Anti-mesothelin polypeptides and proteins
Inventors
Pastan, Ira H. • Onda, Masanori • Bera, Tapan • Ho, Mitchell
Assignees
US Department of Health and Human Services
Publication Number
US-11390683-B2
Publication Date
2022-07-19
Expiration Date
2038-05-17
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Abstract
Polypeptides and proteins that specifically bind to and immunologically recognize human mesothelin582-598 (IP-NGYLVLDLSMQEALS) (SEQ ID NO: 1) are disclosed. Anti-mesothelin binding moieties, nucleic acids, recombinant expression vectors, host cells, populations of cells, pharmaceutical compositions, and conjugates relating to the polypeptides and proteins are disclosed. Methods of reducing mesothelin shed from cell membranes, methods of reducing the activity of TNFα converting enzyme, methods of detecting the presence of cancer, and methods of treating or preventing cancer are also disclosed.
Core Innovation
The invention provides polypeptides and proteins that specifically recognize and bind to a defined human mesothelin sequence 582-598 (IPNGYLVLDLSMQEALS) (SEQ ID NO: 1). These polypeptides comprise antigen binding domains of anti-mesothelin antibodies with specific complementarity determining regions (CDRs). The proteins may include various combinations of these CDRs and their respective framework regions, and can exist as fusion proteins or conjugates with effector molecules.
The problem addressed by the invention arises from the constant shedding of mesothelin from cells via TNFα converting enzyme (TACE), leaving only short fragments on the cell surface. Prior antibodies that bind to shed mesothelin may dissociate quickly and have reduced efficacy. The invention seeks to provide polypeptides and proteins that bind the membrane-proximal region of mesothelin (residues 582-598), remaining associated with cancer cells longer and reducing mesothelin shedding and TACE activity.
By specifically targeting the mesothelin582-598 sequence, the polypeptides and proteins can enable detection of mesothelin-expressing cancer cells, enhance targeting and destruction of these cells, and reduce or prevent mesothelin shedding and TACE activity. The inventive materials include nucleic acids, recombinant vectors, host cells, conjugates, and pharmaceutical compositions that can be used for treating or preventing cancer characterized by mesothelin expression or overexpression.
Claims Coverage
The patent claims one independent claim directed to a polypeptide comprising antigen binding domains with specific CDRs binding to a defined mesothelin sequence, and derivative claims covering conjugates, nucleic acids, recombinant vectors, host cells, methods of detection, and treatment of cancer.
Polypeptide antigen binding domain specifically recognizing human mesothelin582-598
A polypeptide comprising an antigen binding domain of an antibody with heavy and light chain CDR amino acid sequences selected from three defined sets (SEQ ID NOs: 2-7, 8-13, 14-19), wherein the antigen binding domain comprises a heavy chain variable region and a light chain variable region, and specifically binds human mesothelin sequence 582-598 (IPNGYLVLDLSMQEALS) (SEQ ID NO: 1).
Polypeptides comprising full variable regions of specific antibodies
The antigen binding domain can comprise amino acid sequences of variable regions from antibodies 2B4 (SEQ ID NOs: 20 and 21), 7B5 (SEQ ID NOs: 22 and 23), or 15B6 (SEQ ID NOs: 24 and 25).
Conjugates with effector molecules
Conjugates comprising the above polypeptides conjugated or fused to an effector molecule, which may be a drug, toxin (including Pseudomonas exotoxin A or variants), label, small molecule, or antibody.
Pharmaceutical compositions and kits
Pharmaceutical compositions comprising the polypeptides and kits for treating cancer comprising the polypeptides.
Nucleic acids and recombinant expression vectors
Nucleic acids encoding the polypeptides, recombinant expression vectors comprising such nucleic acids, isolated host cells containing these vectors, and populations of such host cells.
Method of detecting cancer
A method of detecting the presence of cancer in a mammal by contacting a sample with the polypeptides and detecting the formed complex, wherein detection indicates presence of cancer.
Method of treating cancer
A method of treating cancer in a mammal by administering an effective amount of the polypeptide to treat cancer.
Antibodies or antigen binding portions with specific CDR sequences
An antibody or antigen binding portion comprising heavy and light chain CDR sequences as in the polypeptide claim, specifically binding human mesothelin582-598, including Fab fragments, F(ab′)2 fragments, diabodies, and bispecific antibodies.
The claims cover polypeptides comprising defined antigen binding CDRs that specifically bind human mesothelin582-598, their conjugates with effector molecules, nucleic acids, recombinant vectors, host cells, methods for cancer detection and treatment, and antibodies or fragments with specific CDR sequences recognizing the target mesothelin region.
Stated Advantages
Specifically recognize and bind to membrane-proximal mesothelin region, enabling stronger and longer association with cancer cells.
Reduce shedding of mesothelin from cell membranes, potentially preserving antibody effector functions.
Reduce activity of TNFα converting enzyme (TACE), which mediates mesothelin shedding.
Enable detection of mesothelin-expressing cancer cells.
Facilitate treatment or prevention of various cancers characterized by mesothelin expression or overexpression.
Documented Applications
Detecting presence of cancer in a mammal by binding to mesothelin on cancer cells.
Treating or preventing cancer, including a variety of solid and liquid tumors expressing mesothelin such as ovarian cancer, pancreatic cancer, lung cancer, mesothelioma, synovial sarcoma, gastric cancer, esophageal cancer, and others.
Reducing mesothelin shed from cell membranes in cancer cells.
Reducing activity of TNFα converting enzyme (TACE) to inhibit mesothelin shedding.
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