Antigen binding polypeptides
Inventors
Friedman, Kevin M. • Perkins, Molly R. • Dobson, Connor S. • SAZINSKY, Stephen L. • Contrastano, Shannon G. • Thompson Beura, Emily • Ahonen, Cory • Avery, Andrew
Assignees
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Publication Number
US-12435140-B2
Publication Date
2025-10-07
Expiration Date
Abstract
The present disclosure provides compositions comprising antigen binding polypeptides. More particularly, the disclosure relates to polypeptides comprising antibodies or antigen binding fragments thereof, nucleic acids encoding the polypeptides, and vectors for expressing the same.
Core Innovation
The document describes antibody or antigen binding fragment constructs in which a heavy chain variable region (VH) and a light chain variable region (VL) are defined by specific CDRH1, CDRH2, and CDRH3 amino acid sequences and by specific CDRL1, CDRL2, and CDRL3 amino acid sequences set forth in SEQ ID NOs. The VH and VL are connected by a polypeptide linker, and the construct architecture is further defined by linker sequence selections, variant constraints, and full VH/VL mappings using additional SEQ ID NOs.
The document further provides selectable CAR-related component options, including hinge/spacer domain selections, transmembrane domain selections, and intracellular signaling domain selections. Spacer domains comprise hinge domains selected from CD8α hinge, CD28 hinge, and IgG4 hinge, transmembrane domains are isolated from CD8α and CD28, and intracellular signaling domains include a costimulatory signaling domain and a primary signaling domain isolated from CD35.
The document additionally describes chimeric antigen receptor (CAR) constructs that combine an antibody or antigen binding fragment component with the defined spacer domain, transmembrane domain, one or more intracellular signaling domains, and a primary signaling domain isolated from CD35. It also includes antibody conjugates formed by conjugating an antibody or antigen binding fragment to a cytotoxic agent, together with polynucleotide, promoter, and viral vector architecture features, including lentiviral vector elements and recombinant lentivirus compositions linked to the CAR.
Claims Coverage
The independent claims cover two main inventive features: a sequence-defined antibody or antigen binding fragment with specified VH and VL CDR sets connected by a polypeptide linker, and a CAR comprising a specified antibody or antigen binding fragment sequence together with selected spacer/hinge, transmembrane, costimulatory, and primary signaling domains. Dependent claims further refine linker options, CAR component selections, antibody conjugate cytotoxic agent categories, and CAR-associated polynucleotide, promoter, and viral vector elements.
CDR-defined antibody with polypeptide linker
An antibody or antigen binding fragment comprising a heavy chain variable region (VH) comprising a CDRH1, a CDRH2, and a CDRH3 comprising the amino acid sequences set forth in SEQ ID NOs: 62, 63, and 64; a polypeptide linker; and a light chain variable region (VL) comprising a CDRL1, a CDRL2, and a CDRL3 comprising the amino acid sequences set forth in SEQ ID NOs: 66, 67, and 68.
Car with selected hinge, transmembrane, costimulatory and primary signaling domains
A CAR comprising: (a) an antibody or antigen binding fragment thereof comprising the amino acid sequence set forth in SEQ ID NO: 69 or 70; (b) a spacer domain comprising a hinge domain or fragment thereof selected from the group consisting of a CD8α hinge, a CD28 hinge, and an IgG4 hinge; (c) a transmembrane domain isolated from a polypeptide selected from the group consisting of CD8α and CD28; (d) one or more intracellular signaling domains comprising a costimulatory signaling domain isolated from a polypeptide selected from the group consisting of CD28, CD137 (4-1BB), and CD278 (ICOS); and (e) a primary signaling domain isolated from CD35.
The claim coverage centers on sequence-defined VH/VL CDR architectures connected by a linker, and on CARs that standardize the architecture through selected hinge/spacer, transmembrane, costimulatory signaling, and primary signaling domain sources, together with specified antibody sequence options.
Stated Advantages
Human-derived components are described for CAR designs.
Reduced immunogenicity is stated for the CAR designs.
An improved cytokine profile is stated, with increased IFNγ/IL-2.
Low/absent tonic signaling is stated.
Improved mouse efficacy is stated.
Documented Applications
Anti-BCMA binding polypeptides and related modalities are documented for multiple myeloma.
Bispecific antibody format is documented as anti-BCMA × anti-CD3.
Immunoconjugates are documented as conjugates of anti-BCMA antibodies or antigen binding fragments to cytotoxic agent payload classes.
Anti-BCMA CAR architecture is documented, including CAR constructs with selected spacer/hinge, transmembrane, costimulatory signaling, and primary signaling domains.
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