TACI binding molecules
Inventors
Belk, Jonathan • BOLOTIN, Eugene • Chivukula, Raghavender • Drever, Matthew • Liao, Edward Hai Dhow
Assignees
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Publication Number
US-12337035-B2
Publication Date
2025-06-24
Expiration Date
Abstract
Provided are antibodies, fragments thereof, chimeric antigen receptors (CARs) and T cell receptors (TCRs) comprising one or more of the dual TACI-BCMA binding domains disclosed herein. Provided are compositions, cells and cell therapies comprising the same. Further provided are methods of treatment.
Core Innovation
The invention relates to an antibody, or antigen binding fragment thereof, having specificity to TACI and BCMA. The antibody or antigen binding fragment comprises a heavy chain variable domain (VH) comprising heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3, and a light chain variable domain (VL) comprising light chain complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 comprise amino acid sequences defined by specific SEQ ID NOs.
In described embodiments, the binding domains are provided in antibody or antigen binding fragment formats, including an scFv. The invention further enables the use of the TACI-BCMA binding domain in chimeric antigen receptors and T cell receptors, and includes nucleic acids encoding the antibody or antigen binding fragment into recombinant vectors and configurations suitable for immune-cell expression.
The disclosure also describes engineered immune-cell constructs using transformed host cells including iPSC, T cells, and NK cells. Further engineering features include linkage of the immune-cell construct to a dominant negative TGFβ receptor and/or a membrane bound IL-15/IL-15Rα sushi domain chimeric receptor. The description includes expression in T cells or NK cells to counter TGF-β-mediated suppression and support anti-tumor activity.
Claims Coverage
The provided material covers one independent inventive concept: a dual-specificity antibody or antigen binding fragment to TACI and BCMA defined by VH and VL CDR sequences comprising specific SEQ ID NOs. The broader coverage extends to antibody formats, nucleic acid and recombinant vector constructs, and immune-cell CAR or TCR implementations including engineered receptor features.
Dual TACI-BCMA specificity defined by VH and VL CDR SEQ IDs
An antibody, or antigen binding fragment thereof, having specificity to TACI and BCMA, comprising a VH with HCDR1, HCDR2 and HCDR3 and a VL with LCDR1, LCDR2 and LCDR3, wherein the CDRs comprise the amino acid sequences of specified SEQ ID NO sets.
Single-polypeptide containing HCDRs and LCDRs
A structure in which the three HCDRs and the three LCDRs are all contained within a single polypeptide.
scFv format with selected amino acid sequence
An scFv in which the amino acid sequence is selected from SEQ ID NO:23, 47, 71, 95, 119, 143, 167, 191, or 215.
Chimeric antigen receptor incorporating the antibody binding region
A chimeric antigen receptor that includes the antibody or antigen-binding fragment thereof.
CAR signaling and co-stimulatory component options
A chimeric antigen receptor further including a specified 4-1BB/CD137 transmembrane domain and one or more of various T-cell receptor or co-receptor/costimulatory or activation-related chains or markers.
Dominant-negative TGF-beta receptor co-expression with TACI/BCMA therapies
A therapy concept that proposes co-expression of dominant-negative TGF-beta receptors, including DN TGF-betaRI and DN TGF-betaRII, with dual TACI-BCMA CAR/TCR therapies.
The claims coverage centers on dual TACI/BCMA antibodies whose VH and VL CDRs are defined by specific SEQ ID amino acid sequences, and extends to defined antibody formats including scFv and single-polypeptide organization. The coverage further includes use of the binding region in chimeric antigen receptors with activation and co-stimulation components, and co-expression of dominant-negative TGF-beta receptors in the tumor microenvironment.
Stated Advantages
Restores and/or enhances anti-tumor CAR activity under TGF-β-mediated suppression.
Documented Applications
Treating a cancer patient by administering the T cell and/or NK cell to a patient whose cancer cells express TACI or BCMA.
Treating multiple myeloma using immune-cell constructs incorporating the TACI-BCMA binding domain.
Co-expressing dominant-negative TGF-β receptors with dual TACI-BCMA binding CARs in T cells or NK cells to counter TGF-β-mediated suppression and support anti-tumor CAR activity.
Immunization or inducing immune response approaches described in connection with the disclosed constructs.
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