Neutralizing antibodies to plasmodium falciparum cyrpa protein and RIPR protein and their use

Abstract

Antibodies and antigen binding fragments that specifically bind to P. falciparum CyRPA protein or RIPR 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

[0001] 4239-113564-02

[0002] NEUTRALIZING ANTIBODIES TO PLASMODIUM FALCIPARUM CYRPA PROTEIN AND RIPR PROTEIN AND THEIR USE

[0003] CROSS REFERENCE TO RELATED APPLICATIONS

[0004] This application claims priority to U.S. Provisional Application No. 63 / 777,850, filed March 26, 2025, which is incorporated by reference in its entirety.

[0005] FIELD

[0006] This relates to monoclonal antibodies and antigen binding fragments that specifically bind to Plasmodium falciparum (P. falciparum or Pf) CyRPA protein or RIPR protein and their use, for example, in methods of inhibiting P. falciparum infection in a subject.

[0007] INCORPORATION OF ELECTRONIC SEQUENCE LISTING

[0008] The Sequence Listing is submitted as an XML file named “Sequence.xml,” created on March 24, 2026 (289,405 bytes), which is incorporated by reference herein.

[0009] BACKGROUND

[0010] 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.

[0011] 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. A major protein on the surface of the infecting P. falciparum sporozoites is the circumsporozoite protein (PfCSP) and provides a major target for antibodies and vaccines. 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. Merozoite invasion of red blood cells is facilitated by the binding of the RCR complex on the merozoite surface to a target receptor on the surface of red blood cells, initiating the invasion process. The RCR complex is a heterotrimeric structure formed by three proteins: PfRH5 (Reticulocyte-binding protein homologue 5), PfCyRPA (cysteine-rich protective antigen), and PfRIPR (RH5-interacting protein). The invasion of the erythrocytes by the malarial parasites leads to malarial pathogenesis and clinical infection.

[0012] 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,4239-113564-02

[0013] preventive interventions to inhibit malaria infection are urgently needed for limiting morbidity, mortality, and ultimately eliminating malaria.

[0014] SUMMARY

[0015] This disclosure provides monoclonal antibodies and antigen binding fragments directed against P. falciparum CyRPA protein and RIPR protein.

[0016] In some aspects, a monoclonal antibody is provided that comprises a heavy chain variable region (VH) 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 SEQ ID NOs: 1 and 2, respectively (MAD8-265), SEQ ID NOs: 9 and 10, respectively (MAD8-318), SEQ ID NOs: 17 and 18, respectively (MAD8-498), SEQ ID NOs: 25 and 26, respectively (MAD8-506), or SEQ ID NOs: 33 and 34, respectively (MAD11-0897), wherein the monoclonal antibody specifically binds to P. falciparum CyRPA protein. In some aspects, a monoclonal antibody is provided that comprises a VH and a VL comprising a HCDR1, a HCDR2, and a HCDR3, and a LCDR1, a LCDR2, and a LCDR3 of the VH and VL set forth as SEQ ID NOs: 41 and 42, respectively (MAD11-1129), SEQ ID NOs: 49 and 50, respectively (MAD8-2), SEQ ID NOs: 57 and 58, respectively (MAD8-66), SEQ ID NOs: 65 and 66, respectively (MAD8-72), SEQ ID NOs: 73 and 74, respectively (MAD8-739), or SEQ ID NOs: 301 and 302, respectively (MAD11-1043), wherein the monoclonal antibody specifically binds to P. falciparum RIPR protein. In several aspects, the monoclonal antibody neutralizes P. falciparum.

[0017] 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 VHand VL of the antibody or antigen binding fragment.

[0018] Also provided is a method for inhibiting (including preventing) P. falciparum infection in a subject. 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.

[0019] 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.

[0020] The foregoing and other features and advantages of this disclosure will become more apparent from tire following detailed description of several aspects, which proceeds with reference to the accompanying figures.4239-113564-02

[0021] BRIEF DESCRIPTION OF THE FIGURES FIGs. 1A and IB. Rare, potent anti-CyRPA and anti-RIPR antibodies are elicited by malaria exposure. (1 A) VH somatic mutation frequencies of CyRPA and RIPR mAbs isolated from infected donors. (IB) Binding of CyRPA and RIPR mAbs isolated from infected donors to antigen. mAbs were titrated against antigen-coated beads, and results calculated as AUC.

[0022] FIG.2. The mAbs were evaluated for the ability to inhibit growth of blood-stage Plasmodium falciparum. Three CyRPA mAbs showed the ability to inhibit growth of almost 100% of parasites: MAD08-498, MAD08-506 and MAD08-265. A fourth mAh, MAD08-318, was able to inhibit >75% of parasites. For RIPR mAbs, MAD11-1129, and MAD11-1043 were the most potent in tire panel, inhibiting about 50% of the parasites.

[0023] FIG.3. The three most potent anti-CyRPA mAbs were tested at different concentrations for tire ability to inhibit growth of blood-stage Plasmodium falciparum. MAD08-498 was the most potent out of the three mAbs.

[0024] SEQUENCES

[0025] 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 tire displayed strand.

[0026] DETAILED DESCRIPTION

[0027] Malaria is a mosquito- borne parasitic disease causing 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 PfCyRPA or PfRIPR. The PfCyRPA and PfRIPR -specific antibodies and antigen binding fragments provided herein are useful, for example, for detection of PfCyRPA or PfRIPR protein (such as in diagnostic assays) as well as to inhibit or treat malaria infection in suitable subjects, including travelers, military personnel, and subjects in elimination campaigns.

[0028] I. Summary of Terms

[0029] 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, tire 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 mass4239-113564-02

[0030] 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 aspects, the following explanations of terms are provided:

[0031] 317 Antibody: A monoclonal antibody that specifically binds to an epitope on PfCSP and neutralizes malaria infection. The CIS317 antibody and methods for its production are described, for example, in Oyen et al. (“Structural basis for antibody recognition of the NANP repeats in Plasmodium falciparum circumsporozoite protein,” Proc Natl Acad Sci USA, 114, E10438-E10445, 2017).

[0032] About: Unless context indicated otherwise, “about” refers to plus or minus 5% of a reference value. For example, “about” 100 refers to 95 to 105.

[0033] Administration: The introduction of a composition into a subject by a chosen route.

[0034] 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.

[0035] Antibody and Antigen Binding Fragment: An immunoglobulin, antigen-binding fragment, or derivative thereof, that specifically binds and recognizes an analyte (antigen) such a.v PfCyRPA or PfRIPR. 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.

[0036] 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 Dübel (Eds.), Antibody Engineering, Vols. 1-2, 2nded., Springer-Verlag, 2010).

[0037] Antibodies also include genetically engineered forms such as chimeric antibodies (such as humanized murine antibodies) and heteroconjugate antibodies (such as bispecific antibodies).

[0038] 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.4239-113564-02

[0039] Typically, a naturally occurring immunoglobulin has heavy (H) chains and light (L) 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 (λ) and kappa (κ). There are five main heavy chain classes (or isotypes) which determine the functional activity of an antibody molecule: IgM, IgD, IgG, IgA and IgE.

[0040] 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.

[0041] 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.

[0042] 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, 5thed., NIH Publication No. 91-3242, Public Health Service, National Institutes of Health, U. S. Department of Health and Human Services, 1991). The sequences of tire 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.

[0043] 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, 5thed., 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 etal., (“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.

[0044] In some aspects, 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 tire “ES” mutations) to increase half-life.

[0045] A “monoclonal antibody” is an antibody obtained from a population of substantially homogeneous antibodies, that is, tire individual antibodies comprising the population are identical and / or4239-113564-02

[0046] 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, phagedisplay 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.

[0047] 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, 2nded. New York: Cold Spring Harbor Laboratory Press, 2014.)

[0048] 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 aspect, all the CDRs are from the donor immunoglobulin in a humanized immunoglobulin.

[0049] 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.

[0050] 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.

[0051] 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 aspects, 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 Manual. 1stEd. New York: Cold Spring Harbor Laboratory Press, 2004. Print.; Lonberg, Nat. Biotech., 23: 1117-1125, 2005; Lonberg, Curr. Opin. Immunol., 20:450-459, 2008).

[0052] 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 PfCyRPA or PfRIPR)4239-113564-02

[0053] 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. For example, an antibody or antigen binding fragment that neutralizes P. falciparum may interfere with the pathogen by binding it in the blood and interfering with the merozoite invasion of erythrocytes. Alternately, an antibody may interfere with one or more post-attachment interactions of the pathogen with its receptors, for example, by interfering with pathogen internalization by receptor-mediated endocytosis.

[0054] In some aspects, an antibody or antigen binding fragment that specifically binds to PfCyRPA or PfRIPR and neutralizes P. falciparum inhibits merozoite invasion of erythrocytes, 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 aspects, an antibody or antigen binding fragment that specifically binds to PfCyRPA or PfRIPR 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.

[0055] 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.

[0056] 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.

[0057] Circumsporozoite protein (CSP): The circumsporozoite protein (CSP) is a major malaria parasite surface protein during the sporogonic cycle. PfCSP covers the surface of P. falciparum sporozoites, which are transmitted from the mosquito salivary gland to host hepatocytes.

[0058] 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.

[0059] 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, 2nded. New York: Cold Spring Harbor Laboratory Press, 2014, for a description of4239-113564-02

[0060] 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.

[0061] 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.

[0062] Conjugate: A complex of two molecules linked together, for example, linked together by a covalent bond. In one aspect, an antibody is linked to an effector molecule; for example, an antibody that specifically binds to PfCyRPA or PfRIPR from P. falciparum covalently linked to an effector molecule. The linkage can be by chemical or recombinant means. In one aspect, the linkage is chemical, wherein a reaction between the antibody moiety and tire 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.”

[0063] 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 PfCyRPA- or PfRIPR-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 PfCyRPA or PfRIPR, 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.

[0064] 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 aspects 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.

[0065] The following six groups are examples of amino acids that are considered to be conservative substitutions for one another:

[0066] 1) Alanine (A), Serine (S), Threonine (T);

[0067] 2) Aspartic acid (D), Glutamic acid (E);

[0068] 3) Asparagine (N), Glutamine (Q);

[0069] 4) Arginine (R), Lysine (K);

[0070] 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); and4239-113564-02

[0071] 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W).

[0072] Non-conservative substitutions are those that reduce an activity or function of the PfCyRPA- or PfRIPR-specific antibody, such as the ability to specifically bind to PfCyRPA or PfRIPR 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.

[0073] 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.

[0074] Control: A reference standard. In some aspects, the control is a negative control, such as sample obtained from a healthy patient not infected with P. falciparum. In other aspects, the control is a positive control, such as a tissue sample obtained from a patient diagnosed with P. falciparum infection. In still other aspects, 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).

[0075] 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%.

[0076] Cysteine-Rich Protective Antigen (PfCyRPA): A component of the RCR complex present on the merozoite surface that binds to a target receptor (basigin protein) on the surface of erythrocytes to facilitate erythrocytes invasion. An exemplary sequence for PfCyRPA is provided below:

[0077] MIIPFHKKFISFFQIVLVVLLLCRSINCDSRHVFIRTELSFIKNNVPCIRDMFFIYKRELYNICLDDLKGEEDETHI YVQKKVKDSWITLNDLFKETDLTGRPHIFAYVDVEEI I ILLCEDEEFSNRKKDMTCHRFYSNDGKEYNNSEITISDY ILKDKLLSSYVSLPLKIE REYFLICGVSPYKFKDDNKKDDILCMASHDKGETWGTKIVIKYD YKLGVQYFFLRPY I SKNDLSFHF YVGDNINNVKNVNF IECTHEKDLEFVCSNRDFLKDNKVLQDVSTLNDEYIVSYGNDNNFAECYIFFN NENS IL IKPEKYGNTTAGCYGGTFVKIDENRTLF I YSSSQGI YNIHTI YYANYE (SEQ ID NO: 313)

[0078] 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).4239-113564-02

[0079] 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, 4thed., 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).

[0080] Detecting: To identify the existence, presence, or fact of something.

[0081] 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 P. falciparum sporozoites from invading the liver in the subject or to measurably alter outward symptoms of the P. falciparum infection.

[0082] In some aspects, administration of an effective amount of a disclosed antibody or antigen binding fragment that binds to PfCyRPA or PfRIPR can reduce or inhibit a P. falciparum infection (for example, as measured by infection of 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.

[0083] The effective amount of an antibody or antigen binding fragment that specifically binds PfCyRPA or PfRIPR 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.

[0084] 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.

[0085] 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.

[0086] 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 specifically4239-113564-02

[0087] binds a particular antigenic epitope on a polypeptide. In some examples a disclosed antibody specifically binds to an epitope on PfCyRPA or PfRIPR from P. falciparum.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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 Cγ2 and Cγ3 and optionally the lower part of the hinge between Cγ14239-113564-02

[0093] and Cγ2. 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 Cα2 and Cα3 and optionally the lower part of the hinge between Cα1 and Cα2.

[0094] Host cell: Cells in which a vector can be propagated and its DNA expressed. The cell may be prokaryotic or eukaryotic. The term also includes any progeny of the subject host cell. It is understood that all progeny may not be identical to the parental cell since there may be mutations that occur during replication. However, such progeny are included when the term “host cell” is used.

[0095] 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 IgA1 and IgA2. 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.

[0096] 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 IgG1, IgG2, IgG3, and IgG4.

[0097] 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.

[0098] 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.

[0099] In some aspects, 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, or by other parameters that are specific to the particular disease or condition.4239-113564-02

[0100] In some aspects, the disclosed PfCyRPA- or PfRIPR-specific antibodies and antigen binding fragments inhibit the invasion of Plasmodium falciparum merozoite into human erythrocyte cells. The invasion of erythrocytes is a key event in the infection of a subject with the malaria parasite. Inhibition of the invasion of human erythrocyte cells can be measured using available assays. For example, the disclosed PfCyRPA- or PfRIPR-specific antibodies and antigen binding fragments can inhibit the invasion of Plasmodium falciparum merozoite into human erythrocytes by at least 25%, such as at least 50%, at least 75%, at least 90%, at least 95%, or 100% compared to a suitable control.

[0101] In some aspects, the disclosed PfCyRPA- or PfRIPR-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 PfCyRPA- or PfRIPR-specific antibodies and antigen binding fragments can inhibit the growth of Plasmodium falciparum in a subject by at least 25%, such as at least 50%, at least 75%, at least 90%, at least 95%, or 100% compared to a suitable control.

[0102] 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.

[0103] 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, 5thEdition, Department of Health and Human Services, Public Health Service, National Institutes of Health, Bethesda, NIH Publication No. 91-3242, 1991).

[0104] L9 Antibody: A monoclonal antibody that specifically binds to an epitope on PfCSP and neutralizes malaria infection. The L9 antibody and methods for its production are described, for example, in PCT Pub. No. WO 2020 / 227228.

[0105] 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.

[0106] 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. “Chemical4239-113564-02

[0107] 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.

[0108] 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.

[0109] 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. 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 blood 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, known as gametocytes. These gametocytes are the sexual blood cell stage forms of the parasite.

[0110] Merozoite invasion of red blood cells is facilitated by the binding of the RCR complex on the merozoite surface to a target receptor (basigin protein) on the surface of red blood cells, initiating the invasion process. The RCR complex is a heterotrimeric structure formed by three proteins: PfRH5 (Reticulocyte-binding protein homologue 5), PfCyRPA (cysteine-rich protective antigen), and PfRIPR (RH5-in teracting protein).

[0111] 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.

[0112] 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.4239-113564-02

[0113] “cDNA” refers to a DNA that is complementary or identical to an mRNA, in either single stranded or double stranded form.

[0114] “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.

[0115] 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.

[0116] Generally, operably linked DNA sequences are contiguous and, where necessary to join two proteincoding regions, in the same reading frame.

[0117] Pharmaceutically acceptable carriers: The pharmaceutically acceptable carriers of use are conventional. Remington: The Science and Practice of Pharmacy, 22nded., London, UK: Pharmaceutical Press, 2013, describes compositions and formulations suitable for pharmaceutical delivery of the disclosed agents.

[0118] 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 aspects, 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).4239-113564-02

[0119] 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 aspects, the polypeptide is a disclosed antibody or a fragment thereof.

[0120] 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 aspect, a preparation is purified such that tire protein or peptide represents at least 50% of the total peptide or protein content of the preparation.

[0121] 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 aspects, 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.

[0122] RH5-interacting protein (PfRIPR): A component of the RCR complex present on the merozoite surface that binds to a target receptor (basigin protein) on the surface of erythrocytes to facilitate erythrocytes invasion. An exemplary sequence for PfRIPR is provided below:

[0123] MFRIFFTLLIIILIKKTSAIDLIEGIFYEKNEIDKLTFSLDHRVRDNLKTDLILNNNGENDYAYLNKYVYTILNRDS TEKIKTFFSHNKDMKSCDYFISKEYNSSDKTNQICYKKTFCGWIPNSEEIKTNKITNDKLYCAHFNSTHIIIYYIS QPLLLEPHWYEETFFEKGKNDQINCQGMYISLRSVHVHTHNAILQQETLTYIKNLCDGKNNCKFDFDSIKYENKSL THYLFF INIQYQCI SPLNLQENEMCDVYNDDTHKATCKYGFNKIELLKNVCEENYRCTQD ICSVNQFCDGENETCTC KTSLLPSAKNNCEYNDLCTVLNCPENSTCEQIGNGKKAECKCENGKYYHNNKCYTKNDLELAIKIEPHKKEKFYKNN LYQGKALKPEYIFMQCENGFSIEVINAYVSCYRVSFNLNKLKYVTESLKKMCDGKTKCAYGNTIDPIDDLNHHNICN NFNTIFKYDYLCVFNNQNITSDKNSHLHSNIPSLYNSSILPDINKSKFHLISRNSRTNQYPHNNISMLEIQNEISSH NSNQFSTDPHTNSNNINNMNIKKVEIFRSRFSSKLQCQGGKINIDKAILKGGEGCNDLLLTNSLKSYCNDLSECDIG LIYHFDTYCINDQYLFVSYSCSNLCNKCHNNSTCYGNRFNYDCFCDNPYISKYGNKLCERPNDCESVLCSQNQVCQI LPNDKLICQCEEGYKNVKGKCVPDNKCDLSCPSNKVCVIENGKQTCKCSERFVLENGVCICANDYKMEDGINCIAKN KCKRKEYENICTNPNEMCAYNEETDIVKCECKEHYYRSSRGECILNDYCKDINCKENEECSIVNFKPECVCKENLKK NNKGEC I YENSCLINEGNCPKDSKC I YREYKPHECVCNKQGHVAVNGKCVLEDKCVHNKKCSENS ICVNVMNKEPIC VCTYNYYKKDGVCL IQNPCLKDNGGCSRNSECTFKYSKINCTCKENYKNKDDSCVPNTNEYDESFTFQYNDDAS I IL GACGMIEFSYI YNQI IWKINNSKESYVF YYDYPTAGNIEVQIKNE IFHTI I YLKKKIGNSVI YDDFQVDHQTCI YEN VFYYSNQN (SEQ ID NO: 314 )

[0124] 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.4239-113564-02

[0125] Homologs and variants of a VL or a VHof 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.

[0126] Any suitable method may be used to align sequences for comparison. Non-limiting examples of 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. Sei. 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.

[0127] 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.

[0128] 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 the surface of a pathogen, for example PfCyRPA or PfRIPR) 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, 2nded., Cold Spring Harbor Publications, New York (2013), for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity.

[0129] With reference to an antibody-antigen complex, specific binding of the antigen and antibody has a KDof less than about 10-7Molar, such as less than about 10-8Molar, 10-9, or even less than about 10-10Molar. KDrefers 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.4239-113564-02

[0130] An antibody that specifically binds to an epitope on PfCyRPA or PfRIPR is an antibody that binds substantially to PfCyRPA or PfRIPR, including cells or tissue expressing PfCyRPA or PfRIPR, substrate to which the PfCyRPA or PfRIPR is attached, or PfCyRPA or PfRIPR in a biological specimen. It is, of course, recognized that a certain degree of non-specific interaction may occur between an antibody and a non-target (such as a cell that does not express PfCyRPA or PfRIPR). 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.

[0131] 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.

[0132] 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.

[0133] 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 replication-incompetent, 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 aspects, a viral vector comprises a nucleic acid molecule encoding a disclosed antibody or antigen binding fragment that specifically binds to PfCyRPA or PfRIPR and neutralizes P. falciparum. In some aspects, the viral vector can be an adeno-associated virus (AAV) vector.4239-113564-02

[0134] II. Description of Several Aspects

[0135] A. Monoclonal Antibodies to PfCyRPA- or PfRIPR and Antigen Binding Fragments Thereof

[0136] Isolated monoclonal antibodies and antigen binding fragments that specifically bind an epitope on PfCyRPA or PfRIPR 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 P. falciparum merozoite entry into erythrocytes in vitro and in vivo. 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, tire 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.

[0137] / . Exemplary monoclonal antibodies and antigen binding fragments

[0138] 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 tire 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 tire CDR positions (according to the IMGT numbering scheme) of the heavy and light chains of exemplary monoclonal antibodies that bind to PfCyRPA or PfRIPR and / or neutralize P. falciparum are provided herein and shown in Example 2.

[0139] a. MAD8-265

[0140] In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD8-265 antibody, and specifically binds to PfCyRPA. In some aspects, the antibody or antigen binding fragment 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 MAD8-265 antibody, and specifically binds to PfCyRPA and neutralizes P. falciparum.

[0141] 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 PfCyRPA 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 least4239-113564-02

[0142] 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 2, and specifically binds to PfCyRPA 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 2, respectively, and specifically binds to PfCyRPA and neutralizes P. falciparum.

[0143] 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: 3, 4, and 5, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 6, 7, and 8, respectively, and specifically binds to PfCyRPA and neutralizes P. falciparum.

[0144] 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: 3, 4, and 5, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 6, 7 (KVS), 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: 2 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 2) and tire antibody or antigen binding fragment specifically binds to PfCyRPA and neutralizes P. falciparum.

[0145] 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: 3, 4, and 5, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 6, 7, and 8, respectively, wherein tire 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 as one of 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 one of SEQ ID NO: 2, and the antibody or antigen binding fragment specifically binds to PfCyRPA and neutralizes P. falciparum.

[0146] 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 PfCyRPA and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VLcomprising the amino acid sequence set forth as SEQ ID NO: 2, and specifically binds to PfCyRPA 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 2, respectively, and specifically binds to PfCyRPA and neutralizes P. falciparum.

[0147] In some aspects, the disclosed antibodies and antigen binding fragments inhibit the invasion of Plasmodium falciparum merozoite into human erythrocytes, and / or reduce pathogen load of Plasmodium falciparum in a subject, compared to a control.4239-113564-02

[0148] b. MAD8-318

[0149] In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD8-318 antibody, and specifically binds to PfCyRPA. In some aspects, the antibody or antigen binding fragment neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VHand a VLcomprising 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 MAD8-318 antibody, and specifically binds to PfCyRPA and neutralizes P. falciparum.

[0150] 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 PfCyRPA 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: 10, and specifically binds to PfCyRPA 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 10, respectively, and specifically binds to PfCyRPA and neutralizes P. falciparum.

[0151] In some aspects, tire antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 11, 12, and 13, respectively, and a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 6, 7 (KVS), and 16, respectively, and specifically binds to PfCyRPA and neutralizes P. falciparum.

[0152] 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: 11, 12, and 13, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 6, 7 (KVS), and 16, respectively, wherein the VHcomprises 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: 10 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 10) and the antibody or antigen binding fragment specifically binds to PfCyRPA and neutralizes P. falciparum.

[0153] In some aspects, the antibody or antigen binding fragment comprises a VHcomprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 11, 12, and 13, respectively, a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 6, 7 (KVS), 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 as one of 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 acid4239-113564-02

[0154] sequence set forth as one of SEQ ID NO: 10, and the antibody or antigen binding fragment specifically binds to PfCyRPA and neutralizes P. falciparum.

[0155] 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 PfCyRPA and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VLcomprising the amino acid sequence set forth as SEQ ID NO: 10, and specifically binds to PfCyRPA 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 10, respectively, and specifically binds to PfCyRPA and neutralizes P. falciparum.

[0156] In some aspects, the disclosed antibodies and antigen binding fragments inhibit the invasion of Plasmodium falciparum merozoite into human erythrocytes, and / or reduce pathogen load Plasmodium falciparum in a subject, compared to a control.

[0157] c. MAD8-498

[0158] In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD8-498 antibody, and specifically binds to PfCyRPA. In some aspects, the antibody or antigen binding fragment neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VHand a VLcomprising 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 MAD8-498 antibody, and specifically binds to PfCyRPA and neutralizes P. falciparum.

[0159] 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 PfCyRPA 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: 18, and specifically binds to PfCyRPA and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VLindependently 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 18, respectively, and specifically binds to PfCyRPA and neutralizes P. falciparum.

[0160] 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: 19, 20, and 21, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 22, 7 (KVS), and 24, respectively, and specifically binds to PfCyRPA and neutralizes P. falciparum.

[0161] 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: 19, 20, and 21, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 22, 7 (KVS), and 24, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 17 (such as4239-113564-02

[0162] 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: 18 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 18) and the antibody or antigen binding fragment specifically binds to PfCyRPA and neutralizes P. falciparum.

[0163] In some aspects, the antibody or antigen binding fragment comprises a VHcomprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 19, 20, and 21, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 22, 7 (KVS), 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 as one of SEQ ID NO: 17, and tire 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 one of SEQ ID NO: 18, and the antibody or antigen binding fragment specifically binds to PfCyRPA and neutralizes P. falciparum.

[0164] 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 PfCyRPA 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: 18, and specifically binds to PfCyRPA 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 18, respectively, and specifically binds to PfCyRPA and neutralizes P. falciparum.

[0165] In some aspects, tire disclosed antibodies and antigen binding fragments inhibit the invasion of Plasmodium falciparum merozoite into human erythrocytes, and / or reduce pathogen load Plasmodium falciparum in a subject, compared to a control.

[0166] d. MAD8-506

[0167] In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD8-506 antibody, and specifically binds to PfCyRPA. In some aspects, the antibody or antigen binding fragment neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VHand a VLcomprising 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 MAD8-506 antibody, and specifically binds to PfCyRPA and neutralizes P. falciparum.

[0168] 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 PfCyRPA 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: 26, and specifically4239-113564-02

[0169] binds to PfCyRPA 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: 25 and 26, respectively, and specifically binds to PfCyRPA and neutralizes P. falciparum.

[0170] 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: 27, 28, and 29, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 22, 31 (KIS), and 24, respectively, and specifically binds to PfCyRPA and neutralizes P. falciparum.

[0171] 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: 27, 28, and 29, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 22, 31 (KIS), and 24, 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), tire VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 26 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 26) and the antibody or antigen binding fragment specifically binds to PfCyRPA and neutralizes P. falciparum.

[0172] 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: 27, 28, and 29, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 22, 31 (KIS), 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 tire amino acid sequence set forth as one of 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 one of SEQ ID NO: 26, and the antibody or antigen binding fragment specifically binds to PfCyRPA and neutralizes P. falciparum.

[0173] 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 PfCyRPA and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VLcomprising the amino acid sequence set forth as SEQ ID NO: 26, and specifically binds to PfCyRPA 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 26, respectively, and specifically binds to PfCyRPA and neutralizes P. falciparum.

[0174] In some aspects, the disclosed antibodies and antigen binding fragments inhibit the invasion of Plasmodium falciparum merozoite into human erythrocytes, and / or reduce pathogen load Plasmodium falciparum in a subject, compared to a control.4239-113564-02

[0175] e. MAD11-0897

[0176] In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD11-0897 antibody, and specifically binds to PfCyRPA. In some aspects, the antibody or antigen binding fragment neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VHand a VLcomprising 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 MAD11-0897 antibody, and specifically binds to PfCyRPA and neutralizes P. falciparum.

[0177] 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 PfCyRPA 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: 34, and specifically binds to PfCyRPA 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 34, respectively, and specifically binds to PfCyRPA and neutralizes P. falciparum.

[0178] In some aspects, tire antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 35, 36, and 37, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 38, 39 (TAS), and 40, respectively, and specifically binds to PfCyRPA and neutralizes P. falciparum.

[0179] 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: 35, 36, and 37, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 38, 39 (TAS), and 40, respectively, wherein the VHcomprises 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: 34 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 34) and the antibody or antigen binding fragment specifically binds to PfCyRPA and neutralizes P. falciparum.

[0180] 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: 35, 36, and 37, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 38, 39 (TAS), 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 as one of SEQ ID NO: 33, and tire 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)4239-113564-02

[0181] compared to the amino acid sequence set forth as one of SEQ ID NO: 34, and the antibody or antigen binding fragment specifically binds to PfCyRPA and neutralizes P. falciparum.

[0182] 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 PfCyRPA and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VLcomprising the amino acid sequence set forth as SEQ ID NO: 34, and specifically binds to PfCyRPA 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 34, respectively, and specifically binds to PfCyRPA and neutralizes P. falciparum.

[0183] In some aspects, the disclosed antibodies and antigen binding fragments inhibit the invasion of Plasmodium falciparum merozoite into human erythrocytes, and / or reduce pathogen load Plasmodium falciparum in a subject, compared to a control.

[0184] / . MAD11-1129

[0185] In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD11-1129 antibody, and specifically binds to PfRIPR. In some aspects, the antibody or antigen binding fragment neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VHand a VLcomprising 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 MAD11-1129 antibody, and specifically binds to PfRIPR and neutralizes P. falciparum.

[0186] 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 PfRIPR 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: 42, and specifically binds to PfRIPR 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 42, respectively, and specifically binds to PfRIPR and neutralizes P. falciparum.

[0187] 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: 43, 44, and 45, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 46, 47 (YDK), and 48, respectively, and specifically binds to PfRIPR and neutralizes P. falciparum.

[0188] 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: 43, 44, and 45, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 46, 47 (YDK), and 48, respectively,4239-113564-02

[0189] wherein the VHcomprises 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: 42 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 42) and the antibody or antigen binding fragment specifically binds to PfRIPR and neutralizes P. falciparum.

[0190] 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: 43, 44, and 45, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 46, 47 (YDK), 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 as one of SEQ ID NO: 41, and tire 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 one of SEQ ID NO: 42, and the antibody or antigen binding fragment specifically binds to PfRIPR and neutralizes P. falciparum.

[0191] 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 PfRIPR 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: 42, and specifically binds to PfRIPR 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 42, respectively, and specifically binds to PfRIPR and neutralizes P. falciparum.

[0192] In some aspects, the disclosed antibodies and antigen binding fragments inhibit the invasion of Plasmodium falciparum merozoite into human erythrocytes, and / or reduce pathogen load Plasmodium falciparum in a subject, compared to a control.

[0193] g. MAD8-2

[0194] In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD8-2 antibody, and specifically binds to PfRIPR. In some aspects, the antibody or antigen binding fragment 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 MAD8-2 antibody, and specifically binds to PfRIPR and neutralizes P. falciparum.

[0195] 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 PfRIPR 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 least4239-113564-02

[0196] 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 50, and specifically binds to PfRIPR 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 50, respectively, and specifically binds to PfRIPR and neutralizes P. falciparum.

[0197] 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: 51, 52, and 53, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 54, 55 (KAS), and 56, respectively, and specifically binds to PfRIPR and neutralizes P. falciparum.

[0198] 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: 51, 52, and 53, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 54, 55 (KAS), 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), tire VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 50 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 50) and the antibody or antigen binding fragment specifically binds to PfRIPR and neutralizes P. falciparum.

[0199] In some aspects, tire antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 51, 52, and 53, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 54, 55 (KAS), 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 tire amino acid sequence set forth as one of 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 one of SEQ ID NO: 50, and the antibody or antigen binding fragment specifically binds to PfRIPR and neutralizes P. falciparum.

[0200] In additional aspects, the antibody or antigen binding fragment comprises a VHcomprising the amino acid sequence set forth as SEQ ID NO: 49, and specifically binds to PfRIPR 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: 50, and specifically binds to PfRIPR 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 50, respectively, and specifically binds to PfRIPR and neutralizes P. falciparum.

[0201] In some aspects, the disclosed antibodies and antigen binding fragments inhibit tire invasion of Plasmodium falciparum merozoite into human erythrocytes, and / or reduce pathogen load Plasmodium falciparum in a subject, compared to a control.4239-113564-02

[0202] h. MAD8-66

[0203] In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD8-66 antibody, and specifically binds to PfRIPR. In some aspects, the antibody or antigen binding fragment neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VHand 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 MAD8-66 antibody, and specifically binds to PfRIPR and neutralizes P. falciparum.

[0204] 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: 57, and specifically binds to PfRIPR 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: 58, and specifically binds to PfRIPR 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 58, respectively, and specifically binds to PfRIPR and neutralizes P. falciparum.

[0205] In some aspects, tire antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 59, 60, and 61, respectively, and a VLComprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 62, 63 (WAS), and 64, respectively, and specifically binds to PfRIPR and neutralizes P. falciparum.

[0206] 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: 59, 60, and 61, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 62, 63 (WAS), and 64, respectively, wherein the VHcomprises 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: 58 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 58) and the antibody or antigen binding fragment specifically binds to PfRIPR and neutralizes P. falciparum.

[0207] 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: 59, 60, and 61, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 62, 63 (WAS), 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 as one of SEQ ID NO: 57, and tire framework regions of tire VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6,4239-113564-02

[0208] 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 NO: 58, and the antibody or antigen binding fragment specifically binds to PfRIPR and neutralizes P. falciparum.

[0209] In additional aspects, the antibody or antigen binding fragment comprises a VHcomprising the amino acid sequence set forth as SEQ ID NO: 57, and specifically binds to PfRIPR 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: 58, and specifically binds to PfRIPR 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 58, respectively, and specifically binds to PfRIPR and neutralizes P. falciparum.

[0210] In some aspects, the disclosed antibodies and antigen binding fragments inhibit tire invasion of Plasmodium falciparum merozoite into human erythrocytes, and / or reduce pathogen load Plasmodium falciparum in a subject, compared to a control.

[0211] i. MAD8-72

[0212] In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD8-72 antibody, and specifically binds to PfRIPR. In some aspects, the antibody or antigen binding fragment neutral izes P. falciparum. For example, the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1, the HCDR2, and tire HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD8-72 antibody, and specifically binds to PfRIPR and neutralizes P. falciparum.

[0213] 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: 65, and specifically binds to PfRIPR 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: 66, and specifically binds to PfRIPR and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VLindependently 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 66, respectively, and specifically binds to PfRIPR and neutralizes P. falciparum.

[0214] 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: 67, 68, and 69, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 70, 71 (DVS), and 72, respectively, and specifically binds to PfRIPR and neutralizes P. falciparum.

[0215] 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: 67, 68, and 69, respectively, a VL comprising a4239-113564-02

[0216] LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 70, 71 (DVS), 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 Vi. comprises an amino acid sequence at least 90% identical to SEQ ID NO: 66 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 66) and the antibody or antigen binding fragment specifically binds to PfRIPR and neutralizes P. falciparum.

[0217] 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: 67, 68, and 69, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 70, 71 (DVS), 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 as one of SEQ ID NO: 65, and tire framework regions of tire 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 one of SEQ ID NO: 66, and the antibody or antigen binding fragment specifically binds to PfRIPR and neutralizes P. falciparum.

[0218] 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 PfRIPR and neutralizes P. falciparum. In more aspects, tire antibody or antigen binding fragment comprises a VL comprising tire amino acid sequence set forth as SEQ ID NO: 66, and specifically binds to PfRIPR 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 66, respectively, and specifically binds to PfRIPR and neutralizes P. falciparum.

[0219] In some aspects, the disclosed antibodies and antigen binding fragments inhibit the invasion of Plasmodium falciparum merozoite into human erythrocytes, and / or reduce pathogen load Plasmodium falciparum in a subject, compared to a control.

[0220] j. MAD8-739

[0221] In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD8-739 antibody, and specifically binds to PfRIPR. In some aspects, the antibody or antigen binding fragment 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 MAD8-739 antibody, and specifically binds to PfRIPR and neutralizes P. falciparum.

[0222] 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 tire amino acid sequence set forth as SEQ ID NO: 73, and specifically binds to PfRIPR and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL4239-113564-02

[0223] 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: 74, and specifically binds to PfRIPR and neutralizes P. falciparum. In additional aspects, the antibody or antigen binding fragment comprises a VH and a VLindependently 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 74, respectively, and specifically binds to PfRIPR and neutralizes P. falciparum.

[0224] 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: 75, 76, and 77, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 78, 79 (GNN), and 80, respectively, and specifically binds to PfRIPR and neutralizes P. falciparum.

[0225] 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: 75, 76, and 77, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 78, 79 (GNN), 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), tire VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 74 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 74) and the antibody or antigen binding fragment specifically binds to PfRIPR and neutralizes P. falciparum.

[0226] In some aspects, tire antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 75, 76, and 77, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 78, 79 (GNN), 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 tire amino acid sequence set forth as one of 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 one of SEQ ID NO: 74, and the antibody or antigen binding fragment specifically binds to PfRIPR and neutralizes P. falciparum.

[0227] In additional aspects, the antibody or antigen binding fragment comprises a VHcomprising the amino acid sequence set forth as SEQ ID NO: 73, and specifically binds to PfRIPR 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: 74, and specifically binds to PfRIPR 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 74, respectively, and specifically binds to PfRIPR and neutralizes P. falciparum.4239-113564-02

[0228] In some aspects, the disclosed antibodies and antigen binding fragments inhibit the invasion of Plasmodium falciparum merozoite into human erythrocytes, and / or reduce pathogen load Plasmodium falciparum in a subject, compared to a control.

[0229] k. MAD11-1043

[0230] In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD11-1043 antibody, and specifically binds to PfRIPR. In some aspects, the antibody or antigen binding fragment 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 MAD11-1043 antibody, and specifically binds to PfRIPR and neutralizes P. falciparum.

[0231] 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 tire amino acid sequence set forth as SEQ ID NO: 73, and specifically binds to PfRIPR 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: 74, and specifically binds to PfRIPR 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 tire amino acid sequences set forth as SEQ ID NOs: 73 and 74, respectively, and specifically binds to PfRIPR and neutralizes P. falciparum.

[0232] 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: 315, 316, and 317, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 318, 319 (KDS), and 320, respectively, and specifically binds to PfRIPR and neutralizes P. falciparum.

[0233] 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: 315, 316, and 317, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 318, 319 (KDS), and 320, respectively, wherein the VHcomprises an amino acid sequence at least 90% identical to SEQ ID NO: 301 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 301), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 302 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 302) and the antibody or antigen binding fragment specifically binds to PfRIPR and neutralizes P. falciparum.

[0234] 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: 315, 316, and 317, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 318, 319 (KDS), and 320, 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, up4239-113564-02

[0235] 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 NO: 310, 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 one of SEQ ID NO: 302, and the antibody or antigen binding fragment specifically binds to PfRIPR and neutralizes P. falciparum.

[0236] In additional aspects, the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 301, and specifically binds to PfRIPR 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: 302, and specifically binds to PfRIPR and neutralizes P. falciparum. In some aspects, the antibody or antigen binding fragment comprises a VH and a VL comprising tire amino acid sequences set forth as SEQ ID NOs: 301 and 302, respectively, and specifically binds to PfRIPR and neutralizes P. falciparum.

[0237] In some aspects, the disclosed antibodies and antigen binding fragments inhibit tire invasion of Plasmodium falciparum merozoite into human erythrocytes, and / or reduce pathogen load Plasmodium falciparum in a subject, compared to a control.

[0238] I. Additional antibodies that bind PFCyRPA or PfRIPR

[0239] In some aspects, tire antibody or antigen binding fragment is based on or derived from any one of the antibodies provided in Example 2, and specifically binds to PfCyRPA or PfRIPR. In some aspects, the antibody or antigen binding fragment neutralizes P. falciparum. For example, the antibody or antigen binding fragment comprises a VH and a VL comprising tire HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of any one of the antibodies provided in Example 2 and specifically binds to PfCyRPA or PfRIPR and neutralizes P. falciparum.

[0240] 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 of the VH of any one of the antibodies provided in Example 2, and specifically binds to PfCyRPA or PfRIPR 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 of the VL of any one of the antibodies provided in Example 2, and specifically binds to PfCyRPA or PfRIPR 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 of the VH and the VL of any one of the antibodies provided in Example 2, and specifically binds to PfCyRPA or PfRIPR and neutralizes P. falciparum.4239-113564-02

[0241] In additional aspects, the antibody or antigen binding fragment comprises a VHcomprising the amino acid sequence set forth as the VH of any one of the antibodies provided in Example 2 and specifically binds to PfCyRPA or PfRIPR and neutralizes P. falciparum. In more aspects, the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as the VLof any one of the antibodies provided in Example 2, and specifically binds to PfCyRPA or PfRIPR 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 the VH and the VL of any one of the antibodies provided in Example 2 and specifically binds to PfCyRPA or PfRIPR and neutralizes P. falciparum.

[0242] In some aspects, the disclosed antibodies and antigen binding fragments inhibit the invasion of Plasmodium falciparum merozoite into human erythrocytes, and / or reduce pathogen load Plasmodium falciparum in a subject, compared to a control.

[0243] 2. Additional Description of Antibodies and Antigen Binding Fragments

[0244] The antibody or antigen binding fragment can be a human antibody or fragment thereof.

[0245] 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. Alternatively, a heterologous framework region, such as, but not limited to a mouse or monkey framework region, can be included in tire heavy or light chain of tlie antibodies.

[0246] The antibody can be of any isotype. The antibody can be, for example, an IgM or an IgG antibody, such as IgG1, IgG2, IgG3, or IgG4. The class of an antibody that specifically binds PfCyRPA or PfRIPR 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 CL or CH chain. For example, an antibody that specifically binds PfCyRPA or PfRIPR, 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 IgG1 to IgG2, IgG3, or IgG4.

[0247] In some examples, the disclosed antibodies are oligomers of antibodies, such as dimers, trimers, tetramers, pentamers, hexamers, septamers, octomers and so on.

[0248] 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).4239-113564-02

[0249] a. Binding affinity

[0250] In several aspects, the antibody or antigen binding fragment specifically binds PfCyRPA or PfRIPR with an affinity (e.g., measured by KD) of no more than 1.0 x 10'8M, no more than 5.0 x 10‘8M, no more than 1.0 x 10'9M, no more than 5.0 x 10'9M, no more than 1.0 x 1O1CIM, no more than 5.0 x 10'10M, or no more than 1.0 x 1 O'11M. KDcan be measured, for example, by a radiolabeled antigen binding assay (RIA) performed with the Fab version of an antibody of interest and its antigen. 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 5 pg / 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 [125I]-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.

[0251] 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 tire capture plate for incubation at room temperature (e.g., for one hour). The solution is then removed and tire plate washed eight times with 0.1% polysorbate 20 (TWEEN-20®) in PBS. When the plates have dried, 150 pl / well of scintillant (MicroScint™-20; PerkinElmer) is added, and the plates are counted on a TOPCOUNT™ gamma counter (PerkinElmer) for ten minutes.

[0252] Concentrations of each Fab that give less than or equal to 20% of maximal binding are chosen for use in competitive binding assays.

[0253] In another assay, KDcan 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 pl / 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 251 / min. Association rates (kon) and dissociation rates (kOff) 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 106M-1s-1by the surface plasmon resonance assay4239-113564-02

[0254] 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 spectrophotometer (Aviv Instruments) or a 8000-series SLM-AMINCO™ spectrophotometer (ThermoSpectronic) with a stirred cuvette.

[0255] b. Multispecific antibodies

[0256] In some aspects, a multi-specific antibody, such as a bi-specific antibody, is provided that comprises an antibody or antigen binding fragment as provided herein, and specifically binds to PfCyRPA or PfRIPR. Any suitable method can be used to design and produce the multi-specific antibody, 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. Non-limiting examples of 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).

[0257] The multi-specific antibody may have any suitable format drat allows for antigen binding by the antibody or antigen binding fragment as provided herein, such as any one of MAD8-265, MAD8-318, MAD8-498, MAD8-506, MAD11-0897, MAD11-1129, MAD8-2, MAD8-66, MAD8-72, MAD8-739, or MAD11-1043, or any one of tire antibodies listed in Example 2, or an antigen binding fragment thereof. Bispecific single chain antibodies can be encoded by a single nucleic acid molecule. Non-limiting examples of bispecific single chain antibodies, as well as methods of constructing such antibodies are provided in 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. 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) 93-191, 1997; Loftier 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.

[0258] c. Fragments

[0259] Antigen binding fragments are encompassed by die present disclosure, such as Fab, F(ab')2, and Fv which include a heavy chain and VL and specifically bind PfCyRPA or PfRIPR. These antibody fragments retain the ability to selectively bind with the antigen and are “antigen-binding” fragments. Non-limiting examples of such fragments include:4239-113564-02

[0260] ( 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;

[0261] (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;

[0262] (3) (Fab', the fragment of the antibody that can be obtained by treating whole antibody with the enzyme pepsin without subsequent reduction; F(ab')2 is a dimer of two Fab' fragments held together by two disulfide bonds;

[0263] (4) Fv, a genetically engineered fragment containing the VL and VL expressed as two chains; and

[0264] (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, IDrugs, 13(8)1543-549, 2010). The intramolecular orientation of the Vn-domain and tire VL-domain in a scFv, is not decisive for tire provided antibodies (e.g., for the provided multispecific antibodies). Thus, scFvs with both possible arrangements (Vn-do main-linker domain- V| -domain; VL-domain-linker domain-Vu-domain) may be used.

[0265] (6) A dimer of a single chain antibody (scFVr), defined as a dimer of a scFV. This has also been termed a “miniantibody.”

[0266] Any suitable method of producing the above-discussed antigen binding fragments may be used. Non-limiting examples are provided in Harlow and Lane, Antibodies: A Laboratory Manual, 2nd, Cold Spring Harbor Laboratory, New York, 2013.

[0267] 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.

[0268] Other methods of cleaving antibodies, such as separation of heavy chains to form monovalent light-heavy 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.

[0269] d. Variants

[0270] In some aspects, amino acid sequence variants of the antibodies and antigen binding fragments 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,4239-113564-02

[0271] 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.

[0272] In some aspects, 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.

[0273] The variants typically retain amino acid residues necessary for correct folding and stabilizing between the VH and tire VL regions, and will retain the charge characteristics of tire residues in order to preserve the low pl and low toxicity of the molecules. Amino acid substitutions can be made in tire VH and the VL regions to increase yield.

[0274] In some aspects, 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 tire framework regions of the heavy chain of the antibody, or the light chain of tire antibody, or the heavy and light chains of the antibody, compared to known framework regions, or compared to the framework regions of an antibody as provided herein, and maintain the specific binding activity for PfCyRPA or PfRIPR.

[0275] In some aspects, 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 aspects 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.

[0276] 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 VHand 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 PfCyRPA or PfRIPR.

[0277] In some aspects, an antibody or antigen binding fragment 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.4239-113564-02

[0278] 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 CH2domain of the Fc region. See, e.g., Wright et al. Trends Biotechnol. 15(1):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 aspects, modifications of the oligosaccharide in an antibody may be made in order to create antibody variants with certain improved properties.

[0279] In one aspect, 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-fucosyltransferase 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).

[0280] Antibody 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 / 22764.4239-113564-02

[0281] In several aspects, tire constant region of the antibody (such as any one of MAD8-265, MAD8-318, MAD8-498, MAD8-506, MAD11-0897, MAD11-1129, MAD8-2, MAD8-66, MAD8-72, MAD8-739, or MAD11-1043, or any one of the antibodies listed in Example 2) 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 aspects, the antibody comprises an amino acid substitution that increases binding to the FcRn. Non-limiting examples of such substitutions include substitutions at IgG constant regions T250Q and M428L (see, e.g., Hinton et al., J Immunol., 176( 1):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 (such as any one of MAD8-265, MAD8-318, MAD8-498, MAD8-506, MAD11-0897, MAD11-1129, MAD8-2, MAD8-66, MAD8-72, MAD8-739, or MAD11-1043) and antigen binding fragments can be linked to or comprise an Fc polypeptide including any of the substitutions listed above, for example, tire Fc polypeptide can include the M428L and N434S substitutions.

[0282] In some aspects, 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 aspects, the antibody comprises one or more amino acid substitutions that increase binding to FcyRIIIa. Non-limiting examples of such substitutions include substitutions at IgG constant regions S239D and I332E (see, e.g., Lazar etal., Proc. Natl., Acad. Sci. U. S. A., 103(11 ):4005-4010, 2006); and S239D, A330L, and I332E (see, e.g., Lazar etal., Proc. Natl., Acad. Sci. U. S. A.,

[0283] 103(11):4005-4010, 2006).

[0284] 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.

[0285] In some aspects, 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-l,3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymer, polyaminoacids (either homopolymers or random4239-113564-02

[0286] copolymers), and dextran or poly(n-vinyl pyrrolidone)polyethylene glycol, propropylene glycol homopolymers, 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.

[0287] B. Conjugates

[0288] The antibodies and antigen binding fragments that specifically bind to PfCyRPA or PfRIPR (such as any one of MAD8-265, MAD8-318, MAD8-498, MAD8-506, MAD11-0897, MAD11-1129, MAD8-2, MAD8-66, MAD8-72, MAD8-739, or MAD11-1043, or any one of the antibodies listed in Example 2) 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 as125I,32P,14C,3H and35S 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.

[0289] 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 suitable linker molecule. The linker is capable of forming covalent bonds to both the antibody or antigen binding fragment and to the effector molecule or detectable marker.

[0290] 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.

[0291] 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 other polypeptide can be determined.

[0292] 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,4239-113564-02

[0293] microscopy or diagnostic imaging techniques (such as CT, computed axial tomography (CAT), MRI, magnetic resonance tomography (MTR), 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). 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, P- 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, tire 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.

[0294] 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.

[0295] 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).

[0296] 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 PfCyRPA or PfRIPR 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,99mTc,111In,125I,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.

[0297] 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 aspects, 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 be4239-113564-02

[0298] 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.

[0299] C. Polynucleotides and Expression

[0300] 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 PfCyRPA or PfRIPR (such as any one of MAD8-265, MAD8-318, MAD8-498, MAD8-506, MAD11-0897, MAD11-1129, MAD8-2, MAD8-66, MAD8-72, MAD8-739, or MAD11-1043) are provided. 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 tire art (such as framework or constant region sequences), and the genetic code. In several aspects, a nucleic acid molecules can encode the VH, Hie VL, or both the VH and VL (for example in a bicistronic expression vector) of a disclosed antibody or antigen binding fragment. In several aspects, tire nucleic acid molecules can be expressed in a host cell (such as a mammalian cell) to produce a disclosed antibody or antigen binding fragment.

[0301] 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 tire same antibody sequence, or encode a conjugate or fusion protein including the VL and / or VH nucleic acid sequence.

[0302] Nucleic acid molecules encoding tire antibodies, antigen binding fragments, and conjugates that specifically bind to PfCyRPA or PfRIPR 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.

[0303] 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, 4thed., New York: Cold Spring Harbor Laboratory Press, 2012) and Ausubel etal. (Eds.) (Current Protocols in Molecular Biology, New York: John Wiley and Sons, including supplements).

[0304] 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).

[0305] 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 tire VH and / or VL (linked to an effector molecule or4239-113564-02

[0306] detectable marker as needed), or can be expressed as a fusion protein. Any suitable method of expressing and purifying antibodies and antigen binding fragments may be used; non-limiting examples are provided in 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 VHand VL, and immunoadhesin are provided. The nucleic acid sequences can optionally encode a leader sequence.

[0307] To create a scFv the VH- and VL-encoding DNA fragments can be operatively linked to another fragment encoding a flexible linker, e.g., encoding the amino acid sequence (Gly4-Ser)3, such that the VH and VL 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;

[0308] Kontermann and Dübel (Eds.), Antibody Engineering, Vols. 1-2, 2nded., Springer-Verlag, 2010;

[0309] Greenfield (Ed.), Antibodies: A Laboratory Manual, 2nded. New York: Cold Spring Harbor Laboratory Press, 2014). Optionally, a cleavage site can be included in a linker, such as a furin cleavage site.

[0310] 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 PfCyRPA or PfRIPR and another antigen. The encoded VH and VL optionally can include a furin cleavage site between the VH and VL domains.

[0311] 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 tire 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 may be used. Hybridomas expressing the antibodies of interest are also encompassed by this disclosure.

[0312] 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).

[0313] 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 for4239-113564-02

[0314] 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 any suitable method 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.

[0315] 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 tire amino terminus to provide an initiation site, or additional amino acids (such as poly His) to aid in purification steps.

[0316] 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 et 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 prophy latically, the polypeptides should be substantially free of endotoxin.

[0317] 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, 2nded. 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.

[0318] D. Methods and Compositions

[0319] 1. Inhibiting P. falciparum infection

[0320] 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 (such as any one of MAD8-265, MAD8-318, MAD8-498, MAD8-506, MAD11-0897, MAD11-1129, MAD8-2, MAD8-66, MAD8-72, MAD8-739, or MAD11-1043), antigen binding fragment, conjugate, or a nucleic acid encoding such an4239-113564-02

[0321] 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.

[0322] 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 aspects, the subject can also be treated with an effective amount of an additional agent, such as antimalaria agent.

[0323] In some aspects, 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, growth or invasion) or symptoms of P. falciparum infection in the subject.

[0324] 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 aspects, 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.

[0325] 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.

[0326] In some aspects, the method of inhibiting P. falciparum infection in a subject comprises administration of a first antibody that specifically binds to PfCyRPA or PfRIPR as disclosed herein (such as any one MAD8-265, MAD8-318, MAD8-498, MAD8-506, MAD11-0897, MAD11-1129, MAD8-2, MAD8-66, MAD8-72, MAD8-739, or MAD11-1043) and a second antibody that that specifically binds to Pf (such as L9 or CIS43).

[0327] 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. Any suitable method of nucleic acid administration may be used; non-limiting examples are provided 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.

[0328] 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 antigen4239-113564-02

[0329] 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 aspects, 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).

[0330] In several aspects, 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 comprises 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.

[0331] In one aspect, 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 tire 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.

[0332] 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 ug / 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).

[0333] Single or multiple administrations of a composition including a disclosed PfCyRPA or PfRIPR -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.

[0334] 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 tire ED50, 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.

[0335] The PfCyRPA or PfRIPR -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, intra-arterially, intraperitoneally, intramuscularly, intradermally, or intrathecally. In an aspect, the antibody, antigen binding fragment, conjugate, or nucleic acid molecule encoding such molecules, or a composition including such molecules, is administered by a single4239-113564-02

[0336] 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.

[0337] 2. Compositions

[0338] Compositions are provided that include one or more of the PfCyRPA or PfRIPR-specific antibody, antigen binding fragment, conjugate, or nucleic acid molecule encoding such molecules, that are disclosed herein in a pharmaceutically acceptable carrier. In some aspects, the composition comprises an antibody as provided herein (such as any one of MAD8-265, MAD8-318, MAD8-498, MAD8-506, MAD11-0897, MAD11-1129, MAD8-2, MAD8-66, MAD8-72, MAD8-739, or MAD11-1043). In some aspects, tire composition comprises an antibody as provided herein (such as any one of MAD8-265, MAD8-318, MAD8-498, MAD8-506, MAD11-0897, MAD11-1129, MAD8-2, MAD8-66, MAD8-72, MAD8-739, or MAD11-1043) and one or more additional Pf-specific antibodies, such as L9 or CIS43 or 317. 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 PfCyRPA or PfRIPR-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 PfCyRPA or PfRIPR-specific antibody, antigen binding fragment, conjugate, or nucleic acid molecule encoding such molecules, is formulated for parenteral administration, such as intravenous administration.

[0339] In some aspects, 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 aspects, 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.

[0340] The compositions for administration can include a solution of the PfCyRPA or PfRIPR-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 any suitable technique. 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,4239-113564-02

[0341] 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.

[0342] A typical composition for intravenous administration comprises 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). Any suitable method may be used for preparing administrable compositions; non-limiting examples are provided in such publications as Remington: The Science and Practice of Pharmacy, 22nded., London, UK: Pharmaceutical Press, 2013. In some aspects, 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 PfCyRPA or PfRIPR), 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.

[0343] 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.

[0344] 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,4239-113564-02

[0345] 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.

[0346] Polymers can be used for ion-controlled release of the antibody compositions disclosed herein. Any suitable polymer may be used, such as a degradable or nondegradable polymeric matrix designed for use in controlled drug delivery. Alternatively, hydroxyapatite has been used as a microcarrier for controlled release of proteins. In yet another aspect, liposomes are used for controlled release as well as drug targeting of the lipid-capsulated drug.

[0347] 3. Methods of detection and diagnosis

[0348] Methods are also provided for the detection of the presence of PfCyRPA or PfRIPR in vitro or in vivo. In one example, tire presence of PfCyRPA or PfRIPR 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.

[0349] 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 PfCyRPA or PfRIPR, 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 tire antibody or antigen binding fragment.

[0350] In one aspect, the antibody or antigen binding fragment is directly labeled with a detectable marker. In another aspect, 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.

[0351] In some aspects, the disclosed antibodies or antigen binding fragments thereof are used to test vaccines. For example to test if a vaccine composition including a PfCyRPA or PfRIPR 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 comprises contacting a sample containing the vaccine, such as a PfCyRPA or PfRIPR 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 PfCyRPA or PfRIPR immunogen including the epitope in the sample. In one example, tire detection of the immune complex in tire sample indicates that vaccine component, such as a4239-113564-02

[0352] PfCyRPA or PfRIPR immunogen assumes a conformation capable of binding the antibody or antigen binding fragment.

[0353] E. Additional Aspects of the Disclosure

[0354] Aspect 1. An isolated monoclonal antibody, comprising:

[0355] (A) a heavy chain variable region (VH) 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:

[0356] a) SEQ ID NOs: 1 and 2, respectively (MAD8-265);

[0357] b) SEQ ID NOs: 9 and 10, respectively (MAD8-318);

[0358] c) SEQ ID NOs: 17 and 18, respectively (MAD8-498);

[0359] d) SEQ ID NOs: 25 and 26, respectively (MAD8-506); or

[0360] e) SEQ ID NOs: 33 and 34, respectively (MAD11-0897); and

[0361] wherein the monoclonal antibody specifically binds to P. falciparum CyRPA protein; (B) a VH and a VL comprising a HCDR1, a HCDR2, and a HCDR3, and a LCDR1, a LCDR2, and a LCDR3 of the VH and VL set forth as:

[0362] f) SEQ ID NOs: 41 and 42, respectively (MAD11-1129);

[0363] g) SEQ ID NOs: 49 and 50, respectively (MAD8-2);

[0364] h) SEQ ID NOs: 57 and 58, respectively (MAD8-66);

[0365] i) SEQ ID NOs: 65 and 66, respectively (MAD8-72);

[0366] j) SEQ ID NOs: 73 and 74, respectively (MAD8-739); or

[0367] k) SEQ ID NOs: 301 and 302, respectively (MAD11-1043); and

[0368] wherein tire monoclonal antibody specifically binds to P. falciparum RIPR protein; or (C) a VH and VL comprising a HCDR1, a HCDR2, and a HCDR3, and a LCDR1, a LCDR2, and a LCDR3 of the VHand VL of

[0369] l) any one of the P. falciparum CyRPA or RIPR-specific antibodies described in Example 2, wherein the monoclonal antibody specifically binds to P. falciparum CyRPA protein or RIPR protein, respectively.

[0370] Aspect 2. The monoclonal antibody of Aspect 1, wherein the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2, and the LCDR3 are according to the Kabat, Chothia or IMGT system.

[0371] Aspect 3. The monoclonal antibody of Aspect 1, wherein the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2, and the LCDR3 are set forth as:

[0372] a) SEQ ID NOs: 2, 3, 4, 5, 6, 7 (KVS), 8, respectively (MAD8-265);

[0373] b) SEQ ID NOs: 11, 12, 13, 6, 7 (KVS), 16, respectively (MAD8-318);

[0374] c) SEQ ID NOs: 19, 20, 21, 22, 7 (KVS), 24, respectively (MAD8-498);4239-113564-02

[0375] d) SEQ ID NOs: 27, 28, 29, 22, 31 (KIS), 24, respectively (MAD8-506);

[0376] e) SEQ ID NOs: 35, 36, 37, 38, 39 (TAS), 40, respectively (MAD11-0897);

[0377] f) SEQ ID NOs: 43, 44, 45, 46, 47 (YDK), 48, respectively (MAD11-1129);

[0378] g) SEQ ID NOs: 51, 52, 53, 54, 55 (KAS), 56, respectively (MAD8-2);

[0379] h) SEQ ID NOs: 59, 60, 61, 62, 63 (WAS), 64, respectively (MAD8-66);

[0380] i) SEQ ID NOs: 67, 68, 69, 70, 71 (DVS), 72, respectively (MAD8-72);

[0381] j) SEQ ID NOs: 67, 68, 69, 70, 71 (DVS), 72, respectively (MAD8-72); or

[0382] k) SEQ ID NOs: 315, 316, 317, 318, 319 (KDS), 320, respectively (MAD11-1043).

[0383] Aspect 4. The antibody of any one of the prior Aspects, 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 tire framework regions of the VH and the VL are at least 90% identical to those of: a) SEQ ID NOs: 1 and 2, respectively (MAD8-265);

[0384] b) SEQ ID NOs: 9 and 10, respectively (MAD8-318);

[0385] c) SEQ ID NOs: 17 and 18, respectively (MAD8-498);

[0386] d) SEQ ID NOs: 25 and 26, respectively (MAD8-506);

[0387] e) SEQ ID NOs: 33 and 34, respectively (MAD11-0897);

[0388] f) SEQ ID NOs: 41 and 42, respectively (MAD11-1129);

[0389] g) SEQ ID NOs: 49 and 50, respectively (MAD8-2);

[0390] h) SEQ ID NOs: 57 and 58, respectively (MAD8-66);

[0391] i) SEQ ID NOs: 65 and 66, respectively (MAD8-72);

[0392] j) SEQ ID NOs: 73 and 74, respectively (MAD8-739);

[0393] k) SEQ ID NOs: 301 and 302, respectively (MAD11-1043); or

[0394] l) the VH and VL of any one of the antibodies described in Example 2.

[0395] Aspect 5. The antibody of any one of the prior Aspects, wherein the VH and the VLcomprise amino acid sequences set forth as:

[0396] a) SEQ ID NOs: 1 and 2, respectively (MAD8-265);

[0397] b) SEQ ID NOs: 9 and 10, respectively (MAD8-318);

[0398] c) SEQ ID NOs: 17 and 18, respectively (MAD8-498);

[0399] d) SEQ ID NOs: 25 and 26, respectively (MAD8-506);

[0400] e) SEQ ID NOs: 33 and 34, respectively (MAD11-0897);

[0401] f) SEQ ID NOs: 41 and 42, respectively (MAD11-1129);

[0402] g) SEQ ID NOs: 49 and 50, respectively (MAD8-2);

[0403] h) SEQ ID NOs: 57 and 58, respectively (MAD8-66);

[0404] i) SEQ ID NOs: 65 and 66, respectively (MAD8-72);

[0405] j) SEQ ID NOs: 73 and 74, respectively (MAD8-739);

[0406] k) SEQ ID NOs: 301 and 302, respectively (MAD11-1043); or4239-113564-02

[0407] 1) the VH and VL of any one of the antibodies described in Example 2.

[0408] Aspect 6. The antibody of any one of the prior Aspects, wherein the antibody comprises a human constant domain.

[0409] Aspect 7. The antibody of any one of the prior Aspects, wherein the antibody is a human antibody.

[0410] Aspect 8. The antibody of any one of the prior Aspects, wherein the antibody is an IgG.

[0411] Aspect 9. The antibody of any one of tire prior Aspects, comprising a recombinant constant domain comprising a modification that increases the half-life of the antibody.

[0412] Aspect 10. The antibody of Aspect 9, wherein the modification increases binding to the neonatal Fc receptor.

[0413] Aspect 11. The isolated monoclonal antibody of Aspect 10, wherein tire recombinant constant domain is an IgGl constant domain comprising M428L and N434S mutations.

[0414] Aspect 12. An antigen binding fragment of tire antibody of any one of the prior Aspects, wherein tire antigen binding fragment comprises the VHand the VL of the antibody, specifically binds to P. falciparum CyRPA protein or RIPR protein.

[0415] Aspect 13. The antigen binding fragment of Aspect 12, wherein the antigen binding fragment is a Fv, Fab, F(ab')2, scFV or a scFV2fragment.

[0416] Aspect 14. The antibody or antigen binding fragment of any one of the prior Aspects, conjugated to an effector molecule or a detectable marker.

[0417] Aspect 15. The monoclonal antibody or antigen binding fragment of any one of the prior Aspects, wherein the monoclonal antibody neutralizes P. falciparum.

[0418] Aspect 16. The antibody or antigen binding fragment of any one of the prior Aspects, wherein the antibody or antigen binding fragment inhibits P. falciparum merozoite entry into erythrocytes of the subject.

[0419] Aspect 17. A bispecific antibody comprising tire antibody or antigen binding fragment of any one of the prior Aspects.4239-113564-02

[0420] Aspect 18. An isolated nucleic acid molecule encoding the antibody or antigen binding fragment of any one of the prior Aspects.

[0421] Aspect 19. The isolated nucleic acid molecule of Aspect 18, wherein the nucleic acid molecule is RNA.

[0422] Aspect 20. The nucleic acid molecule of Aspect 18 or Aspect 19, operably linked to a promoter.

[0423] Aspect 21. A vector comprising the nucleic acid molecule of any of Aspects 18-20.

[0424] Aspect 22. A host cell comprising tire nucleic acid molecule or vector of any one of Aspects 18-21.

[0425] Aspect 23. A composition for use in inhibiting P. falciparum infection, comprising an effective amount of dre antibody, antigen binding fragment, nucleic acid molecule, or vector, of any one of the prior Aspects, and a pharmaceutically acceptable carrier.

[0426] Aspect 24. The composition of Aspect 23, further comprising a CIS43 antibody, a L9 antibody, or a 317 antibody.

[0427] Aspect 25. A method of producing an antibody or antigen binding fragment that specifically binds to P. falciparum CyRPA protein or RIPR protein, comprising:

[0428] expressing one or more nucleic acid molecules encoding the antibody or antigen binding fragment of any one of Aspects 1-17 in a host cell; and

[0429] purifying the antibody or antigen binding fragment.

[0430] Aspect 26. A method of detecting the presence of P. falciparum in a biological sample from a human subject, comprising:

[0431] contacting the biological sample with an effective amount of the antibody or antigen binding fragment of any one of Aspects 1-17 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.

[0432] Aspect 27. The method of Aspect 26, wherein detecting the detecting the presence of the immune complex in tire biological sample indicates that tire subject has a P. falciparum infection.4239-113564-02

[0433] Aspect 28. A method of inhibiting a P. falciparum infection in a subject, comprising administering an effective amount of the antibody, antigen binding fragment, nucleic acid molecule, vector, or composition of any one of Aspects 1-21 or 23-24 to the subject, wherein the subject has or is at risk of a P. falciparum infection.

[0434] Aspect 29. The method of Aspect 28, wherein the subject is at risk of a P. falciparum infection.

[0435] Aspect 30. The method of Aspect 28 or Aspect 29, wherein the method inhibits P. falciparum merozoite entry into erythrocytes in the bloodstream of the subject.

[0436] Aspect 31. Use of the antibody, antigen binding fragment, nucleic acid molecule, vector, or pharmaceutical composition of any one of Aspects 1-21 or 23-24, to inhibit P. falciparum infection in a subject or to detect the presence of a P. falciparum in a biological sample.

[0437] III. EXAMPLES

[0438] The following examples are provided to illustrate particular features of certain aspects, but the scope of the claims should not be limited to those features exemplified.

[0439] Example 1

[0440] Anti-Malarial Antibodies

[0441] This example illustrates the isolation and assessment of antibodies that specifically bind to PfCyRPA or PfRIPR.

[0442] Results

[0443] Out of a cohort of individuals living in a malaria-endemic region in Kalifabougou, Mali, 126 monoclonal antibodies (mAbs) were isolated from individuals with polyclonal IgG specific to the bloodstage malaria antigens CyRPA and RIPR. The sequences of the antibodies are provided in Example 2. Isolation was carried out utilizing sequential 384-well oligoclonal B cell culture and optofluidic screening, substantially as described in Dacon et al., 2022. CyRPA and RIPR mAbs exhibited similar levels of VH mutation (FIG. 1 A). We also compared binding of the mAb panel by titration against antigen-coated beads (FIG. IB). Functional assessment was achieved using the growth inhibition assay (GIA), which measures activity against blood-stage P. falciparum in vitro. Five CyRPA mAbs (MAD8-265, MAD8-318, MAD8-498, MAD8-506, MAD11-0897) and two RIPR mAb (MAD11-1043, MAD11- 1129) exceeded 50% growth inhibition at 1 mg / rnL, a standard threshold for this assay (FIG. 2). The three most potent anti-CyRPA mAbs were tested at different concentrations in the GIA for the ability to inhibit growth of blood-stage Plasmodium falciparum. MAD08-498 was the most potent out of tire three mAbs (FIG. 3).4239-113564-02

[0444] Methods for production of antibodies

[0445] Step 1: Memory B cell isolation

[0446] Clinical specimens were derived from 1,187 subjects in the Malian village of Kalifabougou as previously described (Tan et al., 2021; Tran et al., 2013). PBMCs were cryopreserved and later thawed for sorting of Memory B cells 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 FACS ARIA™ IIIu and gated on live singlet CD14-CD3-CD56-CD19+CD38+CD27+ IgM-IgD-IgA- (IgG+ memory B cells).

[0447] Step 2: Memory B cell screening

[0448] MBCs were plated into 384- well plates containing 10,000 cells per well and co-cultured with irradiated 3T3-CD40L feeder cells in 110 media (Iscove’s modified Dulbecco’s Medium, 10% FBS, 1:1000 MycoZap; Thermo Fisher and Lonza) supplemented with 100 U / ml interleukin (IL)-2 (Roche) and 50 ng / ml IL-21 (Thermo Fisher Scientific). After culturing at 37°C for 9 days, supernatants were harvested and incubated for 30 min at 4°C with streptavidin beads (Spherotech) coated with biotinylated CyRPA (Wright lab, University of York) and RIPR (Higgins lab, University of Oxford). Unwashed beads were then incubated with 1 pg / mL goat anti-human IgG-AF647 (Jackson Immunoresearch) for 30 min at 4°C and read with the iQue Screener Plus high-throughput flow cytometer; data were analyzed on the Forecyt program (Intellicyt). Cells from wells screened as positive were collected on Day 10, washed in MACS buffer (0.5% w / v BSA and 2mM EDTA in PBS), and loaded onto an OptoSelect Ilk chip. Single B cells were sorted individually into nanoliter-volume pens by action of OEP light cages.

[0449] Channels were then flooded with antigen-coated streptavidin beads (Spherotech, SVP-60-5) suspended in a cocktail of 2.5 pg / mL goat anti-human IgG-Alexa Fluor 647 (Jackson Immunoresearch 109-606-170). Over a 40 minute time course, cells producing antibodies specific to these antigens were detectable by the appearance of fluorescent ‘blooms’. These cells were then exported, lysed, and cell contents frozen at -80 °C.

[0450] Step 3: mAb expression and assessment

[0451] Antibody heavy and light chains from positive cells were PCR-amplified and sequenced as previously described. VH and VK / 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 was determined by titration4239-113564-02

[0452] against antigen-coated beads. AUC values were calculated using GraphPad Prism and normalized using control mAbs with known affinity. Growth inhibition assays were performed substantially as previously described (Malkin et al., 2005). Briefly, Briefly, anti- P. falciparum CyRPA or RIPR antibody (IgG 1 ) at 1-2.5 mg / mL (or as otherwise indicated) 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. 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 l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride and 100 mM N-hydroxysuccinimide (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 tire 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).

[0453] REFERENCES

[0454] Dacon, C., Tucker, C., Peng, L., Lee, C.-C. D., Lin, T.-H., Yuan, M., Cong, Y., Wang, L., Purser, L., Williams, J. K., et al. (2022). Broadly neutralizing antibodies target the coronavirus fusion peptide. Science 377, 728-735.

[0455] Malkin, E. M., Diemert, D. J., McArthur, J. H., Perreault, J. R., Miles, A. P., Giersing, B. K., Mullen, G. E., Orcutt, A., Muratova, O., Awkal, M., et al. (2005). Phase 1 clinical trial of apical membrane antigen 1: an asexual blood-stage vaccine for Plasmodium falciparum malaria. Infect Immun 73, 3677-3685.

[0456] Tan, J., Cho, H., Pholcharee, T., Pereira, L. S., Doumbo, S., Doumtabe, D., Flynn, B. J., Schon, A., Kanatani, S., Aylor, S. O., et al. (2021). Functional human IgA targets a conserved site on malaria sporozoites. Sci Transl Med 13, eabg2344.

[0457] Tran, T. M., Li, S., Doumbo, S., Doumtabe, D., Huang, C.-Y., Dia, S., Bathily, A., Sangala, J., Kone, Y., Traore, A., et al. (2013). An intensive longitudinal cohort study of Malian children and adults reveals no evidence of acquired immunity to Plasmodium falciparum infection. Clin Infect Dis 57, 417.

[0458] Example 2

[0459] Antibody Sequences

[0460] The heavy and light chain variable regions of P.falciparum CyRPA and RIPR specific antibodies isolated as described in Example 1 are listed below. In some instances, tire CDRs of these antibodies (according to IMGT numbering system) are underlined and / or listed.4239-113564-02

[0461] P. falciparum CyRPA specific antibodies

[0462] SEQ ID NO MAD8-265

[0463] 1 MAD8-265 VH

[0464] EVQLVESGGGLVQPGGSLRLSCAASGFTFRSYSMNWVRQAPGKGLEWVSYIDSSSGTKYYADSVKGRFAVSRDNSKNSLYLQMNSLRDDDTAMYYCARGGWCGSATCYMGVFDFWGQGTMLAVSS

[0465] 2 MAD8-265 VL DWMTQSPRALPVTLGQPASISCKSSQSLVHSDGNTYLNWFQQRPGQSPRRLIYKVSYRDSGVPDR FSGSGSDTDFTLRISRVEADDVGVYYCMQGTHWPPITFGQGTKLEIK

[0466] 3 HCDR1 GFTFRSYS

[0467] 4 HCDR2 IDSSSGTK

[0468] 5 HCDR3 ARGGWCGSATCYMGVFDF

[0469] 6 LCDR1 QSLVHSDGNTY

[0470] 7 LCDR2 KVS

[0471] 8 LCDR3 MQGTHWPPIT

[0472] MAD8-318

[0473] 9 MAD8-318 VH EVQLVESGGGLVKPGGSLRLSCSASGFTFSSYSMNWVRQAPGKGLEWVSYISSSSDTKYYADSVKG RFAISRDNSKNSLYLQLNSLTDEDTAAYYCSRGGWCGSTTCYMSVFDFWGQGTMVAVSS

[0474] 10 MAD8-318 VL DWMTQSPRSLPVTLGQPASISCRSSQSLVHSDGNTYLNWFQQRPGQSPRRLIYKVSYRDSGVPDR FSGSGSDTDFTLKISRVEAEDVGVYYCMQGTHWPPNTFGQGTKLEIK

[0475] 11 HCDR1 GFTFSSYS

[0476] 12 HCDR2 ISSSSDTK

[0477] 13 HCDR3 SRGGWCGSTTCYMSVFDF

[0478] 6 LCDR1 QSLVHSDGNTY

[0479] 7 LCDR2 KVS

[0480] 16 LCDR3 MQGTHWPPNT

[0481] MAD8-498

[0482] 17 MAD8-498 VH

[0483] EVQLVE S GGGLVQP GGS LRL SCAAS GFKFRNYWMSWVRQAPGKGLEWVAT IKHDGAEKYYVD S VKG RFTISRDNAKNSLYVHMNSLRAEDTAVYFCARDFGSGSYKNPIFDYWGQGTLVTVSS

[0484] 18 MAD8-498 VL DWMTQSPLSLPVTLGQPASISCRSSQSLLSSDGNTYLNWFHQRPGQSPRRLIYKVSNRDSGVPDR FSGSGSGTDFTLKISRVEAEDVGVYYCMQGTHWPGTFGQGTKVEIK

[0485] 19 HCDR1 GFKFRNYW

[0486] 20 HCDR2 IKHDGAEK

[0487] 21 HCDR3 ARDFGSGSYKNPIFDY

[0488] 22 LCDR1 QSLLSSDGNTY

[0489] 7 LCDR2 KVS

[0490] 24 LCDR3 MQGTHWPGT4239-113564-02

[0491] MAD8-506

[0492] 25 MAD8-506 VH EVQLVESGGGLVQPGGSLRLSCEASGFKFRNHWMSWVRQAPGEGLGWVATIKQDGSDIYYADSVKG RFTISRDNAKNSLYLQMNSLRAEDTAAYYCVRDFGSGSYKNPIFDYWGQGTLVTVSS

[0493] 26 MAD8-506 VL DWMTQSPLSLPVTLGQPASISCRSSQSLLSSDGNTYLNWFQQRPGQSPRRLIYKISNRDSGVPDR FSGSGSGTDFTLNISRVEAEDVGVYYCMQGTHWPGTFGQGTKVEIK

[0494] 27 HCDR1 GFKFRNHW

[0495] 28 HCDR2 IKQDGSDI

[0496] 29 HCDR3 VRDFGSGSYKNP IFDY

[0497] 22 LCDR1 QSLLSSDGNTY

[0498] 31 LCDR2 KIS

[0499] 24 LCDR3 MQGTHWPGT

[0500] MAD11— 0897

[0501] 33 MAD11- 0897 VH QLQLQESGPGLVKPSETLSLSCNVSGDFINNSSYYWGWIRQPPGKGLEWIASIYSGSSRYYNPSLK SRITISVDSSKGLLSLKVTSVTAADTAVYYCVGEPRHLAAAGRNWFDPWGQGTLVTVSS

[0502] 34 MAD11- 0897 VL DIQMTQSPSSLSASVGDRVTITCRASRSISSYLNWYQQRPGKAPKVLIYTASSLQNGVPSRFSGGG SGTDFTLTISGLQPEDFATYYCQQSYSTPPTFGGGTRVEIK

[0503] 35 HCDR1 GDFINNSSYY

[0504] 36 HCDR2 IYSGSSR

[0505] 37 HCDR3 VGEPRHLAAAGRNWFDP

[0506] 38 LCDR1 RSISSY

[0507] 39 LCDR2 TAS

[0508] 40 LCDR3 QQSYSTPPT

[0509] P. falciparum RIPR Specific antibodies

[0510] MAD11— 1129

[0511] 41 MAD11- 1129 VH QLQLQGSGPGLVKPSETLSLTCTVSDGSINNTDYYWAWIRQPPGKGLQWIGSVYYSGTTYYNPSLK SRVTLSVDTSKNNYSLKLSSVTAADTAVYYCARHSLLYYDSPRPYYFDYWAQGTLVTVSS

[0512] 42 MAD11- 1129 VL SYVLTQPPSVSVAPGKTARITCGGLNIGSKSVHWYQQKPGQAPILVIYYDKDRPSGIPERFSGSNS GNPATLTISRVEAGDEADYYCQVWDISGDQSAWFGGGTKLTVL

[0513] 43 HCDR1 DGSINNTDYY

[0514] 44 HCDR2 VYYSGTT

[0515] 45 HCDR3 ARHSLLYYDSPRPYYFDY

[0516] 46 LCDR1 NIGSKS

[0517] 47 LCDR2 YDK

[0518] 48 LCDR3 QVWDISGDQSAW4239-113564-02

[0519] MAD8-2

[0520] 49 MAD8-2 VH EVQLVEFGGGLVQPGGSLRLSCEGSGFIFSQYWMSWIRQAPGKGLEWVGNIKQDGTEKNYVDSVKG RFTISRDNTNNFLYLQMDSLRAEDTGVYFCARNTFYFDSSGYPLGQGALVAVSS

[0521] 50 MAD8-2 VL AIQMTQSPSTLSASVGDSVTISCRASQSISSWLAWYQQKPGKAPNLLIYKASILESGVPSRFSGSG SGTEFTLTISSLQPDDFATYYCQKYDSYPYSFGPGTKLDIK

[0522] 51 HCDR1 GFIFSQYW

[0523] 52 HCDR2 IKQDGTEK

[0524] 53 HCDR3 ARNTFYFDSSGYP

[0525] 54 LCDR1 QSISSW

[0526] 55 LCDR2 KAS

[0527] 56 LCDR3 QKYDSYPYS

[0528] MAD8-66

[0529] 57 MAD8-66 VH QVQLVQSGSEVKKPGASVKISCKASGYDFNRYFIHWLRQAPGQGLEWVGLIKPNGGNTAYAQKFRD RVTMTKDISTSSVYMELTSLRSDDTAVYFCARVHSVTDAFAFWGQGTLVSISP

[0530] 5

[0531]

[0532] 8 MAD8-66 VL DWMTQSPDSVAVSLGERATINCKSSQNILFSANNKNYLAWYQQKPGQPPKLLIYWASTRESGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQYSSAPWTFGQGTKVEIK

[0533] 59 HCDR1 GYDFNRYF

[0534] 60 HCDR2 IKPNGGNT

[0535] 61 HCDR3 ARVHSVTDAFAF

[0536] 62 LCDR1 QNILFSANNKNY

[0537] 63 LCDR2 WAS

[0538] 64 LCDR3 QQYSSAPWT

[0539] MAD8-72

[0540] 65 MAD8-72 VH QVQLVESGGGWQPGRSLRLSCAASGFTFSSYAMHWVRQAPGKGLEWVAVISYDGNDKYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRPYHAILTGYYG FDYWGQGTLVTVSS

[0541] 66 MAD8-72 VL QSALTQPASVSGSPGQSITISCTGTSSDVGAYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSG SKSGNTASLTISGLQAEDEADYYCSSYTSSSTLVFGGGTKLTVL

[0542] 67 HCDR1 GFTFSSYA

[0543] 68 HCDR2 ISYDGNDK

[0544] 69 HCDR3 ARRPYHAILTGYYGWFDY

[0545] 70 LCDR1 SSDVGAYNY

[0546] 71 LCDR2 DVS

[0547] 72 LCDR3 SSYTSSSTLV4239-113564-02

[0548] MAD8-739

[0549] 73 MAD8-739 VH QVKLQESGPGLLKPSGTLSLTCAVSGASINSDNWWTWVRQSPGKGLEWIGDIYHTGKTNYQSSLKS RVTISLDKSKNNFSMKMTSVTAADTAVYYCARDRAIPVAGTVFDSWGQGLLVTVSS

[0550] 74 MAD8-739 VL QSVLTQPPSVSGAPGQRVTISCTGSTSNIGGGYDVHWYQQLPGTAPKLLIFGNNKRPSGVPDRFSG SKSGTSASLAITGLQDEDEADYYCQSYDDSLSGSLFGGGTKLTVL

[0551] 75 HCDR1 GASINSDNW

[0552] 76 HCDR2 IYHTGKT

[0553] 77 HCDR3 ARDRAIPVAGTVFDS

[0554] 78 LCDR1 TSNIGGGYD

[0555] 79 LCDR2 GNN

[0556] 80 LCDR3 QSYDDSLSGSL

[0557] MAD11— 1043

[0558] 301 MAD11— 1043 VH EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQG QVTISADKSISTAYLQWSSLKASDTAMYYCARHNYGSGSYDYWGQGTLVTVSS

[0559] 302 MAD11— 1043 VL SYELTQPPSVSVSLGQMARITCSGEALPKKYAYWYQQKPGQAPVLVIYKDSERPSGIPERFSGSSS GTIVTLTISGVQAEDEADYYCLSADSSGTYQVFGGGTKLTVL

[0560] 315 HCDR1 GYSFTSYW

[0561] 316 HCDR2 IYPGDSDT

[0562] 317 HCDR3 ARHNYGSGSYDY

[0563] 318 LCDR1 ALPKKY

[0564] 319 LCDR2 KDS

[0565] 320 LCDR3 LSADSSGTY

[0566] Additional P. falciparum CyRPA specific antibodies

[0567] SEQ ID NO MAD8-252

[0568] 81 MAD8-252 VH QVHLVESGGGWQPGGSLRLSCAASGFAFNSYGMHWVRQAPGKGLDWVAFVRYDGSNKYYADSVRG RFTISRDNSKNTLYLQMNSLRAEDTAMYYCAKARGMTMVHGVPGDSWGQGTLVTVSS

[0569] 82 MAD8-252 VL DIVMTQSPDSLAVSLGERATINCKSSQSVFYRSTNKNYLAWYQQKPGQPPKLLIYWASTRESGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYNTPYNFGQGTQLEIK MAD8-242

[0570] 83 MAD8-242 VH EVQLVDSGGGVIQPGGSLRLSCAASGFDVSTNHMSWVRQAPGKGLQWVSIFYSGGGTYYADSVKGR FTISRDSSNNILYLQMNSLRAEDTGLYYCARWVGAYGARRLDHWGQGTLVTVSS

[0571] 84 MAD8-242 VL QSVLTQPPSVSGAPGQKVTISCTGSSTNIGAGYGVNWYQQVPGTAPKLLIYSSTNRPSGVPHRFSG SRSGTSASLAITGLRADDEADYYCQSYDDSLSVSLFGGGTKLTVL MAD8-253

[0572] 85 MAD8-253 VH EVQLVQSGAEVKKPGESLKISCKGSGYSFSKYWIGWVRQMPGKGLEWMGIIFPGDSDTRYSPSFQG QVTISADKSISTAYLQWSSLKASDTAMYYCASSYATNAFDIWGQGTMVTVSS

[0573] 86 MAD8-253 VL SYVLTQPPSVSVAPGKTARITCGGNNIGSKSVHWYQQKPGQAPVLWYDDTDRPSGIPERFSGSNS GNTATLSISRVEAGDEADYYCQVWESSSDPYVFGTGTKVTVL4239-113564-02

[0574] MAD8-149

[0575] 87 MAD8-149 VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSSSWMTWVRQAPGKGLEWVANINEDGSDKYYVDSVKG RFTISRDNAKNSLSLQMNSLRAEDTAVYYCARDLKYYYGSGTAPSPGTLVTVFS

[0576] 88 MAD8-149 VL EWMTQSPATLSVSPGERVTLSCRASQSVSRFLAWYQQTRGQAPRLLIYDASTRATGIPDRFSGSG SGTEFTLTISSLQSEDVADYYCLQYNKWPKTFGQGTKVESK MAD8-691

[0577] 89 MAD8-691 VH QVQLVESGGGEVQPGRSLRLSCAASGFTFSNYGMHWVRQAPGKGLEWVAVIWYDGRNKYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTALYYCAISEGHWGQGTLVTVSS

[0578] 90 MAD8-691 VL SYELTQPPSVSVSPGQTARITCSGDALPKQYAYWYQQKPGQAPVLVIYKDSERPSGIPERFSGSSS GTTATLTISGVQAEDEADYYCQSADSSGSWVFGGGTKLTVL MAD8-656

[0579] 91 MAD8-656 VH EVQLVQSGAEVKKPGESLKISCKGSGYSFSKYWIGWVRQMPGKGLEWMGVIFPGDSDTRYSPSFQG QVRISADKSISTAYLQWSSLKASDTAMYYCASSYATNAFDIWGQGTMVTVSS

[0580] 92 MAD8-656 VL SYVLTQPPSVSVAPGKTARVTCGGNNIGSKSVHWYQQKPGQAPVLWYDDTDRPSGIPERFSGSNS GNTATLTISRVEAGDEADYYCQVWESSSDPYVFGTGTKVTVL MAD8-513

[0581] 93 MAD8-513 VH QVHLVQSGGGWQPGESLRLSCVASGFTFSHYGMHWVRQAPGKGLEWVAFIRHDGSNNYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDAAVYSCAKDRVEYYGTGWWGEGHFFDHWGQGALVTVSS

[0582] 94 MAD8-513 VL EIVMTQSPATLSVSLGERATLSCRASQSVSGNVAWYQQKPGQAPRLLIHGASTRAPGIPARFSGSG SETEFTLTISGLQSEDFALYYCQQYNNWPPWTFGQGTKVEIK MAD8-584

[0583] 95 MAD8-584 VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSRHWMHWVRQAPGKGLVWVSRINRDGSSTNYADSVKG RFTISRDNAGNTLYLQLNSLRAEDTAVYYCARDGVGGMPTDYWGQGTLVTVSS

[0584] 96 MAD8-584 VL DIQMTQSPSSLSASVGDRVTITCRASQVISNSLAWYQQKPGKAPNLLLYATSRLSSGVPSRFSGRG SGTDYNLTISSLQPEDCASYYCQQYHSAPLTFGGGTKVEIK MAD8-235

[0585] 97 MAD8-235 VH EVQLVESGGGLVQPGGSLKLSCAASGFTFSDSAMHWVRQASGKGLEWVGRIRSKVNNYATAFPASV RGRFTISRDDSKNTTYLQMNSLKTEDTAIYYCTRQGGHITGTDGFQHWGQGTLVTVSS

[0586] 98 MAD8-235 VL

[0587] SYELTQPPSVSVSPGQTARITCSGDALPKQYAYWYQQKPGQAPLLI IYKDTERPSEIPERFSGSSS ETTVTLTISGVHAEDEADYYCQSADSSATYWVFGGGTKLTVL MAD8-280

[0588] 99 MAD8-280 VH EVQLVESGGGLVQPGGSLRLSCTASGFSFSGSAMHWVRQASGKGLEWVGQIRSKRNSYTTTYAASV KGRFNISRDDSKNTAYLQMNSLKTDDTAVYYCTRRALPSAFDIWGQGTMVAVSS

[0589] 100 MAD 8- 280 VL DIQMTQSPSSLSASVGDRVTITCRASQGISNSLAWYQQQPGKAPKILLYATSRLESGVPSRFSGSG SGTDYTLTISSLQPEDFATYYCHQYHSTPQTFGQGTKLEIK4239-113564-02

[0590] MAD8-73

[0591] 101 MAD8-73 VH QLQLQESGPGLVKPSETLSLTCSVSNGSIIRSQSYWGWIRQPPGQGLEWIASLYYTGSTYKNASFK KRVATSVDTSKNQFSLTLSAVTAADTAVYYCAVSLPGVSRSAYYFDYWGLGTLVTVSS

[0592] 102 MAD8-73 VL ETVLTQSPATLSLSPGERATLSCRASQNIGSYLAWYQQKPGQAPRLLIYDASNRATGIPGRFSGSG SGTDFTLTISSLEPEDFAVYFCQQRNNWRVTFGQGTRLEIT MAD8-59

[0593] 103 MAD8-59 VH QVHLEESGPGLVKPSETLSLTCTVSNFSISTGDYWGWVRQPPGKELQWIACVFHSGSTYRNPSLKN RVTMSVDTSKNRFSLNLRSVTAADTAIYYCAKMNLGHPFDSWGQGTLVTVSS

[0594] 104 MAD8-59 VL DIQMTQAPSSLSASIGDRVTITCRASQGISTYLAWYQQKPGKVPKLLISAASTLQSGVPSRFSGSG SGTDFTLTISSLQAEDVGVYYCQKYSNALWTFGQGTKVEIK MAD8-316

[0595] 105 MAD8-316 VH EVQLVESGGGLVQPGGSLRVSCAGSGFIFSSYWMTWVRQTPGKGLEWVANIKQDGTEQYYVDSVKG RFTISRDNAKKSLYLQMNTLRAEDTAVYYCARGGRTNWGSARYLDYWGQGTLVSVSS

[0596] 106 MAD8-316 VL EIEMTQSPATLSVSPGERATLSCRASQSVNSSLAWYQQKPGQAPRLLIYGASTRATDIPARFSGSG SGTEFTLTISSLQSEDFALYYCQHYNNWLGTFGQGTKVEIK MAD8-196

[0597] 107 MAD8-196 VH QLQLQESGPGHVKPSETLSLTCTVSGDSITTSSVYWGWIRQTPGEGLEWIASVYYTGSTYHRPSFK SRWMSVDTDKNQFSLRLKSVTAADTAVYYCVRQESWAADYWGQGTLVTVSS

[0598] 108 MAD8-196 VL ETVLTQSPGTLSLSPGQRATLSCRASQSVGNHLAWYQQKFGQAPRLLIYDASNRATGTPARFSGSG SGTDFTLTISSLEPEDVAVYYCQQRNNWLWTFGPGTKVEVK MAD8-278

[0599] 109 MAD8-278 VH QVHLEESGPGLVKPSETLSLTCTVSNYSITDGYYWGWIRQPPGKELQWIACAFHSGSTYRNPSLKS RVTMSVDTTKNRFSLNLRSVTAADTAIYFCARMNMGHPFDSWGQGTLVIVSS

[0600] 110 MAD8-278 VL DIQMTQAPSSLSASVGDRVTITCRASQDISKYLAWYQQKPGKVPKLLISAASTLQSGVPSRFSGSG SGTDFTLTISSLQAEDVGVYYCQKYSNALWTFGQGTKVEIK MAD8-159

[0601] 111 MAD8-159 VH EWLLQSGGGLVQPGGSLRLSCAASGFIFRSHAMAWVRQVPGEGLQWVSTISDSGDMTYYADSVKG RFIISRDNSQRTVHLQMDNLRADDTALYFCARDRFRGLTKNNFDFWGQGSQVTVSS

[0602] 112 MAD8-159 VL EIVLTQSPGTLSLSPGERATLSCRASQSLYDSNLAWYQQKPGQAPRLLIYGASSRATGIPDRFTGS GSGTDFTLTITRLEPEDFAVYYCHQYSLSPFFGQGTRLEIK MAD8-575

[0603] 113 MAD8-575 VH QVQLVESGGGWQPGRSLTLACAGSGFIFSSYPMHWVRQAPGKGLEWVSLISDDGSNKHYAESVKG RFTISRDTSKRTVYLQMNSLRAEDTAVYYCARDRIRGSARMSLGIDYWGQGALVTVSS

[0604] 114 MAD 8- 575 VL EIVLTQSPGTLSLSPGERATLSCRASQSVGSRSLAWYQQKPGQAPRLLVYGASSRAAGISDRFSGS GSGTDFTLTI SRLEPEDFAVYYCQQYGTSPLTFGGGTKLEIK4239-113564-02

[0605] MAD8-248

[0606] 115 MAD8-248 VH QLQLQESGPGLVKPSETLSLTCNVSGATISGSNYYWAWIRQPPGKGPEWIGSVYYSGSSYYNPSLK SRVTISVDTSNNQFSLKLNSVTAADTAVYYCARPFGSSAWYFVYWGQGALVTVSS

[0607] 116 MAD8-248 VL ETVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSG SGTDFTLTISSLEPEDFAVYYCQHRNNWRLTFGGGTKVEIK MAD8-334

[0608] 117 MAD8-334 VH QLQLQESGPGQVKPSETLSVTCTVSGDSIISSSIYWGWIRQPPGKGLEWIGSVYYTGSTYHKPSLK SRWMSVDTDKNQFSLRLKSVTAADTAVYYCVRQKSWAADYWGQGTLVIVSS

[0609] 118 MAD8-334 VL ETELTQSPATLSLSPGHRATLSCRASQSVGNHLAWYQQKLGQAPRLLIYDASNRATGVPARFSGSG SGTDFTLTISSLEPEDFAVYYCQQRNNWLWTFGPGTRVEVK MAD8-398

[0610] 119 MAD8-398 VH

[0611] EVKLVESGGDLIQPGGSLRLSCTTSEFTLTSNYYAWVRQAPGERLKWVSFIYVDNTTYYADSVRGR FAISRDTSATTVYLQMNSLRVEDTATYYCSTSRGLWGQGTLVTVSS

[0612] 120 MAD8-398 VL DWMTQSPFILPVTLGQPASISCRSSESLGHQDGNTYLNWFQQRPGQSPRRLIYRVSKRDFGVPER FSGSGSGTDFTLTISRVEAEDIGVYYCMQSSHWPGTFGQGTELEIK MAD8-184

[0613] 121 MAD8-184 VH EVQLVESGGGLVQPGGTLRLSCAASGFTFSNYGLTWVRQAPGKGLEWVSLISGSGRSTSYADSVKG RFTVSRDNSKNTVYLQMNSLRAEDTAVYYCAKDAALGLGWYYFEYWGQGTLVTVSP

[0614] 122 MAD8-184 VL SYVLTQPPSVSVAPGQTARISCGGNNIGTKSVNWYQQRPGQAPVLWYEDSHRPSGIPQRFSGSNS GNTAALTVSRVEAGDEADYYCQVWDTSSDLWFGGGTKLTVL MAD8-598

[0615] 123 MAD8-598 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPGKGLEWIGSIYYSGSTYYNPSLK SRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGASLLRYFDWLWRGGFDYWGQGTLVTVSS

[0616] 124 MAD8-598 VL EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGS GSGTDFTLTI SRLEPEDFAVYYCQQYGSSPLTFGGGTKVEIK MAD8-354

[0617] 125 MAD8-354 VH QVQLVQSGGGWQPGRSLRLSCASSGFIFSSHALHWVRQAPDKGLEWVAGISDDGTKEFYADSVRG RFSLSRDNSKKTVHLQMNSLRPDDTAVYYCARDRYRGFTYGNFDYWGQGALVTVSS

[0618] 126 MAD8-354 VL EIVLTQSPGTLSLSPGERATLSCRASQSVPNNYLAWYQKKPGQAPRLLIYGASSRATGIPDRFSGS GSGPDFTLTI SRLEPEDFAVYYCHQYGNSPPWTFGQGTKVEIK MAD8-257

[0619] 127 MAD8-257 VH QVQLVESGGGWQPGGYLRLSCTASGFIFSSYSMHWVRQAPGKGLEGVAAISFDGKNEEYADWKG RFTISRDNSRKNVYLEMNSLSLDDTAVYYCARDRGRASSNRYFGLDVWGQGITVTVSS

[0620] 128 MAD 8- 257 VL EIVMTQSPGTLSVSPGERATLSCRASQTVASKLAWYQQKPGQAPRLLIYGASTRATDIPDRFSGRG SETEFTLTISSMQSEDFAVYYCQQYNSWPLTFGGGTKVEIK4239-113564-02

[0621] MAD8-507

[0622] 129 MAD8-507 VH QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWSWIRQPPGKGLEWIGYIYYSGSTTYNPSLKSR VTISTDTSKNQISLKLSSVTAADTAMYYCARRPLTGYYDSSGYYSDPAAFDYWGQGTLVTVSS

[0623] 130 MAD8-507 VL DIQMTQSPSSLSASVGDRVAITCRASQTITTYLNWYQQKPGKAPKLLIYGASSLHSGVPSRFSGSG SGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK MAD8-179

[0624] 131 MAD8-179 VH QLQLVQSGAEVKKDGASVKVSCKASGYNIISYGLTWVRQAPGQGLQWVAWITDYRRHTVYTDELSG RVTMTTDPVTNTAYLELRSLRSDDTAIYYCARVHSDHSRYFDLWGPGTLVIVSS

[0625] 132 MAD8-179 VL DIVMTQSPLSLSVTPGEPASISCRPSQSLLQSNGYNFLAWYLQKPGQSPQLLIYLASHRASGVPDR FSGSGSGTEFTLKISRVQAEDVGIYYCMQALQTPLTFGGGTKVEIK MAD5-142

[0626] 133 MAD5-142 VH EVQLLESGGDLEQPGGSLRLSCAASGFIFSSHAMGWVRQAPGKGLEWVSIISDGGETMHYADSVKG RFTISRDNSNKKVYLQMNRLRGDDTAIYYCARDRYRGFVYGNFDYWGQGTPVTVSS

[0627] 134 MAD5-142 VL DWLTQTPGTLSLSPGERATLSCRASQSITNNYLAWYQQKRGQAPRLLIYGASSRATGIPDRFSGS GSGTDFTLTI SRLEPEDFAVYYCQQYGGSPPYTFGQGTKLDMD MAD8-186

[0628] 135 MAD8-186 VH QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGKALEWLALIYWDDDERYSPSLK SRLTVTKDTSKNQWLTMTNMDPVDTATYYCAHSSRYYAGGAYYGPNFDYWGQGTLVSVSS

[0629] 136 MAD8-186 VL ETVLTQSPATLSLSPGTRATLSCRASQSVGNHLAWYQQRPGQAPRLLIYDTSNRAPGIPARFSGSG SGTDFTLTINSLEPEDFAVYYCQQRNNWLWTFGPGTKVEIK MAD8-273

[0630] 137 MAD8-273 VH QVQLVQSGAEVKKPGSSVKVSCQSSGGTFGSYGMNWVRQAPGQGLEWMGGIIPVFGTPNYAQKFQG RITITTDESTKSVFMELSSLRSEDTAMYYCARDRGRFFGVGRAFDNWGQGTPVTVSS

[0631] 138 MAD8-273 VL SSELTQDPAVSVALGQTVRIACQGDSLRSYYPSWYQQRPGQAPVLVIFGKNNRPSGIPDRFSGSTS GNTASLTITGAQAEDEADYYCHSRDSSAYHHVFGTGTKVTVL MAD8-798

[0632] 139 MAD8-798 VH QVQLVQSGAEVKKPGSSVRVSCKASGGTFSSYGISWLRQAPGHGLEWLGGISPLFGTSNYAQKFQD RVTITADESTTTAYMDLISLRSEDTAVYYCAYDSGTNPWFDPWGQGTLVTVSS

[0633] 140 MAD8-798 VL QSVLTQPPSVSGAPGQRVTISCTGSSSNIGADYDVHWYQQLPGTAPKLLIYNNNNRPSGVPDRFSG SQSGTSASLAIAGLQPEDEADYYCQSYDSLSGSGWFGGGTRLTVL MAPI 1-111

[0634] 141 MAD11— 111 VH EVQLVESGGGLVQPGGSLRLSCSASGFIFSSYPIHWVRQAPGKGLEYVSGISDDGSNTFYSDLVKG RISVSRDNSKKTVHLQMTSLRPEDTAVYYCVRDRYRGMVRGNFDYWGQGTQVTVSS

[0635] 142 MAD11— 111 VL QIVLTQSPGTLSLSPGEEATLSCRASQSVSNSYLAWYQQKPGQPPRLLVYGASSRATGVPDRFRGS GSGTDFTLTVSRLEADDFAVYYCQQYGYPPPVTFGGGTRVDMK4239-113564-02

[0636] MAPI 1-121

[0637] 143 MAP11-121 VH QVQLQESGPGLVKPSETLSLICTVSNFSISSDYYWAWIRQPPGKGLEWVASVYRTGSTYKRKSLKS RVTMAVDTSSNSFSLNLSSVTAADTAIYYCARPRVAVSPSPFDFWGQGILVTVSS

[0638] 144 MAP11— 121 VL EWLTQSPATLSLSSGERATLSCRASQNIGTWLAWYQQKPGQSPRLLIYDASNRAAGVPARFSGSG SGTDFTLTIASLEPEDFAVYYCQQRYNWLITFGQGTRLDIK MAPI 1-123

[0639] 145 MAP11-123 VH QVQLQESGPRLVKPSETLSLICSVSNFSITSDYYWAWIRQPPGKGLEWIASVYHSGSTYKTKSLKS RVTMAVDTSSNSFSLNLSSVTAADTAIYYCARPRVAVSPSPFDFWGQGILVTVSS

[0640] 146 MAP11— 123 VL EWLTQSPATLSLSSGERATLSCRASQNIGTWLAWYQQKPGQSPRLLIYDASNRAAGVPARFSGSG SGTDFTLTISSLEPEDFAVYYCQQRYNWLITFGQGTRLDIK MAP11-129

[0641] 141 MAP11-129 VH EVQLVESGGGLVQPGGSLRLSCSASGFIFSSYPIHWVRQAPGKGLEYVSGISDDGSNTFYSDLVKG RISVSRDNSKKTVHLQMTSLRPEDTAVYYCVRDRYRGMVRGNFDYWGQGTQVTVSS

[0642] 148 MAP11— 129 VL QIVLTQSPGTLSLSPGEEATLSCRASQSVSNSYLAWYQQKPGQPPRLLVYGASSRATGVPDRFRGS GSGTDFTLTVSRLEADDFAVYYCQQYGDPPAVTFGGGTRVDMK MAP11-132

[0643] 141 MAP11-132 VH EVQLVESGGGLVQPGGSLRLSCSASGFIFSSYPIHWVRQAPGKGLEYVSGISDDGSNTFYSDLVKG RISVSRDNSKKTVHLQMTSLRPEDTAVYYCVRDRYRGMVRGNFDYWGQGTQVTVSS

[0644] 150 MAP11-132 VL QIVLTQSPGTLSLSPGEEATLSCRASQSVSNSYLAWYQQKPGQPPRLLVYGASSRATGVPDRFRGS GSGTDFTLTVSRLEADDFAVYYCQQYGYPPAVTFGGGTRVDMK MAPI 1-141

[0645] 151 MAP11-141 VH EVLLLESGGGLVQPGGSLRLSCAASGFIFSSYPIHWVRQAPGKGLEYVSGISDDGNSQFYSDSLKG RIFVSRDNSRKTVYLEMRSLRPEDSALYYCVRDRYRGMVRGNFDYWGQGTLVAVSS

[0646] 152 MAP11— 141 VL EIVLTQSPGTLSLSPGEEATLSCGASQTISNSYLAWYQQKPGQPPRLLIYGASSRATGVPDRFRGS GSGTDFTLTVSRLEPEDFAVYYCQQYGDPPAVTFGAGTRVDLK MAPI 1-160

[0647] 141 MAP11-160 VH EVQLVESGGGLVQPGGSLRLSCSASGFIFSSYPIHWVRQAPGKGLEYVSGISDDGSNTFYSDLVKG RISVSRDNSKKTVHLQMTSLRPEDTAVYYCVRDRYRGMVRGNFDYWGQGTQVTVSS

[0648] 154 MAP11- 160 VL SSELTQDPAVSVALGQTVRISCQGDSLRNNYASWYQQTPGQAPVLVIYANNNRPSGIPDRFSGSSS GNTASLTITGAQAGDEADYYCASRDSSGNRYVFGTATKVTVL MAPI 1-166

[0649] 155 MAP11-166 VH QVRLMESGGGWQPGRSLRLSCAASGFIFRTHALHWVRLTPDKGLEWVGGISDDGTKTYYADSIKG RFTLSRDNSAIKVDLRMDSLRIEDTGVYYCARDRYRGFTYGNFDFWGQGVWTVSS

[0650] 156 MAP11-166 VL EIVLTQSPDTLSLSPGERATLSCRASQTIDNNYLAWYQRKPGQAPRLLIYGAATRATGIPDRFSGS GSGPDFTLTI SRLEPEDFAVYYCHQYGNSPPWTFGQGTKVEIK4239-113564-02

[0651] MAPI 1-171

[0652] 141 MAP11— 171 VH EVQLVESGGGLVQPGGSLRLSCSASGFIFSSYPIHWVRQAPGKGLEYVSGISDDGSNTFYSDLVKG RISVSRDNSKKTVHLQMTSLRPEDTAVYYCVRDRYRGMVRGNFDYWGQGTQVTVSS

[0653] 158 MAP11— 171 VL SYVLTQPPSVSVAPGKTARITCGGNNIGSQSVHWYQQKPGQAPVLVIYYNHDRPSGIPERFSGSNS GNTATLTISRVGAGDEADYYCQVCDSNSDHVIFGGGTKLTVL MAPI 1-446

[0654] 159 MAP11-446 VH

[0655] EVQLVE S GGGLVQP GGS LRL SCAAS GFNFGD STI HWVRQASGKGLEWVGRSRRKGNTYATAFAAS V KGRFTISRDDSKNTAYLQMNSLKTEDTAVYYCARLSRLHGDFGYYYYAMDVWGQGTTVTVSS

[0656] 160 MAP11— 446 VL EIVMTQSPATLSLSPGERATLFCRASQSISSTYVSWYQQKPGQPPRLLIYGASTRATGFPARFSGS GSGTDFTLTINSLQPEDFAVYYCQQDFNLLTFGGGTKVEIK MAPI 1-450

[0657] 161 MAP11-450 VH QVQLVESGGGWQPGRSLRLSCAASGFTFSNYGMHWVRQAPGKGLESVAFIWYDGSSKYYADSVKG RFTISRDNSKNTLYLEMNSLRAEDTAVYYCAKDGPDTRGYYDILTGYYGGHWFDPWGQGTLVTVSS

[0658] 162 MAP11— 450 VL DIQMTQSPSSLSASVGDRVTITCRASQSISTYLNWYQQKPGKAPKFLIYAASSLQSGVPSRFSGSG FGTDFTLTISSLQPEDFATYYCQQSFSFLLYHFGRGTKLEIK MAPI 1-457

[0659] 163 MAP11-457 VH EVQLVESGGGLVQPGGSLRLSCSASGFIFSSHPIHWVRQAPGKGLEYVAGISDDGVSTFYSDSVKG RIIVSRDNSKKTVYLQMSSLRAEDTATYYCARDRYRGMVRGNFDYWGQGTLVTVSS

[0660] 164 MAP11-457 VL QTWTQEPSLTVSPGGTVTLTCASSTGAVTSGYYPNWFQQKPGQAPRALIYSTSNKHSWTPARFSG SLLGGKAALTLSGVQPEDEAEYYCLLYYGGSWVFGGGTKLSVL MAPI 1-476

[0661] 165 MAP11-476 VH QVQLQESGPGLVKASETLSLTCSVSGVSISSHYWSWIRQPPGKGLEWIGYLRYSGSTKYNPSLKSR VTILGDKSKNQFSLNVTSVTAADTAVYFCARVSEDSVSAGAYDIWGQGTMVIVSA

[0662] 166 MAP11— 476 VL SYELTQPPSVSVSPGQTARITCSGDALPKKYVYWYQQKSGQAPVLVIYEDSKRPSEIPERFSGSSS GTMATLTINGAQVEDEADYYCYSTDSSNDLWVFGGGTMLTVL MAPI 1-491

[0663] 167 MAP11-491 VH QVQLVESGGGWQPGRSLRLSCAASGFIFGSHALHWVRQAPDKGLEWVAGISDDGSREYYADSVRG RFTLSRDNSRKMVHLQLNNVRPEDTAIYYCARDRYRGFTYGNFDYWGQGALVTVSS

[0664] 168 MAP11- 491 VL EIVLTQSPGTLSLSPGERATLSCTASQSVTNNYLAWYQKKPGQAPRLLIYGASTRATGIPDRFSGS GSGPDFTLTI SRLEPEDFAVYYCHQYGNSPPWTFGQGTKVEMR MAPI 1-547

[0665] 169 MAP11-547 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISTSSYYWGWIRLPPGKGLEWFGSIYYSGSTYYNPSLK SRVTISVDTSKNQFSLKLRSVTAADAAVYYCARVAYFSDSRGYWFDSWGQGTLVTVSS

[0666] 170 MAP11-547 VL EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSG SGTDFTLTISSLEPEDFAVYYCQQRFNWLFTFGPGTKVDIK4239-113564-02

[0667] MAD11-654

[0668] 171 MAD11-654 VH QITLKESGPTLVKPTQTLTLTCTFSGFSLSTAGVSVAWIRQPPGKALEWLALIYWDDDKLYSPSLK SRLTITKDTSKNQWLTMTNMDPVDTATYYCAKHLRYYFDYWGQGTLVTVSS

[0669] 172 MAD11- 654 VL QSALTQPASVSGSPGQSITISCAGTSSDIGNYNYVSWFQQHPGKAPKLIIYDVSYRPSGVSSRFSG SKSGNTASLTISGLQAEDEADYHCSSYRSNNRIFGGGTKLTVL MAPI 1-0202

[0670] 173 MAD11- 0202 VH QVQLVQSGVEVKKPGASVKVSCKASGYTFTSYGMSWVRQAPGQGLEWMGWISAYNGDTNYAQKFQD RVTMTIDTSTSTAYMELRSLRSDDTAVYYCARDGVNWRDRRPFDYWGQGTLVTVSS

[0671] 174 MAD11- 0202 VL DIVMTQSLDSLAVSLGERATINCKSSQSVMSSFTNKNYLAWYQQKPGQPPKLLIYWASTRESGVPD RFSGSGSGTDFTLTISSLQAEDVAIYYCHQYYSTPLTFGGGTKVEIK MAD11— 0886

[0672] 175 MAD11-0886 VH QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIYYSGSTYYNPSLK SRVTISVDTSKNQFSLKVTSVTAADTAVYYCARDRSQDYDNVWGRQSRWFDPWGQGILVTVSS

[0673] 176 MAD11-0886 VL DIQLTQSPSSLSAFVGDRVTITSQASQDISKYLNWYQQKPGKAPKLLIHGASNLETGVPSRFSGSG SGTDFTFTISSLQPEDIATYYCQQYDNLRITFGPGTKVDIK MAD11-0891

[0674] 177 MAD11-0891 VH EVQLVQSGGGLVQPGGSLRLSCSASGFIFSSHPMHWVRQAPGKGLQYVSGISDSGGDTYYADSVKG RFTVSRDNSRKMIFLQMSSLRPEDTAVYFCVRDRYRGLVRGNFDSWGQGTLVTVSS

[0675] 178 MAD11-0891 VL EIVLTQSPGTLSLSPGERATLSCRASQSISNNYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGS GSGTDFTLTISGLEPEDFAVYYCQQYGSPPALAFGGGAKVEIK MAD8-712

[0676] 179 MAD8-712 VH QVQLVQSGAEVKKPGSSVKVSCKASGGTFSGYAFSWVRQAPGQGLEWMGGIMAIFGTANYAQKFQG RVTITADESTSTVYMELSSLRSEDTAVYYCARHDSSGYYFPWYFDLWGRGTLVIVSS

[0677] 180 MAD8-712 VL DIQMTQSPSSLSASVGDRVTISCRASQGISNYLAWYQQKPGKVPKLLIYAASTLQSGVPSRFSGSG SGTHFTLTISSLQPEDVATYYCQEYNSAPLTFGGGTKLEIR MAD11-0924

[0678] 181 MAD11— 0924 VH QVQLQQWGAGLLKPSETLSLNCAVYGGSFSGYYWTWIRQSPGRGLEWIGEINHSGSSNYNPSLKSR VTISVDTSKNQFSLNLSSVTAVDTAVYYCARGPGGLLWFGEFFDPYDQYGMDVWGQGTTVIVSS

[0679] 182 MAD11- 0924 VL DWMTQTPLSLSVTPGQPASISCKSSRSLLHSDGKTYLYWFLQKPGQPPQLLMYEVSNRFSGVPDR FSGSGSGTDFTLKISRVEAEDVAVYYCMQSVQLPYTFGQGTKLEIK MAD11-1080

[0680] 183 MAD11- 1080 VH QVQLQESGPGLVKPSETLSLTCTVSGGSISNYFWSWIRQPPGKGLEWIGYSYYSGATNYNPSLKSR VTMSVDTSKKQLSLKLSSVTAADTAVYYCARTWAGLDNFYYYMDVWGKGTTVTVSS

[0681] 184 MAD11— 1080 VL DIVMTQTPLSSPVTLGQPATISCRSSQSLVQSDGNTYLSWLQQRPGQPPRLLIYKVSNRFSGVPDR FSGSGAGTDFTLKISRVEAEDVGVYYCMQATQFPHAYTFGQGTKLEIK4239-113564-02

[0682] MAD11— 1151

[0683] 185 MAD11— 1151 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTNHAFSWVRQAPGQGLEWMGWISRDSVNTKSSRNFQG RLTMTTDTSTNTTYMDLRSLRSNDTAIYYCARLAAPGTKGGFDFWGQGTLVTVSS

[0684] 186 MAD11— 1151 VL

[0685] SYELTQSPSVSVSPGETARITCSGDALPKQYAYWYKKKPGQAPVLI IYKDTERPSGIPERISGSSS GTTVTLTISGVQAEDEAEYYCQSMDGGGNYAVFGGGTKLTVL MAPI 1-1165

[0686] 187 MAD11- 1165 VH QVTLKESGPVLVKPTETLTLTCTVSGFSLSKARMGVSWIRQPPGKALEWLAYIFSNDEKSFSTSLK SRLTISKDTSKSQWLTMTNMDPVDTATYYCARSTNGANSYFFDYWGQGTLVTVSS

[0687] 188 MAD11- 1165 VL SYELTQPPSVSVSPGQTARITCSGDALPKRYSYWYQQKSGQAPVLVIYEDSKRPSGIPERFSGSSS GTMATLTISGAQVEDEADYYCYSTDSSGDRGVFGGGTRLTVL MAD8-827

[0688] 189 MAD8-827 VH QVQLVQSGPELRKPGASVKVSCKASGFTLTTYFIHWVRQAPGQGLEWMGIINPGGGNTARYAQKFQ GRVTMTRDTSTNTVYLELSSLTSEDTALYYCARDHGYSSGWTFINWDYWGQGTWTVSS

[0689] 190 MAD8-827 VL QAGLTQPPSVSKGLRQTATLTCTGNSSNVGNQGWWLQQYQGHPPKLLSYRNNNRPSGISERFSAS RSGNTASLTITGLQPDDEADYYCSTWDSSLSAQVFGGGTKLTVL MAD8-731

[0690] 191 MAD8-731 VH EVRLVESGGGLVKSGGSLRLSCWSGFTFSDAWMTWVRQAPGKGLEWVGRIKRISDEGSPDYAAPV KGRFTISRDDSMNTMYLQMNNLKIEDSGVYYCTTLSGMNFRVAPPWGQGTLVTVSS

[0691] 192 MAD8-731 VL SFMLTQPHSVSESPGKTVTISCTRNNGSIGSKYVQWYQRRPGSSPTTVIYEDSSRPSGVPDRFSGS IDKSSNSASLTISGVKPEDEADYYCQSYDSTNWVFGGGTKLTVL MAD8-733

[0692] 193 MAD8-733 VH EVYLVESGGVWHPGGSLRLSCAASGFTFADYAMHWVRQAPGKGLKWVSLITWDGSRTYYADSVKG RFTISRDNSENSLYLQMNSLRTEDTALYYCAKAGGSRVGASVFDIWGQGTMVTVSS

[0693] 194 MAD8-733 VL SYELTQPPSVSVSPGQTARITCSGDALSKQYANWYQQKPGQAPVWIYKDSEKPSGIPERFSGSSS GTTVTLTISGVQAEDEADFYCQSTDGSGTQWVFGGGTKLTVL MAD8-761

[0694] 195 MAD8-761 VH QVQLVESGGGWQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGTNKYYTDSVKG RFTISRDNSKSTLYLQMNSLRAEDTAVYYCAKLGTAVSGPYWFDPWGQGTLVTVSS

[0695] 196 MAD8-761 VL NFMLTQPHSVSESPGKSVTISCTRSSGSIASNYVQWYQQRPGSSPTTVIYEDNQRPSGVPDRFSGS IDSSSNSASLTISGLKTEDEADYYCQSYDSTSWLFGGGTKLTVL MAD8-110

[0696] 197 MAD8-110 VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYNMNWVRQAPGKGLEWVSYISSSSSTIYYADSVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGSGYDSFFLDYWGQGTLVTVSS

[0697] 198 MAD 8- 110 VL SYELTQPPSVSVSPGQTASITCSGDKLGDKYACWYQQKPGQSPVLVIYRDDKRPSGIPERFSGSNS GNTATLTISGTLAVDEADYYCQAWDSSTEDWFGGGTKLTVL4239-113564-02

[0698] Additional P. falciparum RIPR Specific antibodies

[0699] SEQ ID NO MAD8-716

[0700] 199 MAD8-716 VH EVQLAQSRAEVRKPGESLKISCKGSGYMFTRQWIGWVRQMPGKGLESMGIIYPGDSETRYSPSFQG HVTISAEKSTTTAYLEWRSLRVSDTAIYFCALLSNQEIVWGQGTLVTVSS

[0701] 200 MAD8-716 VL DIVLTQSPATLSASPGERATLSCRASQNINTKVAWYQQKPGQAPRLLIYGASIRASDTPARFRGSG SGTEFTLTISTLQSEDFAVYHCQQYNSWPSYSFGQGTKLERK MAD8-443

[0702] 201 MAD8-443 VH EVQLVESGGGLVQPGGSLRLSCEGSGFTFSQYWMSWIRQAPGKGLEWVGNIKQDGSEKNYVDSVKG RFTISRDNAKNSLYLQMDSLRAEDTAIYFCARNTFYFDSSGYPLGQGTLVAVSS

[0703] 202 MAD8-443 VL DIQMTQSPSTLSASVGDSVTISCRASQSISSWLAWYQQKPGKAPNLLIYKASILESGVPSRFSGSG SGTEFTLTIRSLQPDDFATYYCQKYDSYPYSFGPGTKLDIK MAD8-758

[0704] 203 MAD8-758 VH QVHLVQSGAEVKRPGSSLRVSCKASGGTFNNFAINWVRQGPGQRLEWMGGIIPIFETSNYAPRFQG RVTITADKSTNTSHIEVINLKLEDTAVYYCVISYGSGSYGSHWGQGTLITVSS

[0705] 204 MAD8-758 VL EIVLTQSPATLSVSPGETVTLSCRASQSITSKLAWYQQKPGQPPRVLIYGASTRATGIPARFSGSG SGTEFTLTISSLQSEDSAVYHCQQYNNWLTWTFGQGTRVELK MAD8-286

[0706] 205 MAD8-286 VH QVQLQESGPGLLKPSGTLSLTCAVSRASISSDNWWTWVRQPPGKGLEWIGDIHHTGKTNYHPSLKS RLTMSLDKSRNFFSMTMTSVTAGDTAIYFCARDRAIPVAGTVFDAWGQGLLVTVSS

[0707] 206 MAD8-286 VL QSVLTQPPSVSGAPGQRVTISCTGSTSNIGGGYDVQWYQQLPGTAPKLLIFGNHKRPSGVPDRFSG SKSGTSASLAITGLQDEDEADYYCQSYDDSLRGSLFGGGTKLAVL MAD8-282

[0708] 207 MAD8-282 VH QVQLQESGPGLLKPSGTLSLTCAVSRASISSDNWWTWVRQPPGKGLQWIGDIHHSGKTNYQPSLKG RVTISLDKSRNLFSMTMTSVTAADTAMYFCTRDRAIPVAGTVFDAWGQGLLVSVSS

[0709] 208 MAD8-282 VL QSVLTQPPSVSGAPGQRITISCTGSTSNIGGGYDVHWYQQLPGTAPKLLIFGNHKRPSGVPDRFSG SKSGTSASLAITGLQDEDEADYYCQSYDDSLRGSLFGGGTKLTVL

[0710] MftD8-289

[0711] 209 MAD8-289 VH QVQLQESGPGLLKPSGTLSLTCAVSRASISSDNWWTWVRQPPGKGLEWIGDIHHSGKSNYHPSLKS RLSMSLDKSRNFFSMTMTSVTAADTAIYFCARDRAIPVAGTVFDGWGQGLLVTVSS

[0712] 210 MAD8-289 VL QSVLTQPPSVSGAPGQRVTISCTGSTSNIGGGYDVQWYQQLPGTAPKLLIFGNHKRPSGVPDRFSG SKSGTSASLAITGLQDEDEADYYCQSYDDSLRGSLFGGGTKLTVL MAPI 1-095

[0713] 211 MAD11-095 VH QITLKESGPTLVKPTQTLRLTCTFSGFSLSTSGVGVGWVRQPPGKALEWLALIYWDDDKRYSPSLK TRLTITKDTSKNQWLTMTNMDPVDTATYYCAHYFYYYAMDVWGQGTTVTVSS

[0714] 212 MAD11-095 VL QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYLYWYQQLPGTAPKLLIYKSDQRPSGVPDRFSGS KSGTSASLAISGLRSEDEADYYCAAWDDSLSGWVFGGGTKVTVL4239-113564-02

[0715] MAPI 1—124

[0716] 213 MAP11-124 VH EVQLGQSGAEVKKPGETVQISCKVSGYTFIDYYMHWVKQAPGKGLEWVGLIDPEDGRTMYGDRFQG RVTMTVDTLKDTAYLILSSLKSDDTAIYYCTTRSASSFDYWGQGTLVSVYS

[0717] 214 MAD11-124 VL SYELTQPMSVSVSPGQTARITCSGDLLEEKYARWFQQKPGQAPVLVIYKDRERPSGIPERFSGSSS GTTVTLTITGAQIDDEADYYCYAAARNASWIGGGTRLTVL MAPI 1-131

[0718] 215 MAP11-131 VH QEQLVQSGAEVKKPGASVRVSCKASGYIFTTYYLHWVRQAPGQGLEWMGLVKPTDGGTNYAQKFQG RVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGNYGKFDYWGQGTLVTVSS

[0719] 216 MAP11— 131 VL QSALTQPASVSGSPGQSITISCTGTSSNVGTYNLVTWYQQHPGMAPKLMIYEANKRPSGVSDRFSG SKSGNTASLTISGLQAEDEADYYCCSHAGSSSYVFGTGTKVTVL MAPI 1-178

[0720] 217 MAD11-178 VH EVQLEESGGGLIQPGGSLRLSCAASGFMFSSYWMKWVRQAPGKGLQWVSHINTDGKVTTYADFVRG RFTMSRDNAKSTVYLHLDSLTAEDTATYYCARDRFCTGSKCSPGDI ILWGPGTLVTVSS

[0721] 218 MAD11- 178 VL

[0722] SYDLTQPTSVSVSPGQTARITCAGDSLSKQYVYWYQQKPGRAPLLI IYKDTMRPSGIPERFSGSTS GTIVTLTITGVQAEDEADYYCQSSDNSPVSWLFGGGTRLTVL MAPI 1-204

[0723] 219 MAP11-204 VH QVQLVESGGGWQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSKKYYTDSVKG RFTISRDNSKKTLYLQMNSLRAEDTAVYYCAKDFFEVIAVAGIPRNYYYYYMDVWGKGTTVTISS

[0724] 220 MAP11— 204 VL SYELTQPPSVSVSPGQTARITCSADALPKQYAYWYQQKPGQAPVLVIYSDSERPSGIPERFSGSSS GTTVTLTISGVQAEDEADYYCQSTDNSGTYVIFGGGTKLTVL MAPI 1-242

[0725] 221 MAP11-242 VH EVQLVQSGAEVKKPGESLRISCKGSEYRFTTYWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQG QVTISADRSISTAYLQWSSLKASDTAMYYCARPPTTMTGGFWGQGTLVTVSS

[0726] 222 MAP11— 242 VL

[0727] QPVLTQSSSASASLGSSVKLTCTLSSGHSSYI IAWHQQQPGKAPRYLMKLEAGGRYNKGSGVPDRF SGSSSGADRYLTISNFQSEDEADYYCETWDSNNLVFGGGTKLTVL MAP11-303

[0728] 223 MAD11-303 VH QGQWESGGGWQPGGSLRLSCAASGFTFNNYGMHWVRQAPGKGLEWVAFIRYDGNYESYADSVKG RFTVSRDDSKNTVYLQMNSLRTDDTAVFFCTKDPRRGPYWYFDLWGRGTLVIVSS

[0729] 224 MAD11- 303 VL QSALTQPRSVSGSPGQSVTISCTGTSSDVGAYNYVSWYQQHPDKAPKLMIYDVTKRPSGVPDRFSG SKSGNTASLTISGLQAEDEADYHCCSFAGSNTLQFGGGTKLTVL MAP11-342

[0730] 225 MAD11-342 VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMHWVRQPPGKGLVWVSSINSDGSSTNYADSVKG RFTISRDNAENTLFLQMNSLRAEDTAVYYCARDRWPAVISYYYGMDVWGQGTTVTVSS

[0731] 226 MAD11- 342 VL SYELTQPPSVSVSPGQTASITCSGDKLGDKYASWYQQKPGQSPVLVIYQDYKRPSGIPERFSGSNS GNTATLTISGTQAMDEADYYCQAWDSSTAWVFGGGTKLTVL4239-113564-02

[0732] MAPI 1-350

[0733] 225 MAP11-350 VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMHWVRQPPGKGLVWVSSINSDGSSTNYADSVKG RFTISRDNAENTLFLQMNSLRAEDTAVYYCARDRWPAVISYYYGMDVWGQGTTVTVSS

[0734] 228 MAP11— 350 VL SYELTQPPSVSVSPGQTASITCSGDKLGDKYACWYQQKPGQSPVLVIFQDNKRPSGIPERFSGSNS GNTATLTISGTQAMDEADYYCQAWDSSTWFGGGTKLTVL MAPI 1-367

[0735] 229 MAP11-367 VH QVQLVESGGGWQPGGSLRLSCAASGFTFSNYGMHWVRQAPGKGLEWVAWSYDGSHRYYADSLKG RFTISRDNSKNTLYLQMNNLRPEDTAVYYCAKDRQQVNTEYWGQGTHVTVSS

[0736] 230 MAP11-367 VL DIVLTQTPLSTVTLGQPASISCRSSQSLVHSDGNTYLSWLQQRPGQPPRLLIYKISNRLSGVPDRF SGSGAGTDFTLKI SRVEAEDVGVYYCMQATQFPLTFGGGTKVEIK MAPI 1-368

[0737] 231 MAP11-368 VH QVQLVQSGAEVRKPGAAVKVSCKLSGYSLSEISMHWVRQAPGKGLEWMGGFDPDEGKTVYAHQYQG RVTMTEGTHGDTAYLDLTSLTTDDTAVYYCAIGDRYFESSGHLEYWGQGTLVTVSS

[0738] 232 MAP11-368 VL DIHLTQSPSSLSASVGDRVTITCRASQTIGDFLNWYQQTPGKAPKLLIYSSSTLQTGVPPRFSGDG SGTHFTLTISSLQPEDFATYYCQQAFNTPRTFGPGTKVDVQ MAPI 1-375L

[0739] 233 MAP11-375L VH QAQLVESGGGWQPGRSLRLSCAASGFTFSNYGMHWVRQAPGKGLEWVAIVSYDGSTKYYVDSVKG RFTISRDNSKNTLYLQMNSLTTEDTALYYCAKLTGDLGFDRWGQGTLVIVSS

[0740] 234 MAP11-375L VL SYKLTQAPSVSVSPGQTASITCSGDQLDTKYVSWYQQKPGQSPVLVIYYDTKRPSGIPDRFSGSSS GDTATLTISGAQSLDEADYYCQAWHSTTAIFGGGTKLTVL MAP11-376

[0741] 235 MAP11-376 VH EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGITSNSDYTVYTDSVKG RFTISRDNAKKALYLQMNSLRVEDTAFYYCVGWSSGQYRPQGMHYWGQGIQVTVSS

[0742] 236 MAP11— 376 VL SSELTQPPSLSVSPGQTARITCSADALATQYTYWYQKKPGQAPVLVIYNDSERPSGIPPRFSGSSS GKTVTLTISGVQAEDEADYYCQSADSSGAYPVFGGGTKLTVL MAPI 1-390

[0743] 237 MAP11-390 VH EVQLVESGGDLVQPGGSLRLSCAASGLNVSSNYMSWVRQAPGKGLEWVSVIYSGGSTNYADSVKGR FTISRDNSKNTLYLQMNSLRGEDTAVYYCARAQSSSSEFDYWGQGTWTVSS

[0744] 226 MAP11-390 VL SYELTQPPSVSVSPGQTASITCSGDKLGDKYASWYQQKPGQSPVLVIYQDYKRPSGIPERFSGSNS GNTATLTISGTQAMDEADYYCQAWDSSTAWVFGGGTKLTVL MAPI 1-412

[0745] 239 MAP11-412 VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSYISSSSSTIYYADSVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCVKGSSWYKLGGYYYYMDVWGKGTTVTISS

[0746] 240 MAP11-412 VL DIQMTQSPSSLSASVGDRVTITCRATQYIIGYLNWYQHKPGKAPKVLIYAASNLQSGVPSRFSGSG SGTDFTLTISGLQPEDFGTYFCQQSYSMPITFGQGTRLEIK4239-113564-02

[0747] MAP11-421

[0748] 241 MAP11-421 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTRHYMHWVRQAPGQGLEWMGIINPSGGSTSYAQKFQG RVTMTRDTSTSTVYMELSSLRSEDTAVYYCTRDPSIAAAGTNYFDYWGQGTLVTVSS

[0749] 242 MAP11— 421 VL SYELTQPASVSVSPGQTSSITCSGDRLGDKYACWYQQKPGQSPVLVIYQDTKRPSGIPERFSGSNS GNTATLTISGTQAMDEADYYCQAWDSSSWFGGGTKLTVL MAPI 1-423

[0750] 243 MAD11-423 VH QVQLVQSGAEVRKPGAAVKVSCKLSGYSLSEISMHWVRQAPGKGLEWMGGFDPDEGKTVYAHQYQG RVTMTEGTHGDTAYLDLTSLTTDDTAVYYCAIGDRYFESSGHLEFWGQGTLVTVSS

[0751] 232 MAP11- 23 VL DIHLTQSPSSLSASVGDRVTITCRASQTIGDFLNWYQQTPGKAPKLLIYSSSTLQTGVPPRFSGDG SGTHFTLTISSLQPEDFATYYCQQAFNTPRTFGPGTKVDVQ MAPI 1-428

[0752] 245 MAP11-428 VH QVQLQESGPGLVKPSQTLSLTCIVSGASISSGAYYWSWIRQHPGKALEWIGNIYYSGNTFYNPSLK SRITISVDTSKKQFSLNLRSVTAADTAMYYCARESESPGDWYFDLWGRGTLVTVSS

[0753] 246 MAP11— 428 VL SSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVLYGKNNRRASGIPERFSGST SGNTDSLIITGAQAEDEADYYCNSRDSSGNHVLFGGGTKLTVL MAPI 1-493

[0754] 247 MAP11-493 VH EAQLEESGGGPTQPGGSLRLSCAASGFVFSSYWMKWVRQAPGKGLEWVAHINTDGKVTTYADFVRG RFTLSRDNAKSTVFLDLDNLSADDTATYYCARDRFCTGSKCSPGDI ILWGPGTLVTVSS

[0755] 248 MAP11-493 VL

[0756] SYDLTQPRSVSVSPGQTARITCAGDSLSKQYVYWYQQKPGQAPVLI IYKDTMRPSGIPERFSGSTS GTTVTLTITGIQAEDEADYYCQSSDMSPVSWLFGGGTKLTVL MAPI 1-519

[0757] 249 MAP11-519 VH QVQLVEAGGGWQPGRSLRLSCSASGFSFSNYGIHWVRQAPGKGLEWVAVIVYDGTRRVYGESARG RFSISRDNSRNTVYLQMNSLTADDTAVYYCVRDYIGSIDNYFDYWGQGTLVTVSS

[0758] 250 MAP11— 519 VL NWMTQSPLSLWTLGQPASIACRSSLSLAHSDGKTYFNWFHQRPGQSPRRLIYMVSKRDSWVPDR FSASGSGTDFTLKISRVEAEDAGFYYCMQGTHWPVAFGQGTRLEIK MAPI 1-544

[0759] 251 MAP11-544 VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYWMTWVRQAPGKGLEWVANIKKDGSVKHYVDSVKG RFTVSRDIAKNSLYLQMNSLRAEDTAVYYCARDRSPGDSSAWYDAFDIWGQGTMVIVSS

[0760] 252 MAP11— 544 VL AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKPPKLLIYAASSLQTGVPSRFSGSG SGTDFTLTISSLQPEDFATYYCLQDYNYPRTFGQGTKVEIK MAPI 1-550

[0761] 253 MAP11-550 VH

[0762] E VQWE S GGGL VQP GGS LRL S C VAT GF TF S S YWMHWVRQAP GKGL VWVS RI KTD GS TP RY AD S VKG RFTISRDNAKNTVFLQMNSLRPEDTAIYYCARWRAVAGGYFDLWGRGTLVTVSS

[0763] 254 MAP11-550 VL QSVLTQAPSASGTPGQRVTISCSGSSSSIGSNTVNWYQQLPGTAPKLLIYNNDERPSGVPDRFSGS KSG SASLAISGLQSEDEADYYCATWDDSLNGPVFGGGTKLTVL4239-113564-02

[0764] MAPI 1-553

[0765] 255 MAP11-553 VH QVQLQESGPGLVKPSETLTLTCTVSNGSISTYYWSWVRQTPAKGLEWIGYISYGGSTNYIPSLKRR VTISLDTPKNQVSLKVTSVTAADTAVYYCARVRLYMDGGVIKFDGMDVWGQGTTVTVSS

[0766] 256 MAP11— 553 VL EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQQPGRAPRLLIYGASTRATGIPARFSGSG SGTEFTLTISSVQSEDFALYYCQQYMGTFGQGTKLEIK MAPI 1-564

[0767] 257 MAP11-564 VH

[0768] QVHLVQSGAEVKKPAASVKVSCKASGYTFTAYYI YWLRQAPGQGLEWMGWINPNTGRTNYAQKFEG WVTMTSDTSISTAYMELTRLRPDDTAVYYCARWDSGYGNDYWGQGTLVTVSS

[0769] 258 MAP11— 564 VL QSVLTQPPSASGTPGQRITMSCSGSSSNIGSNFVYWYQQFPGTAPRLLIYRNNQRPSGVPDRFSGS KSGTSASLAISGLRSEDEADYYCATWDDSLSGPVFGGGTKLTVL MAPI 1-570

[0770] 259 MAP11-570 VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMHWVRQTPGKGLVWVSRLKSDGSTTRYADSVKG RFTISRDNAKNTLFLQMNSLRAEDTAVYYCVRWRAVSGGYFDLWGRGTLVTVSS

[0771] 260 MAP11— 570 VL QSVLTQPPSASGTPGQRVTMSCSGSSSNIGSNTVNWYQQLPGTAPQLLIYNNDERPSGVPHRFSGS KSGTAASLAIRGLQSEDEADYYCETWDDSLNGPVFGGGTKLTVL MAPI 1-588

[0772] 261 MAP11-588 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYAIHWVRQAPGQRLEWMGWINAGIGFTKYSQKFQG RVTITRDTSASTAYMELNSLRSEDTAVYYCARSLGYCSGGGCYNTLVQAFDMWGQGTMVTVST

[0773] 262 MAP11-588 VL SYVLTQPPSVSVAPGKTARITCGGNNIGSKSVHWYQQKPGQAPVLWHDDSDRPSGIPERFSGSNS GNTATLTISRVEAGDEADYYCQVWDSSSDHWVFGGGSKLTVL MAPI 1-597

[0774] 263 MAP11-597 VH QITLKESGPTLVKPTQTLTVTCTFSGFSLTTSGLGVAWIRQPPGKALEWLAHIYWDGDKRYSPSLK S RL T I TKDT S KNQWL TMTNMDP VD TAT Y Y C AHMD Y YDNME YWGQGT LVTVS S

[0775] 264 MAP11— 597 VL QSELTQPPSASGTPGQRVTISCIGSSSNIGRNSVYWYQHLPGTAPKLLINREMQRPSGVSARFSGS KSGTSASLAISGLRSEDEADYYCAAWDDSLWGWVFGGGTKLTVL MAP11-637

[0776] 265 MAP11-637 VH QVQLVESGGGWQPGRSLRLSCAASGFTFSSYAMHWVRQAPGKGLEWVAVISFDGSNKYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCASDGNYARFDPWGQGTLVTVPS

[0777] 266 MAP11- 637 VL SYELTQPPSVSVSPGQTARITCSGDALPKQYAYWYQQKPGQAPVLVIYKDSERPSGIPERFSGSSS GTTVTLTISGVQAEDEADYYCQSADSSGTYHYVFGTGTKVTVL MAP11-642

[0778] 267 MAP11-642 VH QITLKESGPTLVKPTQTLTLTCTFSGFSLTSNGEAVGWVRRPPGKALEWLALVYWDDDKRYSPSLK DRLTITKDTSGDQWLTMTNMEPIDTATYYCTHTVYYYAMDVWGQGTTVSVSS

[0779] 268 MAP11-642 VL QSVLTQPPSASETPGQRVTISCSGSDSNIGSRDVYWYQQLPGMAPKLLIFNSSRRPSGVPDRFSGS KSGTSASLAISGLRSEDEADYYCAAWDDSLNAWLFGGGTKVTVL4239-113564-02

[0780] MAD11-0756

[0781] 269 MAD11— 0756 VH EVQLVESGGGLVKPGGSLRLSCAASGFTLSNAWMSWVRQVPGKGLEWVGRIKTKSDGGTTDYAAPV KGRFTISRDDSKNTLYLQLNSLKTEDTAVYYCTTDNYGDPFGLFDYWGQGTLVTVSS

[0782] 270 MAD11- 0756 VL DIVMTQSPDSLAVSLGERATINCKSSQSVLYRSNNKNYLAWYQQRPGQPPKLLIYWASTRESGVPD RFSGSGSGTDFTLTISSLQAEDVALYYCQQYYSTPTFGGGTKVEIK MAD11-0760

[0783] 271 MAD11- 0760 VH QVQLVESGGGWHPGRSLRLSCAASGFTFSSYAMHWVRQAPGKGLEWVALISDDGSTKYYADSVKG RFTVSRDNSKNTLYLQMNSLRAEDTAVYYCAREGHGYNSNAFDIWGQGTLVTVSS

[0784] 272 MAD11- 0760 VL DWMTQSPLSLPVTLGQPASISCRSSQSLVYSDGNTYLNWFHQRPGQSPRRLIYKVSNRDSGVPDR FSGSGSGTDFTLKISRVEAEDVGVYYCMQGTHWPLTFGGGTKVEIK MAD11— 0784

[0785] 273 MAD11- 0784 VH EVQLVESGGGLVKPGGSLRVSCAASGFTFTNAWMSWVRQAPGKGLEWIGLIKSKNDGASTDYAAPV KGRFTVSRDDSKHTLYLHMNSLKIEDTAVYYCTTDGGVTSGSPLDYWGQGTLVTVSS

[0786] 274 MAD11- 0784 VL SSELTQPPSVSVSPGQTARITCSGHRLPKQFAYWYQQKAGQAPVLVIYKDRERPSGIPERFSGSTS GTWTLTITGVHAEDEADYYCQSADSSGAWVFGGGTKLTVL MAD11-0787

[0787] 275 MAD11— 0787 VH QVQLVESGGGWQPGRSLRLSCAASGFTFSNYAMHWVRQAPGKGLEWVSAISYDGSNKYYADSVKG RFTISRDNSKNTLYLQMNSLIPEDTAVYHCARNSLPYITMASLFDYWGQGTLVTVSS

[0788] 276 MAD11— 0787 VL SYELTQPPSVSVSPGQTASITCSGDKLGDRYAFWYQQKPGQSPVWIYQDIRRPSGIPERFSGSNS ENT AT L T I S GAQAMDE D Y YCQAWD S T TAVF GGGTKL T VL MAD11-0796

[0789] 277 MAD11— 0796 VH EVQLVESGGGLVKPGGSLRVSCAASGFTFTNAWMSWVRQAPGKGLEWIGLIKSKNDGASTDYAAPV KGRFTVSRDDSKHTLYLHMNSLKIEDTAVYYCTTDGGVTSGSPLDYWGQGTLVAVSS

[0790] 274 MAD11- 0796 VL SSELTQPPSVSVSPGQTARITCSGHRLPKQFAYWYQQKAGQAPVLVIYKDRERPSGIPERFSGSTS GTWTLTITGVHAEDEADYYCQSADSSGAWVFGGGTKLTVL MAD11-0819

[0791] 279 MAD11-0819 VH QVQLQQWGAGLLKTSETLSLTCAVYGGSLSGNYWSWIRQPPGKGLEWIGDVSQSGRTNYSPSLKSR VTISVDTSKNQFSLKVTSVTAADTALYYCARLGTADYWGQGTLVTVSS

[0792] 280 MAD11-0819 VL QAWTQEPSLTVSPGGTVTLTCASTTGNVTSGHWPYWFQQKPGQAPRALIYDTSNKHSWTPARFSG SLLGGKAALTLSGAQPEDEAEYYCLLSQSGARVFGGGTKVTVL MAD11-0820

[0793] 281 MAD11- 0820 VH LVESGGGWQPGRSLRLSCTASGFSRFTFSNYAMHWVRQAPGKGLEWVAVISYDGSNKYYTDSVKG RFTISRDNSKDTLYLQLNRLRAEDTGVYYCARSERSGFHFGYSTSYDYYGMDVWGQGTTVTVSS

[0794] 282 MAD11- 0820 VL SYELSQPPSVSVSPGQTASITCSGDKLGDKYACWYQQKPGQSPVLVIYQDTKRPSGIPERFSGSNS GNTATLTISGTQAMDEADYYCQAWDSTTWFGGGTKLTVL4239-113564-02

[0795] MAD11-0821

[0796] 283 MAD11— 0821 VH EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMTWVRQAPGKGLEWVSAISASGDSTYYPDSVKG RFTISRDNSKNILYLQMNSLRAGDTAVYYCAKSRREYQLPPYYFDSWGQGSLVTVSS

[0797] 284 MAD11- 0821 VL QLVLTQSPSASASLGAPVKLTCTLSSGHSDYAIAWHQQQPEKGPRYLMRLNSDGSHSKGDGIPDRF SGSSSGAERYLTISSLQSEDEADYYCQTWGTGIEVFGGGTKLTVL MAD11-0842

[0798] 285 MAD11- 0842 VH QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGPEWMGRIIPMFDTTDYAQKFQG RVTISADESTSTAYMQMRSLKSEDTATYYCVKSSNSGTYYGRDAFDIWGPGTMVTVSS

[0799] 286 MAD11- 0842 VL DIQMTQSPSSLSASVGDRVTISCRASQSISSYLNWYQQKPGKAPKLLIYASSSLQSGVPSRFSGSG SGTDFTLTISNLQPEDFAIYYCQQSYSIPPYTFGQGTKLEIK MAD11— 0845

[0800] 287 MAD11- 0845 VH QVQLVQSGAEVKRPGASVKVSCKVSGYTLTELSMHWVRQAPGEGLEWMGGFDPEHSETIYAQKFQG RVSMTEDTSTDTAYMELRSLRSEDTAVYYCARVRYNWNYVFDEWGQGTLVSVSS

[0801] 288 MAD11- 0845 VL DIQLTQSPSFLSASVGDRVTITCRASQGFINYLAWYQQKPGKAPKLLIYAASALRSGVPSRFSGSG SGTEFTLTISTLQPEDFATYYCQQLNSFPYTFGQGTKVEIK MAD11-0847

[0802] 289 MAD11— 0847 VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYEMTWVRQAPGKGLEWVSYITSSGTTIYYADSVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCARVFTYGLDAFDIWGQGTMVTVSS

[0803] 290 MAD11— 0847 VL DIQMTQSPSTLSASVGDRVTITCRASQNIRHWLAWYQQKPGKAPNLLIYKASSLQSGVPSRFSGSG SGTEFTLTISSLQPDDFATYYCQQYNGYSYTFGQGTKLEIK MAD11— 0865

[0804] 291 MAD11— 0865 VH QVQLQESGPGLVKPSETLSLTCAVSGFSINSGYSWAWLRQPPGKGLEWIGTVDHTGNTYFNPSLKS RVTLFLDTSKNQVSLTLSSVTAADTAMFYCARLGYTGGAFDYWGQGTLVTVSS

[0805] 292 MAD11- 0865 VL QSALTQPASVSGSPGQSITISCTGTSSDVGGYYYVSWYQQHPGKAPKLVIYEVSSRPSGVSDRFSG SKSGSTASLTISGLQAEDEADYYCSSYTTISSYVFGTGTKVTVL MAD11-0890

[0806] 293 MAD11-0890 VH QVQLVQSGAEVKKPGASVKISCKTSGYTFSSYTIHWVRQAPGHSLEWLGWINPGNGNTKYSQKFQG RVTITRDTSASTAYMELSSLTSEDTAVYYCARDHAYLHGSGGGAMDVWGKGSTVIVSS

[0807] 294 MAD11-0890 VL EIVLTQSPATLSLSPGERATLSCRASQSISKYLVWYQQKPGQAPRLLIYDASNRATDIPARFSGSG SGRDFTLTISSLEPDDYAVYYCQHRSLWEITFGQGTRLDTK MAD11-0904

[0808] 295 MAD11- 0904 VH

[0809] QVQLVE S GGGWQP GRS LRL SCAAS GFTF SNYGMHWVRQTPGKGLEWVAVI WYDASKRYYAD S VMG RFTVSRDTSTNIVYLQMNSLRAEDTAIYYCARPGYYDIEGLDYWGQGTLVSVSS

[0810] 296 MAD11- 0904 VL DIQMTQSPSSLSASVGDKVTITCRANHGIDNYLAWFQQKPGKAPKSLIYGASNLHTEVPSKFSGSR SGTDFTLTINSLQPEDFATYYCQQYFAYPWTFGQGTKVEMK4239-113564-02

[0811] MAD11-0920

[0812] 297 MAD11— 0920 VH EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISAGPGLTYYADSVKA RFTISRDNSKNTLYLQMTSLRAEDTAVYYCAKFLSGGSTRHYYMDVWGKGTTVAVSS

[0813] 298 MAD11- 0920 VL DIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWFQQKPGKAPKSLIYAASSLQSGVPSKFSGSG SGTDFTLTISSLQPEDFATYYCQQYSTFPLTFGGGTRVEIK MAPI 1-0982

[0814] 299 MAD11- 0982 VH EVQWESGGGLVKPGGSLRLSCAASGFTFSDGWMNWARQAPGKGLEWVGRIKSKTYGGTTDYAAPV KGRFTISRDDSKGWYLQMNSLKIEDTAVYYCTTDGGVMAMVIFGHWGQGTLVTVSS

[0815] 300 MAD11- 0982 VL EIVLTQSPGTLSLSPGERATLSCRASQSVRSNYLAWYQQKAGQAPRLLMYGASTRATGIPDRFSGS GSGTDFTLTI SRLEPEDFAVYFCQQYGSTPPYTFGQGTKLEIK MAD11— 1051

[0816] 303 MAD11- 1051 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNSGGTNYAQKFQG RVTMTRDTSISTAYMELSRLRSDDTAVYYCASQGGMVRGVIHAFDIWGQGTMVTVSS

[0817] 304 MAD11- 1051 VL SYELTQPPSVSVSPGQTARITCSGDALPKKYAYWYQQKSGQAPVLVIYEDSKRPSGIPERFSGSSS GTMATLTISGAQVEDEADYYCYSTDSSGKGVFGGGTKLTVL MAD11-1077

[0818] 305 MAD11— 1077 VH EVQLVESGGGLVQPGGSLRLSCAASRFTFSNYWMTWVRQAPGKGLEWVANINRDGSVKSYVDSVKG RLTISRDNAKNSLYLQMSSLRAEDTAVYYCARDQSPSWNDYYYDVFDIWGQGTMVTVSS

[0819] 306 MAD11— 1077 VL AIQMTQSPSSLSASVGDRVTITCRASQGIRNELGWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSG SGTDFTLSISSLQPEDFATYYCLQDYNYPRTFGQGTKLEIK MAD11— 1128

[0820] 307 MAD11— 1128 VH QITLRESGPTLVKPTQTLTLTCTFSGFSLATTEVGVAWIRQPPGKALEWLALVYWDDDKRYSPSLK S RL T I TKDT S KNQWL TMTNMDP VD TAT YF C AHMTVFD S FDVWGQGTMVTVS S

[0821] 308 MAD11- 1128 VL QSVLTQPPSASGTPGQSITISCSGIRSNTGRNYVYWYQQLPGSAPKLLISWDDKRPSGVPDRFSGS RSGTSASLAISGLRSDDEADYYCATWDVTLSSWVFGGGTKLTVL MAD8-664

[0822] 309 MAD8-664 VH EVQLVQSVAEVKKPGASVKVSCKASGYTFTTNYIHWVRQAPGQGLEWMAIINPSGGNTNYARQFQG RVNVTRDTSATTVYMELSSLRSEDTAVYYCTRMGKGWAHPFDNWGQGTLVTVSS

[0823] 310 MAD8-664 VL DIQMTQSPSSLSASVGDRVTITCRASQGISTYLGWFQQKPGKAPKSLIYGASTLQSGVPPNFSGTG SGTDFTLTISSLQPEDFATYYCQQYYSYPLTFGGGTKVEIK MAD11-1139

[0824] 311 MAD11- 1139 VH EVQLLESGGGLAQPGGSLRLSCAASGFTFSTYAMSWVRQAPGKGLEWVSTISGSGSSTYYADSVKG RFTISRDNSKNTLYLQINSLTAEDTAVYYCANLGASVGAFDIWGQGTMVTVSS

[0825] 312 MAD11— 1139 VL QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSG SKSGTSASLAITGLQADDEADYYCQSYDSSLSGWVFGGGTKLTVL4239-113564-02

[0826] It will be apparent that the precise details described may be varied or modified without departing from the spirit of the described invention. We claim all such modifications and variations that fall within the scope and spirit of the claims below.

Claims

1. 4239-113564-02It is claimed:

1. An isolated monoclonal antibody, comprising:a heavy chain variable region (VH) and a light chain variable region ( Vi.) 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 VHand VL set forth as:(A)a) SEQ ID NOs: 17 and 18, respectively (MAD8-498);b) SEQ ID NOs: 1 and 2, respectively (MAD8-265);c) SEQ ID NOs: 9 and 10, respectively (MAD8-318);d) SEQ ID NOs: 25 and 26, respectively (MAD8-506); ore) SEQ ID NOs: 33 and 34, respectively (MAD11-0897); andwherein the monoclonal antibody specifically binds to P. falciparum CyRPA protein; or (B)f) SEQ ID NOs: 41 and 42, respectively (MAD11-1129);g) SEQ ID NOs: 49 and 50, respectively (MAD8-2);h) SEQ ID NOs: 57 and 58, respectively (MAD8-66);i) SEQ ID NOs: 65 and 66, respectively (MAD8-72);j) SEQ ID NOs: 73 and 74, respectively (MAD8-739); ork) SEQ ID NOs: 301 and 302, respectively (MAD11-1043); andwherein tire monoclonal antibody specifically binds to P. falciparum RIPR protein.

2. The monoclonal antibody of claim 1, wherein the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2, and the LCDR3 are according to the Kabat, Chothia or IM GT system.

3. The monoclonal antibody 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: 19, 20, 21, 22, 7 (KVS), 24, respectively (MAD8-498);b) SEQ ID NOs: 2, 3, 4, 5, 6, 7 (KVS), 8, respectively (MAD8-265);c) SEQ ID NOs: 11, 12, 13, 6, 7 (KVS), 16, respectively (MAD8-318);d) SEQ ID NOs: 27, 28, 29, 22, 31 (KIS), 24, respectively (MAD8-506);e) SEQ ID NOs: 35, 36, 37, 38, 39 (TAS), 40, respectively (MAD11-0897);f) SEQ ID NOs: 43, 44, 45, 46, 47 (YDK), 48, respectively (MAD11-1129);g) SEQ ID NOs: 51, 52, 53, 54, 55 (KAS), 56, respectively (MAD8-2);h) SEQ ID NOs: 59, 60, 61, 62, 63 (WAS), 64, respectively (MAD8-66);i) SEQ ID NOs: 67, 68, 69, 70, 71 (DVS), 72, respectively (MAD8-72);j) SEQ ID NOs: 67, 68, 69, 70, 71 (DVS), 72, respectively (MAD8-72); ork) SEQ ID NOs: 315, 316, 317, 318, 319 (KDS), 320, respectively (MAD11-1043).4239-113564-024. The antibody of any one of the prior claims, wherein the VHand 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 Vi. are at least 90% identical to those of:a) SEQ ID NOs: 17 and 18, respectively (MAD8-498);b) SEQ ID NOs: 1 and 2, respectively (MAD8-265);c) SEQ ID NOs: 9 and 10, respectively (MAD8-318);d) SEQ ID NOs: 25 and 26, respectively (MAD8-506);e) SEQ ID NOs: 33 and 34, respectively (MAD11-0897);f) SEQ ID NOs: 41 and 42, respectively (MAD11-1129);g) SEQ ID NOs: 49 and 50, respectively (MAD8-2);h) SEQ ID NOs: 57 and 58, respectively (MAD8-66);i) SEQ ID NOs: 65 and 66, respectively (MAD8-72);j) SEQ ID NOs: 73 and 74, respectively (MAD8-739); ork) SEQ ID NOs: 301 and 302, respectively (MAD11-1043).

5. The antibody of any one of the prior claims, wherein the VH and tire VL comprise amino acid sequences set forth as:a) SEQ ID NOs: 17 and 18, respectively (MAD8-498);b) SEQ ID NOs: 1 and 2, respectively (MAD8-265);c) SEQ ID NOs: 9 and 10, respectively (MAD8-318);d) SEQ ID NOs: 25 and 26, respectively (MAD8-506);e) SEQ ID NOs: 33 and 34, respectively (MAD11-0897);f) SEQ ID NOs: 41 and 42, respectively (MAD11-1129);g) SEQ ID NOs: 49 and 50, respectively (MAD8-2);h) SEQ ID NOs: 57 and 58, respectively (MAD8-66);i) SEQ ID NOs: 65 and 66, respectively (MAD8-72);j) SEQ ID NOs: 73 and 74, respectively (MAD8-739); ork) SEQ ID NOs: 301 and 302, respectively (MAD11-1043).

6. The antibody of any one of the prior claims, wherein the antibody comprises a human constant domain.

7. The antibody of any one of the prior claims, wherein the antibody is a human antibody.

8. The antibody of any one of the prior claims, wherein the antibody is an IgG.

9. The antibody of any one of the prior claims, comprising a recombinant constant domain comprising a modification that increases the half-life of tire antibody.4239-113564-0210. The antibody of claim 9, wherein the modification increases binding to the neonatal Fc receptor.

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

12. An antigen binding fragment of the antibody of any one of the prior claims, wherein the antigen binding fragment comprises the VH and the VL of the antibody, specifically binds to P. falciparum CyRPA protein or RIPR protein.

13. The antigen binding fragment of claim 12, wherein the antigen binding fragment is a Fv, Fab, Ftab'), scFV or a scFVz fragment.

14. The antibody or antigen binding fragment of any one of the prior claims, conjugated to an effector molecule or a detectable marker.

15. The monoclonal antibody or antigen binding fragment of any one of tire prior claims, wherein tire monoclonal antibody neutralizes P. falciparum.

16. The antibody or antigen binding fragment of any one of the prior claims, wherein the antibody or antigen binding fragment inhibits P. falciparum merozoite entry into erythrocytes of tire subject.

17. A bispecific antibody comprising the antibody or antigen binding fragment of any one of the prior claims.

18. An isolated nucleic acid molecule encoding the antibody or antigen binding fragment of any one of the prior claims.

19. The isolated nucleic acid molecule of claim 18, wherein the nucleic acid molecule is RNA.

20. The nucleic acid molecule of claim 18 or claim 19, operably linked to a promoter.

21. A vector comprising the nucleic acid molecule of any of claims 18-20.

22. A host cell comprising tire nucleic acid molecule or vector of any one of claims 18-21.4239-113564-0223. A composition for use in inhibiting P. falciparum infection, comprising an effective amount of the antibody, antigen binding fragment, nucleic acid molecule, or vector, of any one of the prior claims, and a pharmaceutically acceptable carrier.

24. The composition of claim 23, further comprising a CJS43 antibody, a L9 antibody, or a 317 antibody.

25. A method of producing an antibody or antigen binding fragment that specifically binds to P. falciparum CyRPA protein or RIPR protein, comprising:expressing one or more nucleic acid molecules encoding the antibody or antigen binding fragment of any one of claims 1-17 in a host cell; andpurifying tire antibody or antigen binding fragment.

26. A method of detecting tire presence of P. falciparum in a biological sample from a human subject, comprising:contacting the biological sample with an effective amount of the antibody or antigen binding fragment of any one of claims 1-17 under conditions sufficient to form an immune complex; and detecting the presence of tire immune complex in the biological sample, wherein the presence of the immune complex in the biological sample indicates the presence of tire P. falciparum in the sample.

27. The method of claim 26, wherein detecting the detecting the presence of the immune complex in the biological sample indicates that the subject has a P. falciparum infection.

28. A method of inhibiting a P. falciparum infection in a subject, comprising administering an effective amount of the antibody, antigen binding fragment, nucleic acid molecule, vector, or composition of any one of claims 1-21 or 23-24 to the subject, wherein the subject has or is at risk of a P. falciparum infection.

29. The method of claim 28, wherein the subject is at risk of a P. falciparum infection.

30. The method of claim 28 or claim 29, wherein the method inhibits P. falciparum merozoite entry into erythrocytes in the bloodstream of the subject.

31. Use of the antibody, antigen binding fragment, nucleic acid molecule, vector, or pharmaceutical composition of any one of claims 1-21 or 23-24, to inhibit P. falciparum infection in a subject or to detect the presence of a P. falciparum in a biological sample.

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