Antibodies against the MUC1-C/extracellular domain (MUC1-C/ECD)
Inventors
Kufe, Donald W. • Kharbanda, Surender
Assignees
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Publication Number
US-11136410-B2
Publication Date
2021-10-05
Expiration Date
Abstract
The present invention is directed to antibodies binding to MUC1-C/extracellular domain (MUC1-C/ECD) and methods of using such antibodies to treat cancers that express the MUC1 antigen.
Core Innovation
The invention relates to a chimeric antigen receptor (CAR) comprising an ectodomain, a transmembrane domain, and an endodomain in which the ectodomain includes a single chain antibody variable region that binds selectively to MUC1-C/extracellular domain (MUC1-C/ECD) defined by SEQ ID NO: 2. The single chain antibody variable region comprises a variable heavy chain with CDR1, CDR2, and CDR3 regions defined by SEQ ID NOS: 76, 77, and 78, respectively, and a variable light chain with CDR1, CDR2, and CDR3 regions defined by SEQ ID NOS: 79, 80, and 81, respectively, with a flexible hinge attached at the C-terminus of the single chain antibody variable region.
The CAR is configured such that its endodomain comprises a signal transduction function when the single-chain antibody variable region is engaged with MUC1. The described architecture links selective binding to MUC1-C/ECD with an endodomain signaling function through an antibody-based ectodomain, and dependent refinements specify particular endodomain components and domain origins within the CAR structure.
The document also connects MUC1 targeting to antibody-based MUC1 detection and targeted formats, including immunodetection assays and antibody conjugate approaches. MUC1-C/ECD is described as a target relevant to these approaches and to therapeutic actions for conjugate and combination therapy concepts.
Claims Coverage
The independent claim covers a CAR construct with an ectodomain single-chain antibody that selectively binds MUC1-C/ECD defined by SEQ ID-listed CDR regions, where engagement with MUC1 activates a signaling endodomain function. Dependent claims further refine the CAR architecture by constraining transmembrane/endodomain derivation, specifying endodomain components, and specifying the flexible hinge source.
MUC1-C/ECD-selective single-chain ectodomain with SEQ ID-defined CDRs
A CAR comprising an ectodomain including a single chain antibody variable region that binds selectively to MUC1-C/ECD defined by SEQ ID NO: 2, wherein the single chain antibody comprises a variable heavy chain with CDR1, CDR2, CDR3 regions comprising SEQ ID NOS: 76, 77 and 78, respectively, and a variable light chain with CDR1, CDR2 and CDR3 regions comprising SEQ ID NOS: 79, 80 and 81, respectively, with a flexible hinge attached at the C-terminus of the single chain antibody variable region.
Endodomain signal transduction function upon MUC1 engagement
The CAR where the endodomain comprises a signal transduction function when the single-chain antibody variable region is engaged with MUC1.
Transmembrane and endodomain derived from the same molecule
In the CAR, the transmembrane domain and the endodomain are derived from the same molecule.
Endodomain comprises CD3-zeta or high-affinity FcεRI
In the CAR, the endodomain includes either a CD3-zeta domain or a high-affinity FcεRI.
Flexible hinge derived from CD8α or Ig
In the CAR, the flexible hinge is derived from CD8α or Ig.
Overall, the claim set focuses on an MUC1-C/ECD-selective CAR defined by SEQ ID-defined antibody CDR regions, coupled to an endodomain that provides signal transduction upon MUC1 engagement. Dependent claims further restrict CAR construction by specifying endodomain signaling component choices, the derivation source of the transmembrane/endodomain, and the derivation source of the flexible hinge.
Stated Advantages
Documented Applications
Immunodetection assays for MUC1.
Antibody conjugate approaches.
Combination therapy with cancer chemotherapeutic co-agents, including SERMs, DNA-damaging agents, mitotic inhibitors, HSP90 inhibitors, growth-factor/mTOR/EGFR inhibitors, and TNF-α.
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