Neutralizing antibodies to plasmodium falciparum circumsporozoite protein and their use
Inventors
SEDER, Robert • Kisalu, Neville • Idris, Azza • Flynn, Barbara • Hoffman, Stephen
Assignees
Sanaria Inc • US Department of Health and Human Services
Publication Number
US-11760794-B2
Publication Date
2023-09-19
Expiration Date
2038-02-12
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Abstract
Antibodies and antigen binding fragments that specifically bind to P. falciparum circumsporozoite protein and neutralize P. falciparum 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 the Plasmodium falciparum circumsporozoite protein (PfCSP). The antibodies, including CIS43, potently neutralize P. falciparum and confer sterile protection in multiple animal models of malaria infection. Such antibodies exhibit specific binding to defined epitopes on PfCSP and inhibit P. falciparum infection in vitro and in vivo.
A particular focus is on antibody CIS43, which preferentially binds with high affinity to a unique junctional epitope at the junction of the N-terminus and central repeat domain of PfCSP. CIS43 prevents cleavage of PfCSP on sporozoites, showing sequential and multivalent binding, including recognition of six sites per PfCSP. The mAbs have multiple mechanisms for mediating protection, including inhibition of sporozoite motility and limiting hepatocyte invasion.
The problem solved by this invention is the urgent need for preventive interventions to inhibit malaria infection caused by P. falciparum. Malaria is a deadly infectious disease with no FDA-approved vaccines and increasing resistance to antimalarial drugs. P. falciparum sporozoites invade liver cells via CSP, and neutralizing this protein can prevent infection. The disclosed antibodies offer a solution for passive prevention of malaria, providing high-level sterile protection and broad utility in treatment and diagnosis.
Claims Coverage
There is one independent claim, which relates to an isolated nucleic acid molecule encoding a monoclonal antibody or antigen binding fragment thereof, characterized by specific heavy and light chain complementarity determining regions (CDRs).
Nucleic acid molecule encoding a monoclonal antibody with defined CDR sequences
An isolated nucleic acid molecule encoding a monoclonal antibody or antigen binding fragment comprising a heavy chain variable region (VH) with HCDR1, HCDR2, and HCDR3 as set forth by SEQ ID NOs: 15, 45, 17 and a light chain variable region (VL) with LCDR1, LCDR2, and LCDR3 as set forth by SEQ ID NOs: 18, 46, 20.
Antibody variable regions with high sequence identity to specified VH and VL sequences
The VH and VL comprise amino acid sequences at least 90% identical to SEQ ID NOs: 11 and 12, respectively.
Inclusion of human framework regions in the VH and VL
The VH and/or VL include human framework regions.
Monoclonal antibody comprising human constant domain of IgG isotype with modifications
The monoclonal antibody comprises a human IgG constant domain optionally including recombinant modifications to increase half-life, such as mutations M428L and N434S that increase neonatal Fc receptor binding.
Encoding antigen binding fragments
The nucleic acid molecule can encode antigen binding fragments such as Fv, Fab, F(ab′)2, scFv or scFv2 comprising the VH and VL sequences.
Expression vector and production method
An expression vector including the nucleic acid molecule and a method of producing the antibody by expression in a host cell and purification.
Pharmaceutical composition
A composition comprising an effective amount of the nucleic acid molecule and a pharmaceutically acceptable carrier.
The independent claim covers nucleic acid molecules encoding antibodies or antigen binding fragments with specified CDR sequences of heavy and light chains, including humanized features, constant domain modifications for increased half-life, and their uses in expression vectors, production methods, and pharmaceutical compositions.
Stated Advantages
The disclosed mAbs potently neutralize P. falciparum and confer sterile protection in multiple animal models of malaria infection.
mAb CIS43 exhibits high affinity, sequential, and multivalent binding to a unique junctional epitope, contributing to superior protective efficacy.
Binding of mAb CIS43 interferes with cleavage of PfCSP, limiting hepatocyte invasion by sporozoites.
Combination of antibodies targeting multiple epitopes may provide broader neutralization and enhanced efficacy.
Documented Applications
Passive prevention of P. falciparum infection in subjects at risk, such as travelers, military personnel, and subjects in malaria elimination campaigns.
Use in methods for inhibiting or preventing P. falciparum infection by administering effective amounts of antibodies, antigen binding fragments, or nucleic acid molecules encoding these.
Diagnostics for detecting P. falciparum infection by detecting PfCSP using the disclosed antibodies or antigen binding fragments.
Expression of antibodies in vivo via nucleic acid vectors, including AAV viral vectors, for prophylactic or therapeutic administration.
Testing vaccine compositions containing PfCSP or fragments thereof for binding to disclosed antibodies to confirm presence of relevant epitopes.
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