Human anti-mesothelin monoclonal antibodies
Inventors
Dimitrov, Dimiter S. • Feng, Yang • Pastan, Ira H.
Assignees
US Department of Health and Human Services
Publication Number
US-8357783-B2
Publication Date
2013-01-22
Expiration Date
2029-03-25
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Abstract
Disclosed herein are isolated human monoclonal antibodies that specifically bind human mesothelin with a binding affinity of about 25 nM or less. Nucleic acids encoding these antibodies, expression vectors including these nucleic acid molecules, and isolated host cells that express the nucleic acid molecules are also disclosed. The antibodies can be used to detect human mesothelin in a sample. Methods of diagnosing cancer, or confirming a diagnosis of cancer, are disclosed herein that utilize these antibodies. Methods of treating a subject with cancer are also disclosed.
Core Innovation
This invention relates to isolated fully human monoclonal antibodies that specifically bind human mesothelin with a binding affinity of about 25 nM or less. These antibodies are produced using a human library and can be in various forms, including Fab fragments. The invention also provides nucleic acids encoding these antibodies, expression vectors, isolated host cells expressing the antibodies, and immunoconjugates comprising the antibodies linked to effector molecules such as toxins or detectable labels. The antibodies can be used for diagnostic purposes to detect human mesothelin in samples and for confirming diagnoses of cancer. Therapeutic methods involving administration of these antibodies or their immunoconjugates to subjects with mesothelin-expressing cancers are also disclosed.
The problem addressed is the limitation of mouse monoclonal antibodies in clinical use due to the human anti-murine antibody (HAMA) response, which includes allergic reactions and rapid clearance of the antibody from serum. Currently, there is a need for fully human antibodies that bind mesothelin with high affinity to improve diagnosis and treatment of cancer. However, producing fully human antibodies against human antigens like mesothelin is difficult because such antigens are generally recognized as self.
The disclosed fully human antibodies avoid HAMA response as both the framework regions and complementarity determining regions (CDRs) are from human antibodies, thus providing high affinity binding to mesothelin (about 25 nM or less). The antibodies specifically bind mesothelin present on cancer cells, including mesothelioma, pancreatic, prostate, ovarian, lung, stomach, and squamous cell carcinomas, which express mesothelin highly compared to normal cells. The antibodies can be utilized in diagnostic assays to detect mesothelin protein in blood or tissue samples and in therapeutic interventions to treat mesothelin-expressing cancers using antibodies or immunoconjugates.
Claims Coverage
The patent claims cover an isolated human monoclonal antibody specific for human mesothelin, compositions including the antibody and immunoconjugates, methods of treatment, diagnostics, and related nucleic acid molecules and host cells. There are multiple inventive features addressing the antibody structure, binding characteristics, and uses.
Specific high affinity binding to human mesothelin
An isolated human monoclonal antibody that specifically binds human mesothelin with a binding affinity of about 20 nM or less, characterized by specific amino acid sequences in the light chain (amino acids 27-32, 50-52, 89-98 of SEQ ID NO: 1) and heavy chain (amino acids 26-35, 53-59, 98-109 of SEQ ID NO: 2).
Antibody formats and isotypes
The antibody can be in formats including Fab fragment, Fab′ fragment, F(ab)′2 fragment, single chain Fv protein (scFv), disulfide stabilized Fv protein (dsFv), or as an IgG. The antibody can be labeled with detectable moieties.
Pharmaceutical compositions comprising the antibody
Compositions comprising a therapeutically effective amount of the human monoclonal antibody in a pharmaceutically acceptable carrier are included.
Immunoconjugates comprising the antibody and effector molecules
Isolated immunoconjugates including the human monoclonal antibody linked to an effector molecule such as a toxin or a detectable label, as well as compositions comprising these immunoconjugates, are claimed.
Methods of treating mesothelin-positive cancers
Methods include administering to a subject with mesothelioma, prostate cancer, lung cancer, stomach cancer, squamous cell carcinoma, pancreatic cancer or ovarian cancer a therapeutically effective amount of the antibody composition to treat the cancer.
Methods for diagnosing and confirming diagnosis of cancer
Methods for determining if a subject has cancer or confirming a diagnosis by contacting a sample from the subject with the antibody and detecting antibody binding, where increased binding compared to controls indicates presence or confirmation of cancer.
Use of labeled antibodies and secondary antibodies for detection
Diagnostic methods also include use of directly labeled antibodies or contacting a second antibody that binds the primary antibody to detect binding, enhancing detection specificity.
Nucleic acid molecules and expression systems encoding the antibody
Isolated nucleic acid molecules encoding the antibody, vectors comprising these nucleic acids operably linked to promoters, and transformed host cells expressing the antibody are covered.
The claims comprehensively cover the fully human monoclonal antibodies specific to human mesothelin with defined amino acid sequences and high binding affinity, their pharmaceutical and immunoconjugate compositions, diagnostic and therapeutic methods involving these antibodies, and the genetic materials and host cells for producing these antibodies.
Stated Advantages
The antibodies are fully human, thus avoiding the human anti-murine antibody (HAMA) response seen with mouse monoclonal antibodies.
They specifically bind mesothelin with high affinity (about 25 nM or less), allowing precise targeting of mesothelin-expressing cancer cells.
The antibodies can be used both therapeutically to treat mesothelin-expressing cancers and diagnostically to detect mesothelin in biological samples to diagnose or confirm cancer.
Immunoconjugates can be formed with toxins or detectable labels, broadening therapeutic and diagnostic applications.
Documented Applications
Treatment of mesothelin-expressing cancers including mesothelioma, pancreatic cancer, prostate cancer, ovarian cancer, lung cancer, stomach cancer, and squamous cell carcinoma by administering the human monoclonal antibody or immunoconjugate.
Detection of mesothelin protein in biological samples such as blood, urine, biopsy, serum, sputum, plasma, or cerebral spinal fluid to diagnose or confirm diagnosis of mesothelin-positive cancers.
Use in diagnostic immunoassays including ELISA, flow cytometry, immunohistochemistry, western blotting, and immunoprecipitation to detect mesothelin presence and levels in samples.
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