.0 x 10⁹ M, no more than 1.0 x 10 ¹⁰ M, no more than 5.0 x 10 ¹⁰ M, or no more than 1.0 x 10 ¹¹ M. KD can be measured, for example, by a radiolabeled antigen binding assay (RIA) performed with the Fab version of an antibody of interest and its antigen using known methods. In one assay, solution binding affinity of Fabs for antigen is measured by equilibrating Fab with a minimal concentration of (¹²⁵I)- labeled antigen in the presence of a titration series of unlabeled antigen, then capturing bound antigen with an anti-Fab antibody-coated plate (see, e.g., Chen et al., J. Mol. Biol. 293(4):865-881, 1999). To establish conditions for the assay, MICROTITER® multi-well plates (Thermo Scientific) are coated overnight with 5ig/ml of a capturing anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), and subsequently blocked with 2% (w/v) bovine serum albumin in PBS for two to five hours at room temperature (approximately 23° C.). In a non-adsorbent plate (Nunc™ Catalog #269620), 100 pM or 26 pM [¹²³I]- antigen are mixed with serial dilutions of a Fab of interest (e.g., consistent with assessment of the anti- VEGF antibody, Fab-12, in Presta et al., Cancer Res. 57(20):4593-4599, 1997). The Fab of interest is then incubated overnight; however, the incubation may continue for a longer period (e.g., about 65 hours) to ensure that equilibrium is reached. Thereafter, the mixtures are transferred to the capture plate for incubation at room temperature (e.g., for one hour). The solution is then removed and the plate washed eight times with 0.1% polysorbate 20 (TWEEN-20®) in PBS. When the plates have dried, 150 nl/well of scintillant (MicroScint™-20; PerkinEmler) is added, and the plates are counted on a TOPCOUNT™ gamma counter (PerkinEmler) for ten minutes. Concentrations of each Fab that give less than or equal to 20% of maximal binding are chosen for use in competitive binding assays.

In another assay, KD can be measured using surface plasmon resonance assays using a BIACORE®- 2000 or a BIACORE®-3000 (BIAcore, Inc., Piscataway, N.J.) at 25° C with immobilized antigen CM5 chips at -10 response units (RU). Briefly, carboxymethylated dextran biosensor chips (CM5, BIACORE®, Inc.) are activated with N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N- hydroxysuccinimide (NHS) according to the supplier's instructions. Antigen is diluted with 10 mM sodium acetate, pH 4.8, to 5 pg/ml (-0.2 pM) before injection at a flow rate of 5 1/minute to achieve approximately 10 response units (RU) of coupled protein. Following the injection of antigen, 1 M ethanolamine is injected to block unreacted groups. For kinetics measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) are injected in PBS with 0.05% polysorbate 20 (TWEEN-20™) surfactant (PBST) at 25° C at a flow rate of approximately 25 1/min. Association rates (k_on) and dissociation rates (k_Off) are calculated using a simple one-to-one Langmuir binding model (BIACORE® Evaluation Software version 3.2) by simultaneously fitting the association and dissociation sensorgrams. The equilibrium dissociation constant (KD) is calculated as the ratio koff/kon. See, e.g., Chen et al., J. Mol. Biol. 293:865-881 (1999). If the on-rate exceeds 10⁶ M^-1 s^-1 by the surface plasmon resonance assay above, then the on-rate can be determined by using a fluorescent quenching technique that measures the increase or decrease in fluorescence emission intensity (excitation=295 nm; emission=340 nm, 16 nm band-pass) at 25° C. of a 20 nM anti-antigen antibody (Fab form) in PBS, pH 7.2, in the presence of increasing concentrations of antigen as measured in a spectrometer, such as a stop-flow equipped spectrophometer (Aviv Instruments) or a 8000-series SLM-AMINCO™ spectrophotometer (ThermoSpectronic) with a stirred cuvette.

(b) Multispecific antibodies

In some embodiments, the antibody or antigen binding fragment is included on a multispecific antibody, such as a bi-speciftc antibody. The antibody or antigen binding fragment disclosed herein can be used in combination with antibodies targeting other blood-stage antigens of interest, such as, but not limited to, cysteine-rich protective antigen (CyRPA) and RH5 -interacting protein (RIPR). Such multispecific antibodies can be produced by known methods, such as crosslinking two or more antibodies, antigen binding fragments (such as scFvs) of the same type or of different types. Exemplary methods of making multispecific antibodies include those described in PCT Pub. No. WO2013/163427, which is incorporated by reference herein in its entirety. Suitable crosslinkers include those that are heterobifunctional, having two distinctly reactive groups separated by an appropriate spacer (such as m-maleimidobenzoyl-N- hydroxysuccinimide ester) or homobifunctional (such as disuccinimidyl suberate). Such linkers are available from Pierce Chemical Company, Rockford, Ill. In some embodiments, the bispecific antibodies include a monoclonal antibody, or antigen binding fragment thereof, that specifically bind PfCSP. See for example, PCT Publication No. WO 2018/148660 and PCT Publication No. WO 2020/227228, incorporated herein by reference.

Various types of multi-specific antibodies are known. Bispeciflc single chain antibodies can be encoded by a single nucleic acid molecule. Examples of bispecific single chain antibodies, as well as methods of constructing such antibodies are known in the art (see, e.g., U.S. Pat. Nos. 8,076,459, 8,017,748, 8,007,796, 7,919,089, 7,820,166, 7,635,472, 7,575,923, 7,435,549, 7,332,168, 7,323,440, 7,235,641, 7,229,760, 7,112,324, 6,723,538, incorporated by reference herein). Additional examples of bispecific single chain antibodies can be found in PCT application No. WO 99/54440; Mack et al., J. Immunol., 158(8)3965-3970, 1997; Mack et al., Proc. Natl. Acad. Sci. U.S.A., 92(15):7021-7025, 1995; Kufer et al., Cancer Immunol. Immunother., 45(3-4): 193-197, 1997; Lbffler et al., Blood, 95(6):2098-2103, 2000; and Briihl et al., J. Immunol., 166(4):2420-2426, 2001. Production of bispecific Fab-scFv (“bibody”) molecules are described, for example, in Schoonjans et al. (J. Immunol., 165(12):7050-7057, 2000) and Willems et al. (J. Chromatogr. B Analyt. Technol. Biomed Life Sci. 786(1-2): 161-176, 2003). For bibodies, a scFv molecule can be fused to one of the VL-CL (L) or VH-CH1 chains, e.g., to produce a bibody one scFv is fused to the C-term of a Fab chain.

(c) Fragments

Antigen binding fragments are encompassed by the present disclosure, such as Fab, F(ab')z, and Fv which include a heavy chain and VL and specifically bind RH5. These antibody fragments retain the ability to selectively bind with the antigen and are “antigen-binding” fragments. Non-limiting examples of such fragments include:

(1) Fab, the fragment which contains a monovalent antigen-binding fragment of an antibody molecule, can be produced by digestion of whole antibody with the enzyme papain to yield an intact light chain and a portion of one heavy chain;

(2) Fab', the fragment of an antibody molecule can be obtained by treating whole antibody with pepsin, followed by reduction, to yield an intact light chain and a portion of the heavy chain;

(3) (Fab')2, the fragment of the antibody that can be obtained by treating whole antibody with the enzyme pepsin without subsequent reduction; F(ab^r)2 is a dimer of two Fab' fragments held together by two disulfide bonds;

(4) Fv, a genetically engineered fragment containing the VL and VL expressed as two chains; and

(5) Single chain antibody (such as scFv), defined as a genetically engineered molecule containing the VH and the VL linked by a suitable polypeptide linker as a genetically fused single chain molecule (see, e.g., Ahmad et al., Clin. Dev. Immunol., 2012, doi: 10.1155/2012/980250; Marbry and Snavely, IDntgs, 13(8):543-549, 2010). The intramolecular orientation of the Vu-domain and the VL- domain in a scFv, is not decisive for the provided antibodies (e.g., for the provided multispecific antibodies). Thus, scFvs with both possible arrangements (Vu-domain-linker domain-V -domain; Vi -domain-linker domain- Vu-domain) may be used.

(6) A dimer of a single chain antibody ( scFVi), defined as a dimer of a scFV. This has also been termed a “miniantibody.”

Methods of making these fragments are known (see for example, Harlow and Lane, Antibodies: A Laborator ’ Manual, 2^nd, Cold Spring Harbor Laboratory, New York, 2013).

Antigen binding fragments can be prepared by proteolytic hydrolysis of the antibody or by expression in a host cell (such as an E. coli cell) of DNA encoding the fragment. Antigen binding fragments can also be obtained by pepsin or papain digestion of whole antibodies by conventional methods. For example, antigen binding fragments can be produced by enzymatic cleavage of antibodies with pepsin to provide a 5S fragment denoted F(ab')2. This fragment can be further cleaved using a thiol reducing agent, and optionally a blocking group for the sulfhydryl groups resulting from cleavage of disulfide linkages, to produce 3.5S Fab' monovalent fragments.

Other methods of cleaving antibodies, such as separation of heavy chains to form monovalent lightheavy chain fragments, further cleavage of fragments, or other enzymatic, chemical, or genetic techniques may also be used, so long as the fragments bind to the antigen that is recognized by the intact antibody.

(d) Variants

In some embodiments, amino acid sequence variants of the antibodies provided herein are provided. For example, it may be desirable to improve the binding affinity and/or other biological properties of the antibody. Amino acid sequence variants of an antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., antigen-binding.

In some embodiments, antibody variants having one or more amino acid substitutions are provided. Sites of interest for substitutional mutagenesis include the CDRs and the framework regions. Amino acid substitutions may be introduced into an antibody of interest and the products screened for a desired activity, e.g., retained/improved antigen binding, decreased immunogenicity, or improved ADCC or CDC.

The variants typically retain amino acid residues necessary for correct folding and stabilizing between the VH and the VL regions, and will retain the charge characteristics of the residues in order to preserve the low pl and low toxicity of the molecules. Amino acid substitutions can be made in the VH and the VL regions to increase yield.

In some embodiments, the heavy chain of the antibody comprises up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as one of SEQ ID NOs : 1, 9, 17, 25, 33, 41, 49, 57, 65, 73, 81, 89, 97, 105, 113, 121, 129, 137, 145, 153, 161, 169, 177, 185, 193, 201, 209, 217, 225, 233, 241, 249, 257 265, and 273. In some embodiments, the light chain of the antibody comprises up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as one of SEQ ID NOs: 5, 9, 13, 21, 29, 37, 45, 53, 61, 69, 77, 85, 93, 101, 109, 117, 125, 133, 141, 149, 157, 165, 173, 181, 189, 197, 205, 209, 213, 221, 229, 237, 245, 253, 261, 269 and 277.

In some embodiments, the antibody or antigen binding fragment can include up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) in the framework regions of the heavy chain of the antibody, or the light chain of the antibody, or the heavy and light chains of the antibody, compared to a known framework region, or compared to a known framework region, or compared to the framework regions of the antibody, and maintain the specific binding activity for RH5.

In some embodiments, substitutions, insertions, or deletions may occur within one or more CDRs so long as such alterations do not substantially reduce the ability of the antibody to bind antigen. For example, conservative alterations (e.g., conservative substitutions as provided herein) that do not substantially reduce binding affinity may be made in CDRs. In some embodiments of the variant VH and VL sequences provided above, each CDR either is unaltered, or contains no more than one, two or three amino acid substitutions.

To increase binding affinity of the antibody, the VLand VH segments can be randomly mutated, such as within HCDR3 region or the LCDR3 region, in a process analogous to the in vivo somatic mutation process responsible for affinity maturation of antibodies during a natural immune response. Thus in vitro affinity maturation can be accomplished by amplifying VH and VL regions using PCR primers complementary to the HCDR3 or LCDR3, respectively. In this process, the primers have been “spiked” with a random mixture of the four nucleotide bases at certain positions such that the resultant PCR products encode VH and VL segments into which random mutations have been introduced into the VH and/or VL CDR3 regions. These randomly mutated VH and VL segments can be tested to determine the binding affinity for RH5. In particular examples, the VH amino acid sequence is one of SEQ ID NOs: 1, 9, 17, 25, 33, 41, 49, 57, 65, 73, 81, 89, 97, 105, 113, 121, 129, 137, 145, 153, 161, 169, 177, 185, 193, 201, 209, 217, 225, 233, 241, 249, 257 265, and 273. In other examples, the VL amino acid sequence is one of SEQ ID NOs: 5, 9, 13, 21, 29, 37, 45, 53, 61, 69, 77, 85, 93, 101, 109, 117, 125, 133, 141, 149, 157, 165, 173, 181, 189, 197, 205, 209, 213, 221, 229, 237, 245, 253, 261, 269 and 277. Methods of in vitro affinity maturation are known (see, e.g., Chowdhury, Methods Mol. Biol. 207 : 179-196 (2008)), and Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, N.J., (2001).)

In some embodiments, an antibody or antigen binding fragment, as disclosed herein, is altered to increase or decrease the extent to which the antibody or antigen binding fragment is glycosylated. Addition or deletion of glycosylation sites may be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed.

Where the antibody comprises an Fc region, the carbohydrate attached thereto may be altered. Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 of the CH2 domain of the Fc region. See, e.g., Wright et al. Trends Biotechnol. 15(l):26-32, 1997. The oligosaccharide may include various carbohydrates, e.g., mannose, N-acetyl glucosamine (GlcNAc), galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the “stem” of the biantennary oligosaccharide structure. In some embodiments, modifications of the oligosaccharide in an antibody may be made in order to create antibody variants with certain improved properties.

In one embodiment, antibody variants are provided having a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region. For example, the amount of fucose in such antibody may be from 1% to 80%, from 1% to 65%, from 5% to 65% or from 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn 297 (e.g. complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008/077546, for example. Asn297 refers to the asparagine residue located at about position 297 in the Fc region; however, Asn297 may also be located about ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, e.g., US Patent Publication Nos. US 2003/0157108 (Presta, L.); US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications related to “defucosylated” or “fucose -deficient” antibody variants include: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; W02005/053742; WO 2002/031140; Okazaki et al., J. Mol. Biol., 336(5): 1239-1249, 2004; Yamane- Ohnuki et al., Biotechnol. Bioeng. 87(5):614-622, 2004. Examples of cell lines capable of producing defucosylated antibodies include Lee 13 CHO cells deficient in protein fucosylation (Ripka et al., Arch. Biochem. Biophys. 249(2):533-545, 1986; US Pat. Appl. No. US 2003/0157108 and WO 2004/056312, especially at Example 11), and knockout cell lines, such as alpha- 1,6-fucosyl transferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al., Biotechnol. Bioeng., 87(5): 614-622, 2004; Kanda et al., Biotechnol. Bioeng.. 94(4):680-688, 2006; and W02003/085107). Antibodies variants are further provided with bisected oligosaccharides, e.g., in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc. Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are described, e.g., in WO 2003/011878 (Jean-Mairet et al.) U.S. Pat. No. 6,602,684 (Umana et al.) and US 2005/0123546 (Umana et al.). Antibody variants with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, e.g., in WO 1997/30087; WO 1998/58964; and WO 1999/22764.

In several embodiments, the constant region of the antibody comprises one or more amino acid substitutions to optimize in vivo half-life of the antibody. The serum half-life of IgG Abs is regulated by the neonatal Fc receptor (FcRn). Thus, in several embodiments, the antibody comprises an amino acid substitution that increases binding to the FcRn. Several such substitutions are known, such as substitutions at IgG constant regions T250Q and M428L (see, e.g., Hinton et al., J Immunol., 176(l):346-356, 2006); M428L and N434S (the “LS” mutation, see, e.g., Zalevsky, et al., Nature Biotechnol., 28(2): 157-159, 2010); N434A (see, e.g., Petkova et al.. Int. Immunol., 18(12): 1759-1769, 2006); T307A, E380A, and N434A (see, e.g., Petkova et al., Int. Immunol., 18(12): 1759-1769, 2006); and M252Y, S254T, and T256E (see, e.g., Dall’Acqua et al., J. Biol. Chem., 281(33):23514-23524, 2006). The disclosed antibodies and antigen binding fragments can be linked to or comprise a Fc polypeptide including any of the substitutions listed above, for example, the Fc polypeptide can include the M428L and N434S substitutions.

In some embodiments, the constant region of the antibody comprises one or more amino acid substitutions to optimize ADCC. ADCC is mediated primarily through a set of closely related Fey receptors. In some embodiments, the antibody comprises one or more amino acid substitutions that increase binding to FcyRHIa. Several such substitutions are known, such as substitutions at IgG constant regions S239D and I332E (see, e.g., Lazar et al., Proc. Natl., Acad. Sci. U.S.A., 103(11):4005-4010, 2006); and S239D, A33OL, and I332E (see, e.g., Lazar et al., Proc. Natl., Acad. Sci. U.S.A., 103(11):4005-4010, 2006).

Combinations of the above substitutions are also included, to generate an IgG constant region with increased binding to FcRn and FcyRIIIa. The combinations increase antibody half-life and ADCC. For example, such combinations include antibodies with the following amino acid substitutions in the Fc region: (1) S239D/I332E and T250Q/M428L; (2) S239D/I332E and M428L/N434S; (3) S239D/I332E and N434A; (4) S239D/I332E and T307A/E380A/N434A; (5) S239D/I332E and M252Y/S254T/T256E; (6) S239D/A330L/I332E and 250Q/M428L; (7) S239D/A330L/I332E and M428L/N434S; (8) S239D/A330L/I332E and N434A; (9) S239D/A330L/I332E and T307A/E380A/N434A; or (10) S239D/A330L/I332E and M252Y/S254T/T256E. In some examples, the antibodies, or an antigen binding fragment thereof is modified such that it is directly cytotoxic to infected cells, or uses natural defenses such as complement, ADCC, or phagocytosis by macrophages.

In some embodiments, an antibody provided herein may be further modified to contain additional nonproteinaceous moieties. The moieties suitable for derivatization of the antibody include but are not limited to water soluble polymers. Non-limiting examples of water soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol/propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1, 3-dioxolane, poly-1, 3,6- trioxane, ethylene/maleic anhydride copolymer, polyaminoacids (either homopolymers or random copolymers), and dextran or poly(n-vinyl pyrrolidonejpolyethylene glycol, propropylene glycol honiopolymers, prolypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water. The polymer may be of any molecular weight, and may be branched or unbranched. The number of polymers attached to the antibody may vary, and if more than one polymer are attached, they can be the same or different molecules. In general, the number and/or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular properties or functions of the antibody to be improved, whether the antibody derivative will be used in an application under defined conditions, etc.

B. Conjugates

The antibodies and antigen binding fragments that specifically bind to RH5 can be conjugated to an agent, such as an effector molecule or detectable marker. Both covalent and noncovalent attachment means may be used. Various effector molecules and detectable markers can be used, including (but not limited to) toxins and radioactive agents such as ¹²⁵I, ³²P, ¹⁴C, ³H and ³⁵S and other labels, target moieties and ligands, etc. The choice of a particular effector molecule or detectable marker depends on the particular target molecule or cell, and the desired biological effect.

The procedure for attaching an effector molecule or detectable marker to an antibody or antigen binding fragment varies according to the chemical structure of the effector. Polypeptides typically contain a variety of functional groups, such as carboxyl (-COOH), free amine (-NH2) or sulfhydryl (-SH) groups, which are available for reaction with a suitable functional group on a polypeptide to result in the binding of the effector molecule or detectable marker. Alternatively, the antibody or antigen binding fragment is derivatized to expose or attach additional reactive functional groups. The derivatization may involve attachment of any of a number of known linker molecules, such as those available from Thermo Fisher Scientific, Waltham, MA and MilliporeSigma Corporation, St. Louis, MO. The linker is capable of forming covalent bonds to both the antibody or antigen binding fragment and to the effector molecule or detectable marker. Suitable linkers include, but are not limited to, straight or branched-chain carbon linkers, heterocyclic carbon linkers, or peptide linkers. Where the antibody or antigen binding fragment and the effector molecule or detectable marker are polypeptides, the linkers may be joined to the constituent amino acids through their side chains (such as through a disulfide linkage to cysteine) or the alpha carbon, or through the amino, and/or carboxyl groups of the terminal amino acids.

In view of the large number of methods that have been reported for attaching a variety of radiodiagnostic compounds, radiotherapeutic compounds, labels (such as enzymes or fluorescent molecules), toxins, and other agents to antibodies, a suitable method for attaching a given agent to an antibody or antigen binding fragment or another polypeptide can be determined.

In some embodiments, the antibody or antigen binding fragment can be conjugated with effector molecules such as small molecular weight drugs such as Monomethyl Auristatin E (MMAE), Monomethyl Auristatin F (MMAF), maytansine, maytansine derivatives, including the derivative of maytansine known as DM1 (also known as mertansine), or other agents to make an antibody drug conjugate (ADC). In several embodiments, conjugates of an antibody or antigen binding fragment and one or more small molecule toxins, such as a calicheamicin, maytansinoids, dolastatins, auristatins, a trichothecene, and CC1065, and the derivatives of these toxins that have toxin activity, are provided.

The antibody or antigen binding fragment can be conjugated with a detectable marker; for example, a detectable marker capable of detection by ELISA, spectrophotometry, flow cytometry, microscopy or diagnostic imaging techniques (such as CT, computed axial tomography (CAT), MRI, magnetic resonance tomography (MTR), ultrasound, fiberoptic examination, and laparoscopic examination). Specific, nonlimiting examples of detectable markers include fluorophores, chemiluminescent agents, enzymatic linkages, radioactive isotopes and heavy metals or compounds (for example super paramagnetic iron oxide nanocrystals for detection by MRI). For example, useful detectable markers include fluorescent compounds, including fluorescein, fluorescein isothiocyanate, rhodamine, 5-dimethylamine-l-napthalenesulfonyl chloride, phycoerythrin, lanthanide phosphors and the like. Bioluminescent markers are also of use, such as luciferase, green fluorescent protein (GFP), and yellow fluorescent protein (YFP). An antibody or antigen binding fragment can also be conjugated with enzymes that are useful for detection, such as horseradish peroxidase, 0- galactosidase, luciferase, alkaline phosphatase, glucose oxidase and the like. When an antibody or antigen binding fragment is conjugated with a detectable enzyme, it can be detected by adding additional reagents that the enzyme uses to produce a reaction product that can be discerned. For example, when the agent horseradish peroxidase is present, the addition of hydrogen peroxide and diaminobenzidine leads to a colored reaction product, which is visually detectable. An antibody or antigen binding fragment may also be conjugated with biotin, and detected through indirect measurement of avidin or streptavidin binding. It should be noted that the avidin itself can be conjugated with an enzyme or a fluorescent label.

The antibody or antigen binding fragment can be conjugated with a paramagnetic agent, such as gadolinium. Paramagnetic agents such as superparamagnetic iron oxide are also of use as labels. Antibodies can also be conjugated with lanthanides (such as europium and dysprosium), and manganese. An antibody or antigen binding fragment may also be labeled with a predetermined polypeptide epitope recognized by a secondary reporter (such as leucine zipper pair sequences, binding sites for secondary antibodies, metal binding domains, epitope tags).

The antibody or antigen binding fragment can also be conjugated with a radiolabeled amino acid, for example, for diagnostic purposes. For instance, the radiolabel may be used to detect RH5 expressing cells by radiography, emission spectra, or other diagnostic techniques. Examples of labels for polypeptides include, but are not limited to, the following radioisotopes: ³H, ¹⁴C, ³⁵S, ⁹⁰Y, ⁹⁹ⁿⁱTc, ^1HIn, ²d, ¹³¹I. The radiolabels may be detected, for example, using photographic film or scintillation counters, fluorescent markers may be detected using a photodetector to detect emitted illumination. Enzymatic labels are typically detected by providing the enzyme with a substrate and detecting the reaction product produced by the action of the enzyme on the substrate, and colorimetric labels are detected by simply visualizing the colored label.

The average number of effector molecule or detectable marker moieties per antibody or antigen binding fragment in a conjugate can range, for example, from 1 to 20 moieties per antibody or antigen binding fragment. In some embodiments, the average number of effector molecules or detectable marker moieties per antibody or antigen binding fragment in a conjugate range from about 1 to about 2, from about 1 to about 3, about 1 to about 8; from about 2 to about 6; from about 3 to about 5; or from about 3 to about 4. The loading (for example, effector molecule per antibody ratio) of a conjugate may be controlled in different ways, for example, by: (i) limiting the molar excess of effector molecule-linker intermediate or linker reagent relative to antibody, (ii) limiting the conjugation reaction time or temperature, (iii) partial or limiting reducing conditions for cysteine thiol modification, (iv) engineering by recombinant techniques the amino acid sequence of the antibody such that the number and position of cysteine residues is modified for control of the number or position of linker-effector molecule attachments.

C. Polynucleotides and Expression

Nucleic acid molecules (for example, cDNA or RNA molecules) encoding the amino acid sequences of antibodies, antigen binding fragments, and conjugates that specifically bind to RH5 are provided. In some aspects, the antibody is MAD8-502, MAD8-151, MAD10-192, MAD10-219, MAD10-255, MAD10- 466, MAD10-437, MAD10-291, MAD10-349, MAD10-439, MAD10-30, MAD10-447, MAD10-378, MAD10-137, MAD10-434, MAD10-410, MAD10-371, MAD10-313, MAD10-479, MAD10-326, MAD10- 216, MAD10-385, MAD10-494, MAD10-485, MAD10-416, MAD10-458, MAD10-409, MAD10-412, MAD10-435, MAD10-81, MAD10-429, MAD10-407, MAD10-432 , MAD10-50, or MAD10-37. Nucleic acids encoding these molecules can readily be produced using the amino acid sequences provided herein (such as the CDR sequences and VH and VL sequences), sequences available in the art (such as framework or constant region sequences), and the genetic code. In several embodiments, a nucleic acid molecule can encode the VH, the VL, or both the VH and VL (for example in a bicistronic expression vector) of a disclosed antibody or antigen binding fragment. In several embodiments, the nucleic acid molecules can be expressed in a host cell (such as a mammalian cell) to produce a disclosed antibody or antigen binding fragment.

The genetic code can be used to construct a variety of functionally equivalent nucleic acid sequences, such as nucleic acids which differ in sequence but which encode the same antibody sequence, or encode a conjugate or fusion protein including the VL and/or VH nucleic acid sequence.

Nucleic acid molecules encoding the antibodies, antigen binding fragments, and conjugates that specifically bind to RH5 can be prepared by any suitable method including, for example, cloning of appropriate sequences or by direct chemical synthesis by standard methods. Chemical synthesis produces a single stranded oligonucleotide. This can be converted into double stranded DNA by hybridization with a complementary sequence or by polymerization with a DNA polymerase using the single strand as a template.

Exemplary nucleic acids can be prepared by cloning techniques. Examples of appropriate cloning and sequencing techniques can be found, for example, in Green and Sambrook (Molecular Cloning: A Laboratory Manual, 4^th ed., New York: Cold Spring Harbor Laboratory Press, 2012) and Ausubel et al. (Eds.) (Current Protocols in Molecular Biology, New York: John Wiley and Sons, including supplements, 2017).

Nucleic acids can also be prepared by amplification methods. Amplification methods include the polymerase chain reaction (PCR), the ligase chain reaction (LCR), the transcription-based amplification system (TAS), and the self-sustained sequence replication system (3SR).

The nucleic acid molecules can be expressed in a recombinantly engineered cell such as bacteria, plant, yeast, insect and mammalian cells. The antibodies, antigen binding fragments, and conjugates can be expressed as individual proteins including the VH and/or VL (linked to an effector molecule or detectable marker as needed), or can be expressed as a fusion protein. Methods of expressing and purifying antibodies and antigen binding fragments are known and further described herein (see, e.g., Al-Rubeai (Ed.), Antibody Expression and Production, Dordrecht; New York: Springer, 2011). An immunoadhesin can also be expressed. Thus, in some examples, nucleic acids encoding a VH and VL, and immunoadhesin are provided. The nucleic acid sequences can optionally encode a leader sequence.

To create a scFv the VH- and V -encoding DNA fragments can be operatively linked to another fragment encoding a flexible linker, e.g., encoding the amino acid sequence (Gly i-Ser) t. such that the VH and V sequences can be expressed as a contiguous single-chain protein, with the VL and VH domains joined by the flexible linker (see, e.g.. Bird et al., Science, 242(4877) :423-426, 1988; Huston et al.. Proc. Natl. Acad. Sci. U.S.A., 85(16) :5879-5883, 1988; McCafferty et al., Nature, 348:552-554, 1990; Kontermann and Diibel (Eds.), Antibody Engineering, Vols. 1-2, 2^nd ed., Spring er- Verlag, 2010; Greenfield (Ed.), Antibodies: A Laboratory Manual, 2^nd ed. New York: Cold Spring Harbor Laboratory Press, 2014). Optionally, a cleavage site can be included in a linker, such as a furin cleavage site.

The single chain antibody may be monovalent, if only a single VH and VL are used, bivalent, if two VH and VL are used, or polyvalent, if more than two VH and VL are used. Bispecific or polyvalent antibodies may be generated that bind specifically to RH5 and another antigen. The encoded VH and VL optionally can include a furin cleavage site between the VH and VL domains.

One or more DNA sequences encoding the antibodies, antigen binding fragments, or conjugates can be expressed in vitro by DNA transfer into a suitable host cell. The cell may be prokaryotic or eukaryotic. Numerous expression systems available for expression of proteins including E. coli, other bacterial hosts, yeast, and various higher eukaryotic cells such as the COS, CHO, HeLa and myeloma cell lines, can be used to express the disclosed antibodies and antigen binding fragments. Methods of stable transfer, meaning that the foreign DNA is continuously maintained in the host, are known in the art. Hybridomas expressing the antibodies of interest are also encompassed by this disclosure. The expression of nucleic acids encoding the antibodies and antigen binding fragments described herein can be achieved by operably linking the DNA or cDNA to a promoter (which is either constitutive or inducible), followed by incorporation into an expression cassette. The promoter can be any promoter of interest, including a cytomegalovirus promoter. Optionally, an enhancer, such as a cytomegalovirus enhancer, is included in the construct. The cassettes can be suitable for replication and integration in either prokaryotes or eukaryotes. Typical expression cassettes contain specific sequences useful for regulation of the expression of the DNA encoding the protein. For example, the expression cassettes can include appropriate promoters, enhancers, transcription and translation terminators, initiation sequences, a start codon (i.e., ATG) in front of a protein-encoding gene, splicing signals for introns, sequences for the maintenance of the correct reading frame of that gene to permit proper translation of mRNA, and stop codons. The vector can encode a selectable marker, such as a marker encoding drug resistance (for example, ampicillin or tetracycline resistance).

To obtain high level expression of a cloned gene, it is desirable to construct expression cassettes which contain, for example, a strong promoter to direct transcription, a ribosome binding site for translational initiation (e.g., internal ribosomal binding sequences), and a transcription/translation terminator. For E. coli, this can include a promoter such as the T7, trp, lac, or lambda promoters, a ribosome binding site, and preferably a transcription termination signal. For eukaryotic cells, the control sequences can include a promoter and/or an enhancer derived from, for example, an immunoglobulin gene, HTLV, SV40 or cytomegalovirus, and a polyadenylation sequence, and can further include splice donor and/or acceptor sequences (for example, CMV and/or HTLV splice acceptor and donor sequences). The cassettes can be transferred into the chosen host cell by well-known methods such as transformation or electroporation for E. coli and calcium phosphate treatment, electroporation or lipofection for mammalian cells. Cells transformed by the cassettes can be selected by resistance to antibiotics conferred by genes contained in the cassettes, such as the amp, gpt, neo and hyg genes.

Modifications can be made to a nucleic acid encoding a polypeptide described herein without diminishing its biological activity. Some modifications can be made to facilitate the cloning, expression, or incorporation of the targeting molecule into a fusion protein. Such modifications include, for example, termination codons, sequences to create conveniently located restriction sites, and sequences to add a methionine at the amino terminus to provide an initiation site, or additional amino acids (such as poly His) to aid in purification steps.

Once expressed, the antibodies, antigen binding fragments, and conjugates can be purified according to standard procedures in the art, including ammonium sulfate precipitation, affinity columns, column chromatography, and the like (see, generally, Simpson el al. (Eds.), Basic methods in Protein Purification and Analysis: A Laboratory Manual, New York: Cold Spring Harbor Laboratory Press, 2009). The antibodies, antigen binding fragment, and conjugates need not be 100% pure. Once purified, partially or to homogeneity as desired, if to be used prophylatically, the polypeptides should be substantially free of endotoxin. Methods for expression of antibodies, antigen binding fragments, and conjugates, and/or refolding to an appropriate active form, from mammalian cells, and bacteria such as E. coli have been described and are applicable to the antibodies disclosed herein. See, e.g., Greenfield (Ed.), Antibodies: A Laboratory Manual, 2^nd ed. New York: Cold Spring Harbor Laboratory Press, 2014, Simpson et al. (Eds.), Basic methods in Protein Purification and Analysis: A Laboratory Manual, New York: Cold Spring Harbor Laboratory Press, 2009, and Ward et al., Nature 341(6242):544-546, 1989.

D. Methods and Compositions

1. Inhibiting P. falciparum infection

Methods are disclosed herein for the inhibition of a P. falciparum infection in a subject. The methods include administering to the subject an effective amount (that is, an amount effective to inhibit P. falciparum infection in the subject) of a disclosed antibody, antigen binding fragment, conjugate, or a nucleic acid encoding such an antibody, antigen binding fragment, or conjugate, to a subject at risk of a P. falciparum infection. The methods can be used pre-exposure or post-exposure. The method can include administration of one or more of MAD8-502, MAD8-151, MAD10-192, MAD10-219, MAD10-255, MAD10-466, MAD10-437, MAD10-291, MAD10-349, MAD10-439, MAD10-30, MAD10-447, MAD10- 378, MAD10-137, MAD10-434, MAD10-410, MAD 10-371, MAD10-313, MAD10-479, M ADI 0-326, MAD10-216, MAD10-385, MAD10-494, MAD10-485, MAD10-416, MAD10-458, MAD10-409, MAD10- 412, MAD10-435, MAD10-81, MAD10-429, MAD10-407, MAD10-432 , MAD10-50, and MAD10-37, as described herein.

P. falciparum infection does not need to be completely eliminated or inhibited for the method to be effective. For example, the method can decrease P. falciparum infection by a desired amount, for example by at least 10%, at least 20%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or even at least 100% (elimination or prevention of detectable P. falciparum infection) as compared to P. falciparum infection in the absence of the treatment. In some embodiments, the subject can also be treated with an effective amount of an additional agent, such as anti-malaria agent.

In some embodiments, administration of an effective amount of a disclosed antibody, antigen binding fragment, conjugate, or nucleic acid molecule, inhibits the establishment of P. falciparum infection and/or subsequent P. falciparum disease progression in a subject, which can encompass any statistically significant reduction in P. falciparum activity (for example, blood stage P. falciparum) or symptoms of P. falciparum infection in the subject.

Antibodies and antigen binding fragments thereof are typically administered by intravenous infusion. Doses of the antibody or antigen binding fragment vary, but generally range between about 0.5 mg/kg to about 50 mg/kg, such as a dose of about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 40 mg/kg, or about 50 mg/kg. In some embodiments, the dose of the antibody or antigen binding fragment can be from about 0.5 mg/kg to about 5 mg/kg, such as a dose of about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg or about 5 mg/kg. The antibody or antigen binding fragment is administered according to a dosing schedule determined by a medical practitioner. In some examples, the antibody or antigen binding fragment is administered weekly, every two weeks, every three weeks or every four weeks.

In some aspects, the method of inhibiting P. falciparum infection in a subject further comprises administration of one or more additional agents to the subject. Additional agents of interest include, but are not limited to, anti-malaria agents.

In some aspects, the method of inhibiting P. falciparum infection in a subject comprises administration of a first antibody that specifically binds to RH5 as disclosed herein and a second antibody that that specifically binds to RH5. In some embodiments, the method of inhibiting P. falciparum infection in a subject comprises administration of a first antibody that specifically binds to RH5 as disclosed herein and a second antibody that that specifically binds to PfCSP. In some aspects, the method includes the administration of one or more of MAD8-502, MAD8-I51, MAD10-192, MAD10-2I9, MAD10-255, MAD10-466, MAD10-437, MAD10-291, MAD10-349, MAD10-439, MAD10-30, MAD10-447, MAD10- 378, MAD10-137, MAD10-434, MAD10-410, MAD10-371, MAD10-313, MAD10-479, MAD10-326, MAD10-216, MAD10-385, MAD10-494, MAD10-485, MAD10-416, MAD10-458, MAD10-409, MAD10- 412, MAD10-435, MAD10-81, MAD10-429, MAD10-407, MAD10-432 , MAD10-50, and MAD10-37. The method can include the administration of 2, 3, 4, 5, 6, 7, 8, 9, or 10 of these antibodies, antigen binding fragments thereof, mutlispecific antibodies (such as bispecific antibodies), conjugates, or nucleic acid molecules encoding these antibodies, antigen binding fragments, or multispecific antibodies (such as bispecific antibodies), or vectors include these nucleic acid molecules. The method can include administration of a monoclonal antibody, or antigen binding fragment thereof, that specifically bind a P. falciparum circumsporozoite protein (PfCSP). These antibodies include L9 and CIS43, or any antibody that binds a PfCSP, see for example, PCT Publication No. WO 2018/148660 and PCT Publication No. WO 2020/227228, both incorporated herein by reference. Combination of antibodies that bind pfCSP are also of use.

In some aspects, a subject is administered DNA or RNA encoding a disclosed antibody to provide in vivo antibody production, for example using the cellular machinery of the subject. Administration of nucleic acid constructs is known in the art and taught, for example, in U.S. Patent No. 5,643,578, U.S. Patent No. 5,593,972 and U.S. Patent No. 5,817,637. U.S. Patent No. 5,880,103 describes several methods of delivery of nucleic acids encoding proteins to an organism. One approach to administration of nucleic acids is direct administration with plasmid DNA, such as with a mammalian expression plasmid. The nucleotide sequence encoding the disclosed antibody, or antigen binding fragments thereof, can be placed under the control of a promoter to increase expression. The methods include liposomal delivery of the nucleic acids. Such methods can be applied to the production of an antibody, or antigen binding fragments thereof. In some embodiments, a disclosed antibody or antigen binding fragment is expressed in a subject using the pVRC8400 vector (described in Barouch et al., J. Virol., 79(14), 8828-8834, 2005, which is incorporated by reference herein). In several embodiments, a subject (such as a human subject at risk of P. falciparum infection) can be administered an effective amount of an AAV viral vector that includes one or more nucleic acid molecules encoding a disclosed antibody or antigen binding fragment. The AAV viral vector is designed for expression of the nucleic acid molecules encoding a disclosed antibody or antigen binding fragment, and administration of the effective amount of the AAV viral vector to the subject leads to expression of an effective amount of the antibody or antigen binding fragment in the subject. Non-limiting examples of AAV viral vectors that can be used to express a disclosed antibody or antigen binding fragment in a subject include those provided in Johnson et al., Nat. Med., 15(8):901-906, 2009 and Gardner et al., Nature, 519(7541 ):87-91 , 2015, each of which is incorporated by reference herein in its entirety.

In one embodiment, a nucleic acid encoding a disclosed antibody, or antigen binding fragment thereof, is introduced directly into tissue. For example, the nucleic acid can be loaded onto gold microspheres by standard methods and introduced into the skin by a device such as Bio-Rad’s HELIOS™ Gene Gun. The nucleic acids can be “naked,” consisting of plasmids under control of a strong promoter.

Typically, the DNA is injected into muscle, although it can also be injected directly into other sites. Dosages for injection are usually around 0.5 |J.g/kg to about 50 mg/kg, and typically are about 0.005 mg/kg to about 5 mg/kg (see, e.g., U.S. Patent No. 5,589,466).

Single or multiple administrations of a composition including a disclosed RH5-specific antibody, antigen binding fragment, conjugate, or nucleic acid molecule encoding such molecules, can be administered depending on the dosage and frequency as required and tolerated by the patient. The dosage can be administered once, but may be applied periodically until either a desired result is achieved or until side effects warrant discontinuation of therapy. Generally, the dose is sufficient to inhibit P. falciparum infection without producing unacceptable toxicity to the patient.

Data obtained from cell culture assays and animal studies can be used to formulate a range of dosage for use in humans. The dosage normally lies within a range of circulating concentrations that include the EDso, with little or minimal toxicity. The dosage can vary within this range depending upon the dosage form employed and the route of administration utilized. The effective dose can be determined from cell culture assays and animal studies.

The RH5-specific antibody, antigen binding fragment, conjugate, or nucleic acid molecule encoding such molecules, or a composition including such molecules, can be administered to subjects in various ways, including local and systemic administration, such as, e.g., by injection subcutaneously, intravenously, intraarterially, intraperitoneally, intramuscularly, intradermally, or intrathecally. In an embodiment, the antibody, antigen binding fragment, conjugate, or nucleic acid molecule encoding such molecules, or a composition including such molecules, is administered by a single subcutaneous, intravenous, intra-arterial, intraperitoneal, intramuscular, intradermal or intrathecal injection once a day. The antibody, antigen binding fragment, conjugate, or nucleic acid molecule encoding such molecules, or a composition including such molecules, can also be administered by direct injection at or near the site of disease. A further method of administration is by osmotic pump (e.g., an Alzet pump) or mini-pump (e.g., an Alzet mini-osmotic pump), which allows for controlled, continuous and/or slow-release delivery of the antibody, antigen binding fragment, conjugate, or nucleic acid molecule encoding such molecules, or a composition including such molecules, over a pre-determined period. The osmotic pump or mini-pump can be implanted subcutaneously, or near a target site.

2. Compositions

Compositions are provided that include one or more of the RH5-specific antibody, antigen binding fragment, conjugate, or nucleic acid molecule encoding such molecules, that are disclosed herein in a carrier. In some embodiments, the composition include one or more of MAD8-502, MAD8-151, MAD10-192, MAD10-219, MAD10-255, MAD10-466, MAD10-437, MAD10-291, MAD10-349, MAD10-439, MAD10- 30, MAD10-447, MAD10-378, MAD10-137, MAD10-434, MAD10-410, MAD10-371, MAD10-313, MAD10-479, MAD10-326, MAD10-216, MAD10-385, MAD10-494, MAD10-485, MAD10-416, MAD10- 458, MAD10-409, MAD10-412, MAD10-435, MAD10-81, MAD10-429, MAD10-407, MAD10-432 , MAD10-50, and/or MAD10-37. The compositions are useful, for example, for example, for the inhibition or detection of a P. falciparum infection. The compositions can be prepared in unit dosage forms for administration to a subject. The amount and timing of administration are at the discretion of the administering physician to achieve the desired purposes. The RH5-specific antibody, antigen binding fragment, conjugate, or nucleic acid molecule encoding such molecules can be formulated for systemic or local administration. In one example, the RH5-specific antibody, antigen binding fragment, conjugate, or nucleic acid molecule encoding such molecules, is formulated for parenteral administration, such as intravenous administration.

In some embodiments, the antibody, antigen binding fragment, or conjugate thereof, in the composition is at least 70% (such as at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) pure. In some embodiments, the composition contains less than 10% (such as less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, or even less) of macromolecular contaminants, such as other mammalian (e.g., human) proteins.

The compositions for administration can include a solution of the RH5-specific antibody, antigen binding fragment, conjugate, or nucleic acid molecule encoding such molecules, dissolved in a pharmaceutically acceptable carrier, such as an aqueous carrier. A variety of aqueous carriers can be used, for example, buffered saline and the like. These solutions are sterile and generally free of undesirable matter. These compositions may be sterilized by conventional, well known sterilization techniques. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of antibody in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight and the like in accordance with the particular mode of administration selected and the subject’s needs. A typical composition for intravenous administration includes about 0.01 to about 30 mg/kg of antibody or antigen binding fragment or conjugate per subject per day (or the corresponding dose of a conjugate including the antibody or antigen binding fragment). Actual methods for preparing administrable compositions are known and are described in more detail in such publications as Remington: The Science and Practice of Pharmacy, 22^nd ed., London, UK: Pharmaceutical Press, 2013. In some embodiments, the composition can be a liquid formulation including one or more antibodies, antigen binding fragments (such as an antibody or antigen binding fragment that specifically binds to RH5), in a concentration range from about 0.1 mg/ml to about 20 mg/ml, or from about 0.5 mg/ml to about 20 mg/ml, or from about 1 mg/ml to about 20 mg/ml, or from about 0.1 mg/ml to about 10 mg/ml, or from about 0.5 mg/ml to about 10 mg/ml, or from about 1 mg/ml to about 10 mg/ml.

Antibodies, or an antigen binding fragment thereof or a conjugate or a nucleic acid encoding such molecules, can be provided in lyophilized form and rehydrated with sterile water before administration, although they are also provided in sterile solutions of known concentration. The antibody solution, or an antigen binding fragment or a nucleic acid encoding such antibodies or antigen binding fragments, can then be added to an infusion bag containing 0.9% sodium chloride, USP, and typically administered at a dosage of from 0.5 to 15 mg/kg of body weight. Considerable experience is available in the art in the administration of antibody drugs, which have been marketed in the U.S. since the approval of Rituximab in 1997. Antibodies, antigen binding fragments, conjugates, or a nucleic acid encoding such molecules, can be administered by slow infusion, rather than in an intravenous push or bolus. In one example, a higher loading dose is administered, with subsequent, maintenance doses being administered at a lower level. For example, an initial loading dose of 4 mg/kg may be infused over a period of some 90 minutes, followed by weekly maintenance doses for 4-8 weeks of 2 mg/kg infused over a 30-minute period if the previous dose was well tolerated.

Controlled-release parenteral formulations can be made as implants, oily injections, or as particulate systems. For a broad overview of protein delivery systems see, Banga, Therapeutic Peptides and Proteins: Formulation, Processing, and Delivery Systems, Lancaster, PA: Technomic Publishing Company, Inc., 1995. Particulate systems include microspheres, microparticles, microcapsules, nanocapsules, nanospheres, and nanoparticles. Microcapsules contain the active protein agent, such as a cytotoxin or a drug, as a central core. In microspheres, the active protein agent is dispersed throughout the particle. Particles, microspheres, and microcapsules smaller than about 1 pm are generally referred to as nanoparticles, nanospheres, and nanocapsules, respectively. Capillaries have a diameter of approximately 5 pm so that only nanoparticles are administered intravenously. Microparticles are typically around 100 pm in diameter and are administered subcutaneously or intramuscularly. See, for example, Kreuter, Colloidal Drug Delivery Systems, J. Kreuter (Ed.), New York, NY: Marcel Dekker, Inc., pp. 219-342, 1994; and Tice and Tabibi, Treatise on Controlled Drug Delivery: Fundamentals, Optimization, Applications, A. Kydonieus (Ed.), New York, NY: Marcel Dekker, Inc., pp. 315-339, 1992. Polymers can be used for ion-controlled release of the antibody compositions disclosed herein. Various degradable and nondegradable polymeric matrices for use in controlled drug delivery are known in the art (Langer, Acc. Chem. Res. 26(10):537-542, 1993). For example, the block copolymer, polaxamer 407, exists as a viscous yet mobile liquid at low temperatures but forms a semisolid gel at body temperature. It has been shown to be an effective vehicle for formulation and sustained delivery of recombinant interleukin- 2 and urease (Johnston et al., Pharm. Res., 9(3):425-434, 1992; and Pec et al., J. Parent. Sci. Tech., 44(2):58-65, 1990). Alternatively, hydroxyapatite has been used as a microcarrier for controlled release of proteins (Ijntema et al., Int. J. Pharm. 112(3):215-224, 1994). In yet another aspect, liposomes are used for controlled release as well as drug targeting of the lipid-capsulated drug (Betageri et al., Liposome Drug Delivery Systems, Lancaster, PA: Technomic Publishing Co., Inc., 1993). Numerous additional systems for controlled delivery of active protein agent are known (see U.S. Patent No. 5,055,303; U.S. Patent No. 5,188,837; U.S. Patent No. 4,235,871; U.S. Patent No. 4,501,728; U.S. Patent No. 4,837,028; U.S. Patent No. 4,957,735; U.S. Patent No. 5,019,369; U.S. Patent No. 5,055,303; U.S. Patent No. 5,514,670; U.S. Patent No. 5,413,797; U.S. Patent No. 5,268,164; U.S. Patent No. 5,004,697; U.S. Patent No. 4,902,505; U.S. Patent No. 5,506,206; U.S. Patent No. 5,271,961; U.S. Patent No. 5,254,342 and U.S. Patent No. 5,534,496).

3. Methods of detection and diagnosis

Methods are also provided for the detection of the presence of RH5 in vitro or in vivo. In one example, the presence of RH5 is detected in a biological sample from a subject, and can be used to identify a subject with P. falciparum infection. The sample can be any sample, including, but not limited to, tissue from biopsies, autopsies and pathology specimens. Biological samples also include sections of tissues, for example, frozen sections taken for histological purposes. Biological samples further include body fluids, such as blood, serum, plasma, sputum, spinal fluid or urine. The method of detection can include contacting a cell or sample, with an antibody or antigen binding fragment that specifically binds to RH5, or conjugate thereof (e.g., a conjugate including a detectable marker) under conditions sufficient to form an immune complex, and detecting the immune complex (e.g., by detecting a detectable marker conjugated to the antibody or antigen binding fragment.

In one embodiment, the antibody or antigen binding fragment is directly labeled with a detectable marker. In another embodiment, the antibody that binds P. falciparum (the primary antibody) is unlabeled and a secondary antibody or other molecule that can bind the primary antibody is utilized for detection. The secondary antibody is chosen that is able to specifically bind the specific species and class of the first antibody. For example, if the first antibody is a human IgG, then the secondary antibody may be an anti- human-IgG. Other molecules that can bind to antibodies include, without limitation, Protein A and Protein G, both of which are available commercially. Suitable labels for the antibody, antigen binding fragment or secondary antibody are known and described above, and include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, magnetic agents and radioactive materials. In some embodiments, the disclosed antibodies or antigen binding fragments thereof are used to test vaccines. For example, to test if a vaccine composition including a RH5 or fragment thereof assumes a conformation including the epitope of a disclosed antibody. Thus, provided herein is a method for testing a vaccine, wherein the method includes contacting a sample containing the vaccine, such as a RH5 immunogen, with a disclosed antibody or antigen binding fragment under conditions sufficient for formation of an immune complex, and detecting the immune complex, to detect the vaccine with an RH5 immunogen including the epitope in the sample. In one example, the detection of the immune complex in the sample indicates that v ccine component, such as a RH5 immunogen assumes a conformation capable of binding the antibody or antigen binding fragment.

III. EXAMPLES

The following example is provided to illustrate particular features of certain embodiments, but the scope of the claims should not be limited to those features exemplified.

Example 1 Results

Out of a cohort of 758 individuals living in Kalifabougou, Mali, monoclonal antibodies (mAbs) were isolated from four individuals with high polyclonal IgG specific to the blood-stage malaria antigen RH5. Isolation was carried out utilizing sequential 384-well oligoclonal B cell culture and optofluidic screening (Dacon et al., Broadly neutralizing antibodies target the coronavirus fusion peptide. Science 377, 728-735. doi.org/10.1126/science.abq3773, 2022). mAbs were also isolated by the same method from five RH5 vaccinees. RH5-specific IgG⁺ B cells were present at a > 100-fold higher frequency among memory B cells from vaccinees than from malaria-exposed donors (FIG. 1A). mAbs from malaria-exposed donors exhibited higher levels of VH mutation than those from vaccinees (FIG. IB). The binding of the mAb panel was also compared by titration against RH5-coated beads (FIG. 1C). Functional assessment was achieved using the growth inhibition assay (GIA), which measures activity against blood-stage P. falciparum in vitro. GIA scores were significantly higher among vaccinee-derived mAbs than among infection-derived mAbs; only two of 22 mAbs from the Malian cohort exceeded 50% growth inhibition at 1 nig/mL, a standard threshold for this assay, compared to 94 of the 164 mAbs from vaccinees (FIG. ID). The 35 mAbs with highest inhibition values at 1 mg/mL were titrated for use in further GIA assessment, and this revealed that two Malian-derived mAbs (MAD8-151 and MAD8-502, indicated with * in FIG. IE) ranked among the most potently neutralizing mAbs out of both cohorts combined (FIG. IE).

Considering that differences in binding could not explain potency differences between vaccination- and infection-derived mAbs, SPR was employed to assess mAb epitope specificity. By including reference mAbs with known binding sites on RH5, the epitopes of the majority of mAbs were mapped from both cohorts, leading to the identification of five major epitope bins, three of them (1-111) located near the basigin- binding site or ‘top’ of the RH5 molecule, and two (IV-V) located near the CyRPA-binding site or ‘bottom’ of the RH5 molecule (FIGS. 2A and 2B). Several mAbs could not be confined to these five major bins, and were assigned either to smaller ‘adjunct’ bins (I_a, H_a, IV_a or V_a) or a hypothetical sixth bin (VI), likely also a location near the bottom of the molecule. Regardless of antibody source, representatives of bins I-III (RH5 ‘top-binders’) were predominantly neutralizing, while members of bins IV-VI (RH5 ‘bottom-binders’) were non-neutralizing (FIG. 2C). Of the 35 most potent mAbs already identified, the top 26 mAbs bound to bins I and II, suggesting that these two regions on RH5 are the most vulnerable to antibody -mediated neutralization (FIG. 2D). Just 25% of infection-derived antibodies targeted neutralizing ‘top’ epitopes, compared to 68.2% of vaccinee-derived antibodies (FIG. 2E). A drawback of this technique for identifying antibody epitopes is low sensitivity, leading to inability to bin low-affinity antibodies. A more sensitive bead-based assay was developed to assess the epitope specificity of a larger array of antibodies, including low-affinity antibodies. Results from assay supported findings from SPR: antibodies derived from natural infection disproportionately targeted the bottom of RH5, while vaccinee-based antibodies were more likely to target the top of the molecule (FIG. 2F).

Correlation analysis revealed that for bins I and II, binding to RH5-coated beads was more strongly correlated with GIA potency than other parameters (FIG. 3A). However, this correlation was not detectable when all mAbs were considered as a single group (FIG. 3B). Separation of mAbs into their epitope bins revealed divergent patterns (FIG. 3C); correlation of binding affinity with GIA potency was recovered clearly for bins I and II, less clearly for bin III, and not recovered for bins IV and V. Thus, epitope specificity determines whether binding affinity to RH5 translates into inhibition of blood-stage malaria.

Example 2 Materials and Methods

Step 1: Memory B cell isolation

Clinical specimens were derived from 1,187 subjects in the Malian village of Kalifabougou as previously described (Tan et aL, Sci Transl Med 13, eabg2344. doi.org/10.1126/scitranslmed.abg2344, 2021; Tran et aL, Clin Infect Dis 57, 40^-7. doi.org/10.1093/cid/citl74, 2013) and from the VAC063 study conducted in the UK by the University of Oxford (NCT02927145) as previously described (Minassian et al., Med (N Y) 2, 701-719.el9, doi.org/10.1016/j.medj .2021.03.0142021). PBMCs were cryopreserved and later thawed for sorting of plasmablasts (PBs) and memory B cells (MBCs) by staining with the following panel: LIVE/DEAD™ Fixable Aqua Dead Cell Stain Kit (Invitrogen L34966), CD14-BV510 (BioLegend 301842), CD3-BV510 (BioLegend 317332), CD56-BV510 (BioLegend 318340), CD19-ECD (Beckman Coulter IM2708U), CD21-BV711 (563163), IgA-Alexa Fluor 647 (Jackson Immunoresearch 109-606-011), IgD-PE-Cy7 (BD 561314), and IgM-PerCP-Cy5.5 (BD561285), CD27-ALEXA FLUOR® 488 (BioLegend 393204) and CD38-APC-Cy7 (BioLegend 303534). The cells were sorted using the BD FACSARIA™ IIIu in a BSL3 facility and gated on live singlet CD14-CD3-CD56-CD19+CD38+CD27-I- IgM-IgD-IgA- cells (IgG+ PBs) and CD14-CD3-CD56-CD19+ IgM-IgD-IgA- (IgG+ MBCs).

Step 2: Memory B cell screening

Plasmablasts were sorted directly into Plasma Cell Survival Medium (Berkeley Lights). These cells were deposited into an OptoSelect 1 Ik chip and the Beacon’ s Cell Analysis Suite (Berkeley Lights was used to partition cells into microwells using opto-electropositioning (OEP) light cages. Streptavidin beads (Spherotech) coated with 10 pg/rnL of biotinylated RH5 were co-incubated with 2.5 pg/ml of IgG-AF647 above the plasmablasts and a 30 minute time course was performed to measure secretion of IgG that bound the RH5-coated beads. Subsequently, OEP light cages were used to unload plasmablasts identified as RH5- specific into lysis buffer (Cell Unload protocol, Berkeley Lights). Memory B cells were stimulated using two protocols: 1) 2,500 MBCs/well cultured in commercially-available memory B cell stimulation media (Berkeley Lights) for 6 days in 96-well U-bottom plates or, 2) 100 MBCs/well and 10,000 3T3-CD40L feeder cells/well cultured in 110 media (Iscove’s modified Dulbecco’s Medium, 10% FBS, 1:1000 MycoZap; Thermo Fisher and Lonza) supplemented with 100 ng/mL IL-21 (Gibco), 0.5 pg/rnL R848 (Mabtech), and 1 pg/mL human CD40L (R&D Systems) for 6 days in 384- well plates. Subsequently, memory B cell culture supernatants were screened for binding to RH5-coated beads as above. RH5-specific MBCs were loaded onto the Beacon, screened for RFL5 binding, and unloaded as above.

Step 3: mAb expression and assessment

Antibody heavy and light chains from positive cells were PCR-amplified and sequenced as previously described. VH and VL sequences and somatic mutation assessments were determined using the International Immunogenetics Information System database. For antibody expression, sequences were cloned into plasmids (Genscript) which were then transfected into Expi293 cells (Thermo Fisher Scientific). Cell culture supernatants were then purified for recombinant IgG using HiTrap Protein A columns (GE Healthcare Life Sciences). Antibody binding strength was determined by titration against antigen-coated beads. AUC values were calculated using GraphPad Prism and normalized using control mAbs with known affinity. Growth inhibition assays were performed by the GIA Reference Center, NIH, USA as previously described (Malkin et al., 2005). Briefly, l-2.5mg/mL IgGl was incubated with Plasmodium falciparum- infected erythrocytes (strain 3D7) at 37°C for 40 h. GIA score was determined by detection of Pf lactate dehydrogenase levels. Titration of select mAbs was also done to determine GIA EC50. For determination of mAb epitopes, binning experiments were run with the Carterra LSA. Briefly, an HC30M chip (Carterra) was primed with Hepes-buffered saline Tween-EDTA (HBSTE). The chip was activated with 400 mM 1-ethyl- 3-(3-dimethylaminopropyl) carbodiimide hydrochloride and 100 mM N-hydroxy succinimide (Thermo Fisher Scientific). Coupling of antibodies to the activated chip was carried out at 10 pg/mL in 10 mM sodium acetate (pH 5.0), with chip blocking achieved with 1 M ethanolamine (pH 8.5). Printed antibodies were bound to RH5, and then sequentially assayed against all other antibodies. Competition was indicated by binding failure of the second (‘analyte’) antibody, while non-competition was indicated by retention of the second antibody, producing an elevated SPR signal in RUs. Binning data were analyzed using the Epitope Software (Carterra).

In view of the many possible embodiments to which the principles of our invention may be applied, it should be recognized that illustrated embodiments are only examples of the invention and should not be considered a limitation on the scope of the invention. Rather, the scope of the invention is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims.

Claims

We claim:

1. An isolated monoclonal antibody or antigen binding fragment thereof, comprising a heavy chain variable (VH) region and a light chain variable region (VL) comprising a heavy chain complementarity determining region (HCDR)l, a HCDR2, and a HCDR3, and a light chain complementarity determining region (LCDR)l, a LCDR2, and a LCDR3 of the VH and VL set forth as any one of: a) SEQ ID NOs: 1 and 5, respectively (MAD8-502); b) SEQ ID NOs: 9 and 13, respectively (MAD8-151); c) SEQ ID NOs: 17 and 21, respectively (MAD10-192); d) SEQ ID NOs: 25 and 29, respectively (MAD10-219); e) SEQ ID NOs: 33 and 37, respectively (MAD10-255); f) SEQ ID NOs: 49 and 53, respectively (MAD10-466); g) SEQ ID NOs: 41 and 45, respectively (MAD10-437); h) SEQ ID NOs: 57 and 61, respectively (MAD10-291); i) SEQ ID NOs: 65 and 69, respectively (MAD10-349); j) SEQ ID NOs: 73 and 77, respectively (MAD10-439); k) SEQ ID NOs: 81 and 85, respectively (MAD10-30); l) SEQ ID NOs: 89 and 93, respectively (MAD 10-447); m) SEQ ID NOs: 97 and 101, respectively (MAD10-378): n) SEQ ID NOs: 105 and 109, respectively (MAD10-137); o) SEQ ID NOs: 113 and 117, respectively (MAD10-434); p) SEQ ID NOs: 121 and 125, respectively (MAD10-410); q) SEQ ID NOs: 129 and 133, respectively (MAD10-371); r) SEQ ID NOs: 137 and 141, respectively (MAD10-313); s) SEQ ID NOs: 145 and 149, respectively (MAD10-479); t) SEQ ID NOs: 153 and 157, respectively (MAD10-326); u) SEQ ID NOs: 161 and 165, respectively (MAD10-216); v) SEQ ID NOs: 169 and 173, respectively (MAD10-385); w) SEQ ID NOs: 177 and 181, respectively (MAD10-494); x) SEQ ID NOs: 185 and 189, respectively (MAD10-485); y) SEQ ID NOs: 193 and 197, respectively (MAD10-416); z) SEQ ID NOs: 201 and 205, respectively (MAD10-458); aa) SEQ ID NOs: 209 and 213, respectively (MAD10-409); bb) SEQ ID NOs: 217 and 221, respectively (MAD10-412); cc) SEQ ID NOs: 225 and 229, respectively (MAD10-435); dd) SEQ ID NOs: 233 and 237, respectively (MAD10-81); ee) SEQ ID NOs: 241 and 245, respectively (MAD10-429); ff) SEQ ID NOs: 249 and 253, respectively (MAD10-407); gg) SEQ ID NOs: 257 and 261, respectively (MAD10-432); hh) SEQ ID NOs: 265 and 269, respectively (MAD 10-50); or ii) SEQ ID NOs: 273 and 277, respectively (MAD10-370), wherein the monoclonal antibody specifically binds to P. falciparum reticulocyte binding protein homolog (RH)5 and neutralizes P. falciparum.

2. The isolated monoclonal antibody or antigen binding fragment of claim 1, wherein the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2, and the LCDR3 are set forth as: a) SEQ ID NOs: 2, 3, 4, 6, EVS, and 8; b) SEQ ID NOs: 10, 11, 12, 14, DVS and 16; c) SEQ ID NOs: 18, 19, 20, 22, QDS, and 24; d) SEQ ID NOs: 26, 27, 28, 30, AAS, and 32; e) SEQ ID NOs: 34, 35, 36, 38, DAS, and 40; f) SEQ ID NOs: 50, 51, 52, 54, EVS , and 56; g) SEQ ID NOs: 42, 43, 44, 46, DAS, and 48; h) SEQ ID NOs: 58, 59, 60, 62, DAS, and 64; i) SEQ ID NOs: 66, 67, 68, 70, DAS, and 72; j) SEQ ID NOs: 74, 75, 76, 78, GAS, and 80; k) SEQ ID NOs: 82, 83, 84, 86, GAS, and 88; l) SEQ ID NOs: 90, 91, 92, 94, AAS, and 96; m) SEQ ID NOs: 98, 99, 100, 102, DAS, and 104; n) SEQ ID NOs: 106, 107, 108, 110, DAS, and 112; o) SEQ ID NOs: 114, 115, 116, 118, GAS, and 120; p) SEQ ID NOs: 122, 123, 124, 126, DAS, and 128; q) SEQ ID NOs: 130, 131, 132, 134, GAS, and 136; r) SEQ ID NOs: 138, 139, 140, 142, SAS, and 144; s) SEQ ID NOs: 146, 147, 148, 150, DAS, and 152; t) SEQ ID NOs: 154, 155, 156, 158, AAS, and 160; u) SEQ ID NOs: 162, 163, 164, 166, LGS, and 168; v) SEQ ID NOs: 170, 171, 172, 174, GAS, and 176; w) SEQ ID NOs: 178, 179, 180, 182, GAS, and 184; x) SEQ ID NOs: 186, 187, 188, 190, AAS, and 192; y) SEQ ID NOs: 194, 195, 196, 198, AAS, and 200; z) SEQ ID NOs: 202, 203, 204, 206, AAS, and 208; aa) SEQ ID NOs: 210, 211, 212, 214, GAS, and 216; bb) SEQ ID NOs: 218, 219, 220, 222, ANS, and 224; co) SEQ ID NOs: 226, 227, 228, 230, EVT, and 232; dd) SEQ ID NOs: 234, 235, 236, 238, AAS, and 240; ee) SEQ ID NOs: 242, 243, 244, 246, GPS, and 248; ff) SEQ ID NOs: 250, 251, 252, 254, DAS, and 256; gg) SEQ ID NOs: 258, 259, 260, 262, AAS, and 264; hh) SEQ ID NOs: 266, 267, 268, 270, GAS, and 272; or ii) SEQ ID NOs: 274, 275, 276, 278, DAS, and 280, respectively.

3. The isolated monoclonal antibody or antigen binding fragment of claim 1 or claim 2, wherein the VH and the VL comprise the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2, and the LCDR3 and the amino acid sequences of the framework regions of the VH and the VL are at least 90% identical to those of: a) SEQ ID NOs: 1 and 5; b) SEQ ID NOs: 9 and 13; c) SEQ ID NOs: 17 and 21; d) SEQ ID NOs: 25 and 29; e) SEQ ID NOs: 33 and 37; f) SEQ ID NOs: 49 and 53; g) SEQ ID NOs: 41 and 45; h) SEQ ID NOs: 57 and 61; i) SEQ ID NOs: 65 and 69; j) SEQ ID NOs: 73 and 77; k) SEQ ID NOs: 81 and 85; l) SEQ ID NOs: 89 and 93; m) SEQ ID NOs: 97 and 101; n) SEQ ID NOs: 105 and 109; o) SEQ ID NOs: 113 and 117; p) SEQ ID NOs: 121 and 125; q) SEQ ID NOs: 129 and 133; r) SEQ ID NOs: 137 and 141; s) SEQ ID NOs: 145 and 149; t) SEQ ID NOs: 153 and 157; u) SEQ ID NOs: 161 and 165; v) SEQ ID NOs: 169 and 173; w) SEQ ID NOs: 177 and 181; x) SEQ ID NOs: 185 and 189; y) SEQ ID NOs: 193 and 197; z) SEQ ID NOs: 201 and 205; aa) SEQ ID NOs: 209 and 213; bb) SEQ ID NOs: 217 and 221; cc) SEQ ID NOs: 225 and 229; dd) SEQ ID NOs: 233 and 237; ee) SEQ ID NOs: 241 and 245; ff) SEQ ID NOs: 249 and 253; gg) SEQ ID NOs: 257 and 261; hh) SEQ ID NOs: 265 and 269; or ii) SEQ ID NOs: 273 and 277.

4. The isolated monoclonal antibody or antigen binding fragment of any one of claims 1-3, wherein the VH and the VL comprise amino acid sequences set forth as: a) SEQ ID NOs: 1 and 5; b) SEQ ID NOs: 9 and 13; c) SEQ ID NOs: 17 and 21; d) SEQ ID NOs: 25 and 29; e) SEQ ID NOs: 33 and 37; f) SEQ ID NOs: 49 and 53; g) SEQ ID NOs: 41 and 45; h) SEQ ID NOs: 57 and 61; i) SEQ ID NOs: 65 and 69; j) SEQ ID NOs: 73 and 77; k) SEQ ID NOs: 81 and 85; l) SEQ ID NOs: 89 and 93; m) SEQ ID NOs: 97 and 101; n) SEQ ID NOs: 105 and 109; o) SEQ ID NOs: 113 and 117; p) SEQ ID NOs: 121 and 125; q) SEQ ID NOs: 129 and 133; r) SEQ ID NOs: 137 and 141; s) SEQ ID NOs: 145 and 149; f) SEQ ID NOs: 153 and 157; u) SEQ ID NOs: 161 and 165; v) SEQ ID NOs: 169 and 173; w) SEQ ID NOs: 177 and 181; x) SEQ ID NOs: 185 and 189; y) SEQ ID NOs: 193 and 197; z) SEQ ID NOs: 201 and 205; aa) SEQ ID NOs: 209 and 213; bb) SEQ ID NOs: 217 and 221; cc) SEQ ID NOs: 225 and 229; dd) SEQ ID NOs: 233 and 237; ee) SEQ ID NOs: 241 and 245; ff) SEQ ID NOs: 249 and 253; gg) SEQ ID NOs: 257 and 261; hh) SEQ ID NOs: 265 and 269; or ii) SEQ ID NOs: 273 and 277.

5. The isolated monoclonal antibody or antigen binding fragment of claims 1-4 wherein the antibody comprises a human constant domain.

6. The isolated monoclonal antibody or antigen binding fragment of any one of claims 1-5, wherein the antibody is a human antibody.

7. The isolated monoclonal antibody of any one of claims 1-6, wherein the antibody is an IgG.

8. The isolated monoclonal antibody of any one of claims 1-7, comprising a recombinant constant domain comprising a modification that increases the half-life of the antibody.

9. The isolated monoclonal antibody of claim 8, wherein the modification increases binding to the neonatal Fc receptor.

10. The isolated monoclonal antibody of claim 9, wherein the recombinant constant domain is an IgGl constant domain comprising M428L and N434S mutations.

11. The antigen binding fragment of the antibody of any one of claims 1-6.

12. The antigen binding fragment of claim 11, wherein the antigen binding fragment is a Fv, Fab, F(ab')2, scFV or a SCFV2 fragment.

13. The antibody or antigen binding fragment of any one of claims 1-12, conjugated to an effector molecule or a detectable marker.

14. The isolated monoclonal antibody or antigen binding fragment of any one of claims 1-13, wherein the antibody or antigen binding fragment inhibits blood-stage P. falciparumin.

15. A bispecific antibody or multi-specific antibody comprising the antibody or antigen binding fragment of any one of claims 1-14.

16. An isolated nucleic acid molecule encoding the antibody or antigen binding fragment of any one of claims 1-14, or the bispecific antibody of claim 15.

17. The isolated nucleic acid molecule of claim 16, wherein the nucleic acid molecule is RNA.

18. The nucleic acid molecule of claim 16 or claim 17, operably linked to a promoter.

19. A vector comprising the nucleic acid molecule of any of claims 16-18.

20. A host cell comprising the nucleic acid molecule or vector of any one of claims 16-19.

21 . A composition comprising an effective amount of the monoclonal antibody or antigen binding fragment of any one of claims 1-14, the bispecific antibody or multi-specific antibody of claim 15, the nucleic acid molecule of any one of claims 16-18, or the vector of claim 19, and a pharmaceutically acceptable carrier.

22. The composition of claim 21, further comprising an antibody that specifically binds circumsporozoite protein (PfCSP).

23. A method of producing an antibody or antigen binding fragment that specifically binds to RH5, comprising: expressing one or more nucleic acid molecules encoding the monoclonal antibody or antigen binding fragment of any one of claims 1-14 in a host cell; and purifying the monoclonal antibody or antigen binding fragment.

24. A method of detecting the presence of P. falciparum in a biological sample from a human subject, comprising: contacting the biological sample with an effective amount of the monoclonal antibody or antigen binding fragment of any one of claims 1-14 under conditions sufficient to form an immune complex; and detecting the presence of the immune complex in the biological sample, wherein the presence of the immune complex in the biological sample indicates the presence of the P. falciparum in the sample.

25. The method of claim 24, wherein detecting the detecting the presence of the immune complex in the biological sample indicates that the subject has a P. falciparum infection.

26. A method of inhibiting a P. falciparum infection in a subject, comprising administering an effective amount of the monoclonal antibody or antigen binding fragment of any one of claims 1-14, the bispecific antibody or multi-specific antibody of claim 15, the nucleic acid molecule of any one of claims 16-18, the vector of claim 19, or the composition of claim 21 or claim 22 to the subject, wherein the subject has or is at risk of a P. falciparum infection.

27. The method of claim 26, wherein the subject is at risk of a P. falciparum infection.

28. The method of claim 26 or claim 27, wherein the method inhibits blood-stage P. falciparum.

29. Use of the monoclonal antibody or antigen binding fragment of any one of claims 1-14, the bispecific antibody or multi-specific antibody of claim 15, the nucleic acid molecule of any one of claims 16-18, the vector of claim 19, or the composition of claim 21 or claim 22 to inhibit P. falciparum infection in a subject or to detect the presence of a P. falciparum in a biological sample.