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-11021535-B2
Publication Date
2021-06-01
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 patent provides monoclonal antibodies and antigen binding fragments that specifically bind to the Plasmodium falciparum circumsporozoite protein (PfCSP) and neutralize P. falciparum. The antibodies, including the CIS43 antibody, confer sterile protection in multiple animal models of malaria infection and inhibit P. falciparum infection in vitro and in vivo. Nucleic acids encoding these antibodies, expression vectors, and host cells comprising these nucleic acids are also disclosed, enabling the production and use of such antibodies.
The problem addressed by the invention stems from malaria being a deadly infectious disease caused by Plasmodium parasites, with P. falciparum responsible for the most severe form and causing about 500,000 deaths annually. Current preventive measures are unavailable as there is no FDA-approved malaria vaccine, and parasites have increased resistance to antimalarial drugs. The major protein on the surface of infecting sporozoites is the circumsporozoite protein (CSP), critical in the infection process through invasion of human hepatocytes. Thus, there is an urgent need for preventive interventions to inhibit malaria infection effectively.
The invention tackles this need by providing antibodies targeting PfCSP, particularly those that bind to a unique junctional epitope between the N-terminal and central repeat domains of PfCSP. The CIS43 antibody binds this junctional epitope with high affinity and prevents cleavage of PfCSP on sporozoites. This binding mechanism contributes to its superior potency and durable protection against malaria by possibly inhibiting sporozoite motility and hepatocyte invasion. The patent also presents detailed structural and biophysical characterizations of these antibodies and describes their use in methods for preventing P. falciparum infection in subjects at risk or infected.
Claims Coverage
The patent includes a set of independent claims focusing on a specific isolated monoclonal antibody and its structural and functional characteristics, along with methods and compositions involving this antibody.
Isolated monoclonal antibody with defined variable region sequences
An isolated monoclonal antibody comprising a heavy chain variable region (VH) with HCDR1, HCDR2, and HCDR3 amino acid sequences corresponding to SEQ ID NOs: 15, 45, and 17 and a light chain variable region (VL) with LCDR1, LCDR2, and LCDR3 amino acid sequences corresponding to SEQ ID NOs: 18, 46, and 20.
VH and VL sequences with high sequence identity to defined amino acid sequences
The VH and VL of the antibody comprise amino acid sequences at least 90% identical to SEQ ID NOs: 11 and 12, respectively.
Antibody comprising human framework and constant regions
The antibody includes human framework regions and human constant domains, specifically IgG isotype, with possible modifications for improved half-life, such as M428L and N434S mutations enhancing binding to the neonatal Fc receptor.
Isolated antigen binding fragments
Antigen binding fragments derived from the monoclonal antibody that comprise the VH and VL, including Fv, Fab, F(ab′)2, scFv, or scFv2 fragments.
Conjugated antibodies
Monoclonal antibodies or antigen binding fragments conjugated to effector molecules or detectable markers for functional or diagnostic uses.
Methods for production, detection, and inhibition of P. falciparum infection
Methods include expressing nucleic acids encoding the antibodies in host cells for production, detecting P. falciparum in biological samples using the antibodies, and inhibiting P. falciparum infection in subjects by administering effective amounts of these antibodies.
The claims cover isolated monoclonal antibodies specific to a uniquely defined set of complementarity determining regions (CDRs), including human framework and constant regions, antigen binding fragments thereof, conjugates, compositions, methods for expression, detection of P. falciparum, and inhibition of P. falciparum infection, highlighting the structural and functional specificity of the antibodies to PfCSP.
Stated Advantages
The antibodies, particularly mAb CIS43, provide high-level, sterile protection against malaria infection in vivo, demonstrating superior potency compared to other antibodies.
The antibodies neutralize P. falciparum by binding a unique junctional epitope on PfCSP and preventing cleavage required for sporozoite invasion of hepatocytes.
Binding to a rare conformation and a specific epitope contributes to durable and potent neutralization.
The antibodies can be used for passive prevention in suitable subjects such as travelers, military personnel, and subjects in elimination campaigns.
Documented Applications
Inhibition and prevention of P. falciparum infection in subjects at risk or infected with malaria.
Passive transfer of antibodies or antigen binding fragments for sterile protection against malaria.
Diagnostic detection of P. falciparum infection in biological samples by binding PfCSP with the antibodies.
Use of nucleic acid molecules and expression vectors to produce antibodies for research, diagnostic, and prophylactic purposes.
Testing vaccines incorporating PfCSP epitopes using the antibodies to confirm vaccine antigen conformation.
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