Antibodies against the MUC1-C/extracellular domain (MUC1-C/ECD)
Inventors
Kufe, Donald W. • Kharbanda, Surender
Assignees
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Publication Number
US-10059775-B2
Publication Date
2018-08-28
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 antibodies that bind selectively to the MUC1-C extracellular domain (MUC1-C/ECD) defined by SEQ ID NO:2. In representative embodiments, the antibody comprises a heavy chain variable region with CDR1, CDR2 and CDR3 regions having SEQ ID NOS:76, 77 and 78, and a light chain variable region with CDR1, CDR2 and CDR3 regions having SEQ ID NOS:79, 80 and 81, respectively.
The disclosure further constrains the antibody by specifying homology thresholds for the heavy and light chain variable regions, including protein CDR/variable-region homology and nucleic-acid encoding homology between the provided sequences and defined SEQ ID NO sets. The antibody formats include IgG and antibody variants such as single-chain, chimeric, and Fab formats, and optional labeling.
The disclosure also includes antibody conjugates including drug conjugates, with attachment via photolabile linker or enzymatically cleaved linker, and conjugation to nanoparticles or liposomes. In addition, the invention includes fusion proteins combining a first single-chain antibody that binds selectively to the MUC1-C/ECD defined by SEQ ID NO:2 with a second single-chain antibody that binds to a T cell or a B cell.
The second binding specificity is exemplified by CD3 or B cell targeting, and the disclosure also includes chimeric antigen receptors (CARs) comprising an ectodomain with the MUC1-C binder and a hinge, transmembrane domain and endodomain such as CD3-zeta or FcεRI, and cells expressing the CAR. The document also describes therapeutic use of the MUC1-C/ECD-binding antibodies for treating MUC1-positive cancers by inhibiting growth and inducing cell death.
Claims Coverage
The claim coverage identifies two independent claims. The core inventive elements are a MUC1-C/ECD-selective antibody defined by specific heavy- and light-chain CDR sequence identifiers and a fusion protein that combines this binder with a second single-chain antibody for T-cell or B-cell binding.
Selective MUC1-C/ECD antibody defined by SEQ ID NO:2 and specific CDR sequences
An antibody binds selectively to MUC1-C extracellular domain (MUC1-C/ECD) defined by SEQ ID NO:2, with a heavy-chain variable region containing CDR1, CDR2 and CDR3 regions having SEQ ID NOS:76, 77 and 78, and a light-chain variable region containing CDR1, CDR2 and CDR3 regions having SEQ ID NOS:79, 80 and 81, respectively.
Fusion protein with MUC1-C/ECD binder single-chain antibody and second T- or B-cell binder
A fusion protein comprising a first single-chain antibody that binds selectively to MUC1-C/ECD defined by SEQ ID NO:2 with heavy- and light-chain CDR regions having SEQ ID NOS:76, 77, 78 and 79, 80, 81, respectively, and a second single-chain antibody that binds to a T or B cell.
Overall, the claim coverage centers on antibodies that selectively bind MUC1-C/ECD defined by SEQ ID NO:2 through specific heavy- and light-chain CDR sequence identifiers, and on fusion protein constructs that combine this MUC1-C/ECD binder with an additional single-chain antibody targeting T or B cells.
Stated Advantages
Inhibiting growth in MUC1-positive cancers.
Inducing cell death in MUC1-positive cancers.
Documented Applications
Therapeutic treatment of MUC1-positive cancers using MUC1-C/ECD-binding antibodies that inhibit growth and induce cell death.
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