Anti-BCMA polypeptides and proteins
Inventors
Pastan, Ira H. • Bera, Tapan • Nagata, Satoshi • Ise, Tomoko • Abe, Yasuhiro
Assignees
SANFORD RESEARCH • US Department of Health and Human Services
Publication Number
US-10925969-B2
Publication Date
2021-02-23
Expiration Date
2036-11-10
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Abstract
Polypeptides and proteins that specifically bind to and immunologically recognize B-Cell Maturation Antigen (BCMA) are disclosed. Chimeric antigen receptors (CARs), anti-BCMA binding moieties, nucleic acids, recombinant expression vectors, host cells, populations of cells, pharmaceutical compositions, and conjugates relating to the polypeptides and proteins are also disclosed. Methods of detecting the presence of cancer and methods of treating or preventing cancer are also disclosed.
Core Innovation
The invention provides polypeptides and proteins comprising an antigen binding domain of an anti-B-cell Maturation Antigen (BCMA) antibody, which specifically recognize and bind BCMA with high affinity. The BCMA antigen is expressed or overexpressed in various human cancers, including multiple myeloma and different lymphomas, making it a viable target for cancer diagnosis and therapy.
The inventive polypeptides and proteins include complementarity determining region (CDR) sequences of antibodies BM24 or BM306 and can exist in forms such as single-chain variable fragments (scFv), disulfide-stabilized variable region fragments (dsFv), Fab fragments, or full antibodies. They may be formulated into chimeric antigen receptors (CARs) incorporating antigen binding domains specific to BCMA, linked to transmembrane and intracellular signaling domains to elicit immune responses targeting BCMA-expressing cancer cells.
The invention also encompasses nucleic acids encoding these polypeptides and proteins, recombinant expression vectors, host cells expressing them, conjugates linking the polypeptides or antibodies to effector molecules including toxins like Pseudomonas exotoxin A (PE) variants, and pharmaceutical compositions. Methods are provided for detecting BCMA on cells, as well as treating or preventing cancer by administering these anti-BCMA materials, thereby addressing the unmet need for effective treatments, particularly for multiple myeloma.
Claims Coverage
The claims define eleven main inventive features focused on an anti-BCMA polypeptide, antibodies, chimeric antigen receptors, conjugates, nucleic acids, host cells, and methods of detection and treatment.
Polypeptide comprising an antigen binding domain specific for human BCMA
A polypeptide comprising the heavy chain and light chain complementarity determining regions (CDRs) with sequences of SEQ ID NOs: 7-12, where the antigen binding domain specifically binds human B-cell Maturation Antigen (BCMA).
Antibody or antigen-binding portion specifically binding human BCMA
An antibody or antigen-binding portion comprising heavy chain CDRs (SEQ ID NOs: 7-9) and light chain CDRs (SEQ ID NOs: 10-12) that specifically bind human BCMA. This antibody can be monospecific or bispecific and include Fab, F(ab')2, diabody, triabody, or tetrabody forms.
Chimeric antigen receptor comprising the anti-BCMA polypeptide
A chimeric antigen receptor (CAR) comprising the polypeptide described with BCMA-specific antigen binding domain as in claim 1.
Conjugate of the anti-BCMA antibody or antigen-binding portion fused to an effector molecule
A conjugate including the anti-BCMA antibody or antigen-binding fragment conjugated or fused to an effector molecule such as a drug, toxin (e.g., variants of Pseudomonas exotoxin A), label, small molecule, or another antibody, optionally via a linker.
Nucleic acid encoding the antibody or antigen-binding portion
A nucleic acid encoding the anti-BCMA antibody or antigen-binding fragment comprising the specified heavy and light chain CDR sequences.
Recombinant expression vector comprising the nucleic acid
A recombinant expression vector comprising the nucleic acid encoding the antibody or antigen-binding portion specific for BCMA.
Host cell comprising the recombinant expression vector
A host cell containing the recombinant expression vector encoding the anti-BCMA antibody or antigen-binding fragment.
Population of host cells comprising the recombinant expression vector
A population of at least two host cells each containing the recombinant expression vector encoding the anti-BCMA antibody or antigen-binding fragment.
Pharmaceutical composition comprising the antibody
A pharmaceutical composition containing the anti-BCMA antibody or antigen-binding portion and a pharmaceutically acceptable carrier.
Method of detecting BCMA on cells using the polypeptide
A method for detecting BCMA presence on cells from a human by contacting cells with the polypeptide containing the BCMA-specific antigen binding domain and detecting the formed complex.
Method of treating BCMA positive cancer using the conjugate
A method of treating BCMA positive cancer in a mammal by administering an effective amount of the conjugate (antibody or antigen-binding fragment conjugated to a toxin) that binds specifically to BCMA expressed by cancer cells.
The claims collectively cover anti-BCMA polypeptides and antibodies with defined CDR sequences and specific binding to BCMA, CAR constructs incorporating these domains, conjugates with effector molecules mainly toxins, nucleic acids and vectors encoding them, host cells expressing these constructs, pharmaceutical compositions, and methods for detecting BCMA or treating BCMA-expressing cancers such as multiple myeloma and various lymphomas.
Stated Advantages
Specifically recognize and bind BCMA with high affinity and specificity.
Target BCMA-expressing cancer cells to detect, treat, or prevent cancer, particularly multiple myeloma.
Enable antigen-specific immune response through CARs that redirect T-cell specificity.
Provide therapeutic conjugates combining anti-BCMA binding moieties with cytotoxic or detectable effector molecules.
Facilitate in vivo and in vitro detection of BCMA for diagnostic purposes.
Documented Applications
Detection of BCMA expression on cells from mammals, including humans, particularly for cancer diagnosis.
Treatment or prevention of cancers characterized by BCMA expression or overexpression such as Burkitt's lymphoma, diffuse large B-cell lymphoma (DLBCL), acute lymphocytic leukemia (ALL), Hodgkin's lymphoma, and multiple myeloma.
Use in pharmaceutical compositions for administration to mammals, including humans, to treat or prevent BCMA positive cancers.
Use of recombinant host cells, including T cells expressing anti-BCMA CARs, for adoptive cell therapy against BCMA-expressing tumors.
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