Multispecific heavy chain antibodies with modified heavy chain constant regions
Inventors
Harris, Katherine • Schellenberger, Ute • Vafa, Omid • Trinklein, Nathan • van Schooten, Wim • Force Aldred, Shelley • Pham, Duy • Clarke, Starlynn
Assignees
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Publication Number
US-11186639-B2
Publication Date
2021-11-30
Expiration Date
Abstract
Multispecific, human heavy chain antibodies (e.g., UniAbs™) that have modified heavy chain constant regions that impart advantageous properties are provided. The invention further concerns methods of making such antibodies, compositions, including pharmaceutical compositions, comprising such antibodies, and their use to treat disorders that are characterized by expression of one or more of the binding targets described herein.
Core Innovation
The invention relates to bispecific monoclonal antibodies that bind to human CD3 and human BCMA using defined polypeptide subunits specified by SEQ ID NOs. The antibody architecture includes a first binding moiety formed by a first polypeptide subunit comprising the amino acid sequence of SEQ ID NO: 49 together with a second polypeptide subunit comprising the amino acid sequence of SEQ ID NO: 56 or SEQ ID NO: 75, where the combined subunits bind to human CD3.
A third polypeptide subunit comprising the amino acid sequence of SEQ ID NO: 58 or SEQ ID NO: 76 binds to human BCMA, and the BCMA-binding element is described as a bivalent heavy-chain element. The described human monoclonal IgG4 bispecific antibody comprises a first binding arm that binds human CD3 and a second binding arm that binds human BCMA, with the second binding arm comprising a bivalent second heavy chain. Structural refinements include omission of the CH1 domain, omission of a light chain, and inclusion of a heavy-chain-only variable region arranged in a bivalent configuration.
The patent also relates to multispecific human heavy-chain antibodies, including UniAbs™/three-chain antibody-like molecule formats, engineered with modified human IgG4 Fc constant regions. The modified Fc constant regions include knob and hole Fc mutations to promote correct heavy-chain heterodimerization while reducing effector functions, including reducing CDC and ADCC, and supporting prevention of Fab arm exchange.
Claims Coverage
The independent claims cover CD3/BCMA bispecific monoclonal antibodies in three sequence-defined formats, with specified polypeptide subunits and/or specified heavy- and light-chain amino acid sequences. The main inventive features are the CD3-binding moiety, the BCMA-binding subunit or arm, and the bivalent heavy-chain IgG4 architecture for the BCMA arm.
CD3-binding moiety and BCMA-binding third subunit using specified sequences
A bispecific monoclonal antibody that binds to human CD3 and human BCMA, comprising a first polypeptide subunit comprising the amino acid sequence of SEQ ID NO: 49, a second polypeptide subunit comprising the amino acid sequence of SEQ ID NO: 56 or SEQ ID NO: 75, wherein the first and second polypeptide subunits together form a first binding moiety that binds to human CD3, and a third polypeptide subunit comprising the amino acid sequence of SEQ ID NO: 58 or SEQ ID NO: 76 that binds to human BCMA.
Human monoclonal IgG4 bispecific with CD3 arm defined by heavy and light chains and BCMA arm defined as a bivalent second heavy chain
A human monoclonal IgG4 bispecific antibody comprising a first binding arm that binds to human CD3 and a second binding arm that binds to human BCMA, wherein the first binding arm comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 56 or SEQ ID NO: 75 and a light chain comprising the amino acid sequence of SEQ ID NO: 49, and wherein the second binding arm comprises a bivalent second heavy chain comprising the amino acid sequence of SEQ ID NO: 58 or SEQ ID NO: 76.
Overall, the claim set defines human CD3/BCMA bispecific monoclonal antibodies with sequence-defined CD3-binding subunits and a BCMA-binding bivalent heavy-chain element. Dependent claims further address IgG4 architecture and structural constraints including omission of the CH1 domain, omission of a light chain, and heavy-chain-only variable region arrangement.
Stated Advantages
Reducing effector functions, including reducing CDC and ADCC.
Minimizing IgG4 Fab exchange.
Minimizing heavy-chain exchange.
Promoting correct heavy-chain heterodimerization.
Reduced effector function.
Reduced Fab arm exchange.
Proper heterodimer formation.
Documented Applications
Therapeutic use for BCMA-expressing diseases, including multiple myeloma.
Therapeutic use for PSMA-expressing diseases, including prostate cancer.
Therapeutic use for CD19-expressing disorders, including DLBCL and acute lymphoblastic leukemia, and autoimmune disorders including systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis.
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