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-12269882-B1
Publication Date
2025-04-08
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 invention relates to an antibody or antigen binding fragment comprising a heavy chain variable region (VH) with defined CDRH1, CDRH2, and CDRH3 amino acid sequences and a light chain variable region (VL) with defined CDRL1, CDRL2, and CDRL3 amino acid sequences, as set forth in specific SEQ ID NOs. The antibody includes a polypeptide linker connecting the variable regions. The disclosure presents a defined antibody or antigen binding fragment sequence space for engineered immune therapeutics.
In related embodiments, the defined antibody or antigen binding fragment is used as the antigen recognition element of a chimeric antigen receptor (CAR). The CAR includes a spacer domain comprising hinge or fragment choices, a transmembrane domain selected from specified polypeptides, and one or more intracellular signaling domains, including a costimulatory signaling domain and a primary signaling domain isolated from CD36.
The disclosure further provides polynucleotides, vectors, immune effector cell modifications, and pharmaceutical compositions comprising immune effector cells and pharmaceutically acceptable carriers. These embodiments are configured to express anti-BCMA antibody/variant constructs, including bispecific anti-BCMA/anti-CD3 constructs and anti-BCMA CARs.
Claims Coverage
The independent claims cover two linked inventions: an antibody or antigen binding fragment with specified VH and VL CDR sequences, and a CAR construct that incorporates such an antibody or antigen binding fragment into a defined CAR architecture. Across these independent claims, there are four main inventive feature groups: defined VH/VL CDR sequence sets, a polypeptide linker, defined CAR structural selection, and selected signaling domain sources.
Defined VH and VL with specified CDR sequences
An antibody or antigen binding fragment thereof 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: 82, 83, and 84; 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: 86, 87, and 88.
CAR architecture incorporating the defined antibody or antigen binding fragment
A CAR comprising an antibody or antigen binding fragment thereof comprising the amino acid sequence set forth in SEQ ID NO: 89 or 90; a spacer domain comprising a hinge domain or fragment thereof selected from CD8b1 hinge, CD28 hinge, and IgG4 hinge; a transmembrane domain isolated from a polypeptide selected from CD8b1 and CD28; one or more intracellular signaling domains comprising a costimulatory signaling domain isolated from CD28, CD137 (4-1BB), and CD278 (ICOS); and a primary signaling domain isolated from CD3b6.
Across the independent claims, the coverage is centered on defined sequence sets for VH and VL CDR regions and on CAR constructs that place those antigen-binding sequences into a constrained CAR scaffold. The CAR claim fixes the primary signaling domain to CD3b6 while restricting the hinge or fragment thereof, transmembrane domain source, and costimulatory signaling domain sources to enumerated options.
Stated Advantages
Decreased immunogenicity via human-derived components for anti-BCMA CARs.
Improved cytokine profile, including increased IFNb3 and IL-2.
Low/absent tonic signaling.
Increased efficacy in mouse models.
Documented Applications
BCMA-directed therapeutics including bispecific antibodies (anti-BCMA/anti-CD3).
Antibody-drug immunoconjugates with cytotoxic payload classes including toxins, radioisotopes, RNA polymerase II/III inhibitors, and DNA-damaging agents.
anti-BCMA targeting
bispecific anti-BCMA/anti-CD3 constructs
anti-BCMA CARs
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