Antibodies to coagulation factor XIa and uses thereof
Inventors
Mikita, Thomas • Ely, Lauren K. • GAO, Huilan • Kim, Yun • Rondon, Isaac J. • DAVID, Tovo • Coughlin, Shaun R.
Assignees
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Publication Number
US-11066481-B2
Publication Date
2021-07-20
Expiration Date
Abstract
In one aspect, antibodies, or antigen-binding fragments thereof, that specifically bind to activated Factor XI (FXIa) are provided. Also provided are methods of obtaining such antibodies and nucleic acids encoding the same. In another aspect, compositions and therapeutic prevention of thrombotic diseases, disorders or conditions are provided. In another aspect, anti-idiotype antibodies that bind anti-FXIa antibodies of the disclosure, as well as compositions comprising the anti-idiotype antibodies, methods of obtaining the antibodies and nucleic acids encoding the same, are also provided.
Core Innovation
The disclosure relates to isolated monoclonal antibodies, or antigen-binding portions thereof, that specifically bind the Factor XIa catalytic domain. The antibody comprises HCDR1-3 and LCDR1-3 comprising amino acid sequences defined by SEQ ID NO combinations, with binding directed to the catalytic domain of FXIa and, in narrower embodiments, to the catalytic domain active site.
The invention further includes anti-idiotype antibodies that reverse anti-FXIa effects and anti-FXIa anticoagulant effects. It also describes affinity maturation and selection concepts, including library scanning mutagenesis and subsequent affinity measurement, to obtain FXIa-selective clones and optimize antibody properties.
Broad antibody engineering and modification options are described, including humanization and chimeric and fully human/transgenic formats, together with constant-region and glycosylation-related variations, Fc/FcRn variants, and framework modifications. The disclosure further encompasses development and encoding of antibody polynucleotides, vectors, and host cells, as well as therapeutic and diagnostic use concepts and functional evaluation of anti-FXIa activity.
Claims Coverage
The independent claims are directed to isolated monoclonal antibodies, or antigen-binding portions thereof, that specifically bind the Factor XIa catalytic domain using defined HCDR1-3 and LCDR1-3 amino acid sequence sets. Across the independent-claim scope, the recurring inventive features are catalytic-domain targeting and sequence-defined CDR composition for binding specificity, with additional narrowing to active-site binding and antibody format and composition language.
Factor XIa catalytic domain binding with defined HCDR1-3 and LCDR1-3 sequences
An isolated monoclonal antibody, or an antigen-binding portion thereof, that specifically binds the Factor XIa catalytic domain, wherein the antibody or antigen-binding portion comprises HCDR1-3 and LCDR1-3 comprising the amino acid sequences of the stated SEQ ID NO combinations.
Factor XIa catalytic domain active site binding and antibody format constraints
Dependent claims further narrow the binding epitope to the Factor XIa catalytic domain active site, add specific VH/VL sequence pairing constraints, specify antibody engineering categories including chimeric, humanized, or human, constrain constant-domain definitions including a human IgG1 heavy chain constant region, and include pharmaceutical composition coverage with a pharmaceutically acceptable excipient.
Overall, the claims cover sequence-defined monoclonal antibodies that specifically bind the Factor XIa catalytic domain via defined HCDR1-3 and LCDR1-3 sets, with additional limitations that expand the CDR sequence alternatives and further define antibody formats and pharmaceutical composition inclusion.
Stated Advantages
Prolong APTT without significantly increasing PT.
Reversal of anti-FXIa anticoagulant effects using anti-idiotype antibodies.
Enhanced FXIa dissociation under serine-protease inhibition or after active-site-serine modification.
Documented Applications
Therapeutic and diagnostic use concepts.
Intrinsic-pathway inhibition and clotting-time modulation via APTT.
Reversal of anti-FXIa anticoagulant effects using anti-idiotype antibodies.
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