Neutralizing antibodies to Plasmodium falciparum circumsporozoite protein and their use
Inventors
SEDER, Robert • Wang, Lawrence • Vistein, Rachel • Francica, Joseph
Assignees
US Department of Health and Human Services
Publication Number
US-12269872-B2
Publication Date
2025-04-08
Expiration Date
2040-05-04
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Abstract
Antibodies and antigen binding fragments that specifically bind to P. falciparum circumsporozoite protein are disclosed. Nucleic acids encoding these antibodies, vectors and host cells are also provided. The disclosed antibodies, antigen binding fragments, nucleic acids and vectors can be used, for example, to inhibit a P. falciparum infection.
Core Innovation
This disclosure provides monoclonal antibodies and antigen binding fragments directed against Plasmodium falciparum circumsporozoite protein (PfCSP). Notably, it describes the L9 human monoclonal antibody which confers sterile protection in an animal model of malaria infection containing PfCSP and is more potent in inhibiting malaria infection than prior PfCSP monoclonal antibodies. The L9 antibody preferentially binds with high affinity to the NPNV (SEQ ID NO: 32) epitope, found where an NANP repeat is followed by an NVDP minor repeat, and shows relatively poor affinity to the immunodominant NANP repeats of PfCSP.
The problem addressed is the urgent need for preventive interventions to inhibit malaria infection, given the lack of FDA-approved vaccines and increasing resistance of malarial parasites to antimalarial drugs. Malaria, caused chiefly by P. falciparum, leads to high mortality globally. Existing preventive measures inadequately limit morbidity and mortality or eliminate malaria, necessitating new methods.
The disclosure also includes compositions comprising the antibodies and antigen binding fragments, nucleic acids encoding these molecules, expression vectors harboring these nucleic acids, and isolated host cells expressing them. The disclosed antibodies and fragments potently neutralize PfCSP expressed on infectious sporozoites in vivo and can be used in methods for inhibiting P. falciparum infection in subjects, such as those at risk or infected. Additional uses include diagnosing P. falciparum infection or detecting the parasite in samples.
Claims Coverage
The claims present one independent claim directed to an isolated monoclonal antibody or antigen binding fragment with specific sequence features and functional properties.
Antibody comprising defined heavy and light chain variable regions
An isolated monoclonal antibody or antigen binding fragment comprising a heavy chain variable region (VH) and a light chain variable region (VL) that include a heavy chain complementarity determining region (HCDR) 1, 2, and 3 and a light chain complementarity determining region (LCDR) 1, 2, and 3 of the VH and VL set forth as SEQ ID NOs: 1 and 2, respectively. The antibody specifically binds to PfCSP and neutralizes P. falciparum infection.
Inclusion of specific CDR amino acid sequences
The antibody or antigen binding fragment includes the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences as set forth in SEQ ID NOs: 3, 4, 5, 6, 7, and 8, respectively.
Sequence identity and framework
The VH and VL sequences have at least 90% identity to the amino acid sequences SEQ ID NOs: 1 and 2. The antibody optionally comprises a human framework region and a human constant domain.
Antibody is human IgG with specific heavy and light chain sequences
The antibody is a human IgG comprising heavy and light chain amino acid sequences as set forth in SEQ ID NOs: 9 and 10 (L9 IgG1).
Modifications to constant domain to increase half-life
The antibody constant domain may comprise recombinant modifications that increase half-life, such as mutations enhancing binding to the neonatal Fc receptor, including specific mutations M428L and N434S in IgG1 constant domain.
Antigen binding fragments and multispecific antibodies
Isolated antigen binding fragments such as Fv, Fab, F(ab')2, scFv, or scFv2 that include the VH and VL and specifically bind PfCSP and neutralize P. falciparum. Bispecific antibodies comprising the antibody or antigen binding fragment are also claimed.
Nucleic acids, vectors, and host cells encoding the antibody
Isolated nucleic acid molecules encoding the antibody or antigen binding fragment, including sequences set forth as SEQ ID NOs: 11 and 12. These nucleic acid molecules can be cDNA or RNA, operably linked to promoters, and included in vectors and host cells.
Methods and compositions for inhibiting P. falciparum infection
Methods of inhibiting P. falciparum infection in subjects by administering an effective amount of the antibody, antigen binding fragment, nucleic acid, vector, or composition thereof. The antibodies or fragments inhibit sporozoite entry into blood from skin and/or entry into hepatocytes in liver.
Methods for detecting P. falciparum infection
Methods of detecting P. falciparum in biological samples by contacting the sample with the antibody or antigen binding fragment under conditions sufficient to form an immune complex and detecting the complex indicating infection.
The claims broadly cover the isolated monoclonal antibody L9 or antigen binding fragments thereof with defined variable region sequences that specifically bind PfCSP and neutralize P. falciparum, including related nucleic acids, vectors, host cells, compositions for inhibiting infection, detection methods, and multispecific antibody formats.
Stated Advantages
L9 monoclonal antibody confers sterile protection in animal models of malaria infection and is more potent than prior PfCSP monoclonal antibodies.
Potent neutralization of PfCSP expressed on infectious sporozoites in vivo enables effective inhibition or prevention of P. falciparum infection.
More potent antibodies may provide improved and more durable protection at lower doses and facilitate easier methods of delivery, such as subcutaneous injection versus intravenous infusion.
Documented Applications
Inhibiting or preventing P. falciparum infection in subjects at risk or infected, including humans such as travelers, military personnel, or individuals in malaria elimination campaigns.
Passive immunization by administration of effective amounts of the antibodies, antigen binding fragments, nucleic acids, vectors, or compositions thereof.
Diagnosing P. falciparum infection in biological samples by detecting immune complexes formed with the disclosed antibodies or antigen binding fragments.
Testing vaccines including PfCSP immunogens by detecting binding of the disclosed antibodies, indicating proper epitope conformation.
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