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-10501534-B2
Publication Date
2019-12-10
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
This disclosure provides antibodies that are useful for preventing and/or treating malaria by binding to an epitope located in close proximity to the conserved proteolytic cleavage site of Plasmodium falciparum circumsporozoite protein (CSP). The antibodies can prevent cleavage of CSP and inhibit P. falciparum sporozoites from invading the liver. Because the protease cleavage site is highly conserved among P. falciparum isotypes and other Plasmodium species infecting humans, these antibodies can reduce or prevent infection by various Plasmodium species.
Malaria is an infectious disease transmitted by infected Anopheles mosquitoes, caused by several Plasmodium species including P. falciparum. CSP is the major surface protein on sporozoites, containing an N-terminal domain with a conserved five amino acid proteolytic cleavage site (KLKQP), a repeat region, and other conserved sequences. Proteolytic processing of CSP occurs during hepatocyte invasion, removing the amino-terminal third of CSP. The invention addresses inhibiting this specific cleavage essential for sporozoite invasion of the liver.
The antibodies described, including monoclonal antibody 5D5, specifically bind an epitope near the cleavage site, thereby preventing the proteolytic processing of CSP. This prevents sporozoite invasion of liver cells and provides a therapeutic or prophylactic means to combat malaria. The invention further discloses compositions comprising such antibodies, methods of antibody production, and their pharmaceutical administration to treat or prevent malaria infection, including use in conjunction with vaccines or other anti-malarial drugs.
Claims Coverage
The patent includes multiple independent claims directed to methods of producing heavy and light chains of an antibody possessing specific complementarity determining regions (CDRs) derived from a monoclonal antibody deposited under Accession No. MRA-1242. The inventive features focus on the sequences of these CDRs and the constructs used for expression in host cells.
Heavy chain variable region comprising defined CDR sequences
The method comprises growing a host cell containing a gene expression construct encoding a heavy chain of an antibody, wherein the variable region of the heavy chain includes three specific complementarity determining regions (CDRH1: SEQ ID NO:1, CDRH2: SEQ ID NO:2, CDRH3: SEQ ID NO:3) or the CDRs of the heavy chain variable region of the antibody deposited under Accession No. MRA-1242.
Light chain variable region comprising defined CDR sequences
The method comprises growing a host cell containing a gene expression construct encoding a light chain of an antibody, wherein the variable region of the light chain includes three specific complementarity determining regions (CDRL1: SEQ ID NO:4, CDRL2: SEQ ID NO:5, CDRL3: SEQ ID NO:6) or the CDRs of the light chain variable region of the antibody deposited under Accession No. MRA-1242.
Co-expression of heavy and light chains with defined CDRs in host cells
The method involves growing a host cell comprising gene expression constructs encoding both the heavy chain and the light chain of the antibody, each comprising the defined CDRs as described above, to produce the antibody.
Humanization of framework regions
The method optionally includes humanizing the framework regions of the heavy and/or light chains to comprise human framework sequences in order to reduce antigenicity when administered to humans.
The independent claims cover methods for producing the heavy and light chains of an antibody characterized by specific CDR sequences from the monoclonal antibody 5D5, including co-expression in host cells and humanization of framework regions to produce therapeutic antibodies targeting malaria.
Stated Advantages
The antibodies can prevent cleavage of CSP and inhibit Plasmodium sporozoites from invading the liver, thereby reducing or preventing infection.
The conserved nature of the proteolytic cleavage site among Plasmodium species allows broad applicability of the antibodies against multiple species causing malaria in humans.
Antibodies can be administered prophylactically to malaria-naïve individuals or therapeutically in conjunction with vaccines or anti-malarial drugs, providing flexible treatment options.
Documented Applications
Prophylactic administration to prevent or reduce Plasmodium sporozoite liver invasion in individuals entering endemic malaria regions.
Therapeutic treatment of malaria infections by administering antibodies alone or in combination with known anti-malarial drugs like atovaquone and proguanil, chloroquine, doxycycline, mefloquine, or primaquine.
Combination with traditional malaria vaccines either sequentially or in compositions that raise immune responses against Plasmodium.
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