Chimeric antigen receptors specific for B-cell maturation antigen and encoding polynucleotides
Inventors
SATHER, Blythe D. • Smith, Eric L. • Amin, Rupesh • CHEN, AYE • HARRINGTON, KIMBERLY • HAUSKINS, Collin • HESS, ERIK • De Imus, Cyr • Jones, Jon • OLSHEFSKY, AUDREY • PONKO, STEFAN • SALMON, Ruth • Tareen, Semih • WU, REBECCA • Chen, Yan • Shamah, Steven M. • Pazmany, Csaba • DUTTA-SIMMONS, Jui • STIRNER, MARIANA COTA • WORKS, Melissa
Assignees
Memorial Sloan Kettering Cancer Center • Juno Therapeutics Inc
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Publication Number
US-12428486-B2
Publication Date
2025-09-30
Expiration Date
Abstract
Provided herein are chimeric receptors, including chimeric antigen receptors (CARs), comprising BCMA-binding molecules, including anti-BCMA antibodies and antigen-binding fragments thereof, including heavy chain variable (VH) regions and single-chain antibody fragments, and encoding polynucleotides. In some embodiments, the anti-BCMA chimeric receptors specifically bind to BCMA. Among the anti-BCMA-binding molecules are human antibodies, including those that compete for binding to BCMA with reference antibodies, including a non-human reference antibody. Also provided are genetically engineered cells expressing the CARs and uses thereof including in adoptive cell therapy.
Core Innovation
The disclosed subject matter provides chimeric antigen receptor constructs that specifically bind B cell maturation antigen (BCMA). The extracellular antigen-binding domain comprises a variable heavy chain (V_H) region and a variable light chain (V_L) region, with CDR-H1, CDR-H2, CDR-H3 and CDR-L1, CDR-L2, CDR-L3 amino acid sequences set forth in specified SEQ ID NOS, including additional alternative specified CDR sequence sets.
The CAR architecture places a spacer between the extracellular antigen-binding domain and a transmembrane domain. The spacer comprises a hinge region, a C_H2 region and a C_H3 region of an immunoglobulin constant region, including IgG4-derived hinge and modified IgG4 hinge options, and in particular embodiments the spacer sequence is set forth in SEQ ID NO:649.
The transmembrane domain follows the spacer and the intracellular signaling region is positioned downstream of the transmembrane domain. The intracellular signaling region is described as an activating cytoplasmic signaling domain containing an immunoreceptor tyrosine-based activation motif (ITAM), and in further embodiments comprises a cytoplasmic signaling domain of a CD3ζ chain together with an intracellular signaling domain of a 4-1BB.
Claims Coverage
Two independent claims are identified. Across the claims, the inventive subject matter centers on a BCMA-binding chimeric antigen receptor with specified extracellular V_H/V_L CDR sequences, a spacer positioned between the extracellular antigen-binding domain and the transmembrane domain, and defined intracellular signaling and transmembrane domain configurations.
BCMA-binding extracellular domain with specified V_H/V_L CDR sets
An extracellular antigen-binding domain that specifically binds BCMA, wherein the extracellular antigen-binding domain comprises a variable heavy chain (V_H) region and a variable light chain (V_L) region with CDR-H1, CDR-H2, CDR-H3 and CDR-L1, CDR-L2, CDR-L3 amino acid sequences set forth in specified SEQ ID NOS, together with additional alternative specified CDR sequence sets.
Spacer positioned between extracellular domain and transmembrane domain
A spacer comprising a sequence of a hinge region, a C_H2 region and a C_H3 region of an immunoglobulin constant region, located between the extracellular antigen-binding domain and the transmembrane domain, including an embodiment where the spacer comprises the sequence set forth in SEQ ID NO:649.
Transmembrane domain and intracellular signaling region architecture
A transmembrane domain downstream of the spacer and an intracellular signaling region downstream of the transmembrane domain, including an activating cytoplasmic signaling domain containing an immunoreceptor tyrosine-based activation motif (ITAM), and in another embodiment a cytoplasmic signaling domain of a CD3ζ chain and an intracellular signaling domain of a 4-1BB, with the transmembrane domain specified as from human CD28.
The independent claims share a BCMA-binding requirement defined by specified V_H/V_L CDR sequences and a spacer located between the extracellular antigen-binding domain and the transmembrane domain. The claims further include defined intracellular signaling elements, with one embodiment specifying a human CD28 transmembrane domain and CD3ζ plus 4-1BB signaling.
Stated Advantages
Reduced mRNA/RNA heterogeneity via codon optimization and splice donor/acceptor site modification (splice site elimination; O/SSE).
Improved consistency of CAR expression.
Reduced tonic signaling.
RNA homogeneity is improved to at least 70%–95%.
Counteracts adenosine-mediated immunosuppression, including reduction of A2-adenosinergic T cell immunosuppression.
Reduces hypoxia-driven A2-adenosinergic T cell immunosuppression via hypoxia/HIF-1α pathway inhibitors.
Documented Applications
Treatment of BCMA-associated cancers, including multiple myeloma, as described in the provided summary context.
Combinatorial therapies with BCMA-binding CAR-expressing cells.
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