Anti-mesothelin antibodies
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-8460660-B2
Publication Date
2013-06-11
Expiration Date
2030-03-23
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Abstract
The present invention provides monoclonal anti-mesothelin antibodies and antibody fragments and methods for their use. The antibodies can be completely human.
Core Innovation
The present invention provides monoclonal human anti-mesothelin antibodies and antibody fragments that specifically bind to the mesothelin protein, a glycosylphosphatidylinositol-anchored glycoprotein present on the cell surface. The antibodies include fully human forms and are characterized by specific complementarity determining regions (CDRs) in the heavy and light chain variable domains, with embodiments including the HN1 and HN2 antibodies. These antibodies specifically recognize mesothelin with high affinity and can be engineered into various formats such as intact IgG, single-chain Fv (scFv), or immunotoxins conjugated to therapeutic agents.
The problem being solved relates to the difficulty in developing effective treatments against cancers such as ovarian cancer and mesothelioma, where mesothelin is overexpressed. Existing antibodies against mesothelin often have murine origins that elicit immunogenicity and can have limitations such as lower affinity or inability to block mesothelin-CA125 interactions. The invention addresses the need for fully human, high-affinity anti-mesothelin antibodies that can block mesothelin binding interactions, induce antibody-dependent cellular cytotoxicity (ADCC), and serve as targeting moieties for immunotoxins, thereby providing enhanced therapeutic options for mesothelin-expressing cancers.
Claims Coverage
The claims include 18 inventive features directed to isolated anti-mesothelin antibodies, nucleic acids encoding these antibodies, methods of use for inhibiting mesothelin-related interactions, and compositions thereof.
Anti-mesothelin antibody with specific CDR sequences
An isolated antibody or antibody fragment binding to mesothelin comprising a heavy chain variable domain with CDR1 (SEQ ID NO:9), CDR2 (SEQ ID NO:10), CDR3 (SEQ ID NO:11) and a light chain variable domain with CDR1 (SEQ ID NO:12), CDR2 (SEQ ID NO:13), and CDR3 (SEQ ID NO:14).
Antibody variable domain sequence identity
The antibody has heavy and/or light chain variable domains with at least 90% sequence identity to SEQ ID NOS:2 (heavy chain) and 4 (light chain), respectively.
Antibody human mesothelin specificity
The antibody specifically binds to human mesothelin.
Formats of the antibody
The antibody can be a single-chain Fv (scFv) or an IgG antibody.
Human origin of the antibody
The antibody is a human antibody.
Antibody linked to effector agents
The antibody is linked to an effector agent, such as a cytotoxin.
Use of Pseudomonas exotoxin A as cytotoxin effector
The cytotoxin effector linked to the antibody is Pseudomonas exotoxin A or a variant thereof.
Nucleic acid encoding heavy chain variable domain
Isolated nucleic acids encoding heavy chain variable domains comprising the specified CDR1, CDR2, CDR3 amino acid sequences and having at least 90% identity to SEQ ID NO:1.
Nucleic acid encoding light chain variable domain
Isolated nucleic acids encoding light chain variable domains comprising the specified CDR1, CDR2, CDR3 amino acid sequences and comprising the polynucleotide sequence of SEQ ID NO:3.
Method of inhibiting CA125/mesothelin-dependent cell attachment
A method of inhibiting CA125/mesothelin-dependent cell attachment by contacting mesothelin-expressing cells with the claimed antibody or antibody fragment.
Method of inhibiting CA125/mesothelin-dependent cell attachment in vivo
The inhibiting step is performed in vivo.
Method of inhibiting cancer mediated by CA125/mesothelin-dependent attachment
A method of inhibiting cancers mediated by CA125/mesothelin-dependent cell attachment by contacting mesothelin-expressing cells with the antibody or antibody fragment.
Targeted cancers
The cancers mediated by CA125/mesothelin-dependent attachment include ovarian cancer, mesothelioma, non-small cell lung cancer, lung adenocarcinoma, and pancreatic cancer.
Antibody linked to an effector agent in therapeutic methods
In the methods inhibiting cancer or attachment, the antibody or antibody fragment can be linked to an effector agent.
The claims cover isolated human antibodies specific for mesothelin characterized by defined CDRs, nucleic acids encoding these antibodies, use of the antibodies to inhibit mesothelin-CA125 interactions or CA125/mesothelin-mediated cancer cell attachment, and therapeutic methods for treating related cancers. The antibodies can be in various formats and linked to cytotoxic effectors such as Pseudomonas exotoxin A to enhance therapeutic efficacy.
Stated Advantages
The invention provides fully human anti-mesothelin antibodies with low immunogenicity, suitable for clinical use in humans.
The antibodies have high affinity binding to mesothelin comparable to or better than existing mouse-derived antibodies.
They specifically bind a conformation-sensitive epitope of mesothelin and can block mesothelin-CA125 interactions, potentially inhibiting cancer metastasis.
The antibodies induce strong antibody-dependent cell-mediated cytotoxicity (ADCC) on mesothelin-expressing cancer cells.
When incorporated into immunotoxins, the antibodies mediate effective cytotoxicity and apoptosis in cancer cells.
The antibodies can be converted into various therapeutic formats including intact IgG, scFv, immunoconjugates, and immunotoxins for diverse therapeutic applications.
Documented Applications
Treatment of cancers that overexpress mesothelin, including ovarian cancer, mesothelioma, non-small cell lung cancer, lung adenocarcinoma, and pancreatic cancer.
Methods for inhibiting CA125/mesothelin-dependent cancer cell attachment and metastasis.
Use in immunotoxins targeting mesothelin-expressing tumor cells to induce cytotoxicity.
Diagnostic applications for detecting mesothelin-expressing cells in biological samples using immunoassays and immunohistochemistry.
Use in kits for detection of mesothelin in biological samples.
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