Anti-malarial compositions
Inventors
Gutierrez, Gabriel M. • Pannucci, James • Noe, Amy • Huang, Steve Chienwen • Winram, Scott • Mo, Annie Xiaoyan
Assignees
Leidos Inc • US Department of Health and Human Services
Publication Number
US-9321834-B2
Publication Date
2016-04-26
Expiration Date
2033-12-05
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Abstract
This disclosure provides antibodies that are useful for preventing and/or treating malaria. The epitope to which the antibodies bind is in close proximity to the conserved proteolytic cleavage site of P. falciparum circumsporozoite protein (CSP), and the antibodies provided in this disclosure can prevent cleavage and inhibit P. falciparum sporozoites from invading the liver.
Core Innovation
The invention provides antibodies that bind to an epitope in close proximity to the conserved proteolytic cleavage site of Plasmodium falciparum circumsporozoite protein (CSP). These antibodies can prevent cleavage of CSP and inhibit invasion of the liver by P. falciparum sporozoites, thus useful for preventing and treating malaria infection. The core epitope recognized is near the protease cleavage site, a highly conserved sequence among P. falciparum isotypes and other Plasmodium species that infect humans.
The problem addressed is that during infection, the CSP on the sporozoite surface is proteolytically processed at a conserved cleavage site, which is a critical step during invasion of hepatocytes. This protease cleavage allows the parasite to invade the liver. There was a need for compositions that can prevent this cleavage and thus block sporozoite invasion to reduce or prevent malaria infection.
The invention outlines the identification and characterization of a monoclonal antibody, mAb 5D5, which uniquely binds the N-terminal region of CSP near the conserved cleavage site. Binding of these antibodies prevents the proteolytic processing of CSP and subsequently inhibits liver invasion by Plasmodium sporozoites. The antibodies can be engineered in various forms, including humanized antibodies and antigen-binding fragments, and formulated into pharmaceutical compositions for prophylactic or therapeutic use against malaria.
Claims Coverage
The claims include one independent antibody claim and several method and composition claims centered on this antibody and its use. Five main inventive features are identified regarding the antibody's structure, formats, pharmaceutical compositions, and therapeutic applications.
Isolated antibody comprising specific heavy and light chain CDR sequences
An isolated antibody comprising an immunoglobulin heavy chain variable region with specific CDRH1, CDRH2, and CDRH3 amino acid sequences (SEQ ID NO:1, NO:2, NO:3) and an immunoglobulin light chain variable region with defined CDRL1, CDRL2, and CDRL3 amino acid sequences (SEQ ID NO:4, NO:5, NO:6), or comprising the CDRs of the deposited antibody under Accession No. MRA-1242.
Antibody provided in single-chain variable fragment (scFv) format
The isolated antibody may be provided as an scFv antibody format containing the specified CDRs or those of the deposited antibody.
Pharmaceutical composition comprising the antibody and a pharmaceutically acceptable carrier
A pharmaceutical composition comprising the isolated antibody with specific CDR sequences or deposited antibody, formulated with a pharmaceutically acceptable carrier suitable for administration.
Method of protecting against Plasmodium infection by administering the antibody
A method of prophylactically protecting an individual against malaria by administering an effective amount of the pharmaceutical composition containing the antibody, optionally in conjunction with administration of a malarial antigen.
Method of treating malaria by administering the antibody
A method of treating malaria in an infected individual by administering an effective amount of the pharmaceutical composition containing the antibody, optionally in conjunction with administration of one or more anti-malarial drugs.
The claims cover an isolated antibody with defined CDR sequences binding near the CSP cleavage site, its scFv versions, pharmaceutical compositions containing the antibody, and methods of prevention and treatment of malaria using these compositions, optionally combined with vaccines or anti-malarial drugs.
Stated Advantages
The antibodies can prevent cleavage of CSP and inhibit Plasmodium sporozoite liver invasion, thereby reducing or preventing malaria infection.
The epitope is highly conserved among Plasmodium species infecting humans, enabling broad applicability of the antibodies.
The antibodies can be engineered into various forms including humanized versions and antigen-binding fragments, improving therapeutic potential and reducing antigenicity.
Pharmaceutical compositions can be administered prophylactically to naive individuals or therapeutically to infected individuals, alone or in combination with conventional vaccines or anti-malarial drugs.
Documented Applications
Use of antibodies targeting the CSP cleavage site to prevent or reduce malaria infection by inhibiting sporozoite invasion of the liver.
Prophylactic administration of antibody compositions to malaria-naïve individuals such as military personnel, state-department personnel, and travelers entering endemic regions.
Therapeutic administration of antibody compositions to individuals already infected with Plasmodium species, alone or in combination with anti-malarial drugs including atovaquone, proguanil, chloroquine, doxycycline, mefloquine, and primaquine.
Use of the antibody compositions in conjunction with malarial antigen vaccines to enhance protection against malaria.
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