Cell penetrating nucleolytic antibody based cancer therapy
Inventors
Hansen, James E. • Weisbart, Richard H. • Noble, Philip W.
Assignees
Yale University • US Department of Veterans Affairs
Publication Number
US-10238742-B2
Publication Date
2019-03-26
Expiration Date
2035-06-25
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Abstract
Cancer cells with defects in DNA repair are highly susceptible to DNA-damaging agents, but delivery of therapeutic agents into cell nuclei can be challenging. A sub-set of autoantibodies having nucleolytic activity are capable of nuclear penetration. These antibodies can be used as therapeutic agents targeted towards DNA repair-deficient malignancies.
Core Innovation
The invention relates to the use of a sub-set of cell-penetrating autoantibodies which have nucleolytic activity, capable of penetrating nuclei, as therapeutic agents targeted toward DNA repair-deficient malignancies. These antibodies can induce DNA damage within cancer cells defective in DNA repair mechanisms, resulting in selective cytotoxicity.
The problem being addressed is the difficulty in delivering therapeutic agents effectively into the nuclei of cancer cells, particularly to selectively target malignant cells with defects in DNA repair. Existing therapeutic antibodies lack the ability to penetrate into cancer cells, limiting their efficacy to surface antigens. There is a need for targeted therapies that selectively kill cancer cells deficient in DNA repair while sparing normal cells to reduce side effects associated with non-specific tissue toxicity.
Claims Coverage
The patent contains one independent claim encompassing key inventive features related to pharmaceutical compositions comprising cell-penetrating nucleolytic antibodies and their antigen binding fragments.
Pharmaceutical composition comprising a cell-penetrating nucleolytic antibody
A pharmaceutical composition comprising a cell-penetrating, nucleolytic antibody or antigen binding fragment thereof, characterized by a heavy chain variable region containing the first, second, and third complementarity determining regions (CDRs) of SEQ ID NO:5 or humanized variants thereof, and a light chain variable region containing the first, second, and third CDRs of SEQ ID NO:1 or humanized variants thereof, at a unit dosage between about 0.01 and 100 mg/kg body weight of a human, combined with a pharmaceutically acceptable excipient for injection.
Compositions including additional antineoplastic or radio-sensitizing agents
Pharmaceutical compositions of the cell-penetrating nucleolytic antibody further comprising one or more antineoplastic or radio-sensitizing agents selected from a defined group including cisplatin, cytoxan, doxorubicin, methotrexate, mitomycin c, nitrogen mustard, hydroxyurea, bevacizumab, cetuximab, rituximab, trastuzumab, tirapazamine, temozolomide, camptothecin, gemcitabine, 5-fluorouracil, pentoxifylline, vinorelbine, and their combinations.
Unit dosage forms and administration routes
Pharmaceutical compositions in dosage forms suitable for intravenous injection or intratumoral injection.
Antibody formats included in compositions
The antibody or antigen binding fragment can be a monovalent or multivalent single chain variable fragment (scFv).
Specific CDR amino acid sequences defining antibody specificity
Light chain CDRs comprise amino acid sequences SEQ ID NOS:2, 3, and 4; heavy chain CDRs comprise amino acid sequences SEQ ID NOS:6, 7, and 8.
Variable regions defining antibody structure
Light chain variable region comprises amino acid sequence SEQ ID NO:1; heavy chain variable region comprises amino acid sequence SEQ ID NO:5.
Humanized and chimeric antibody embodiments
The antibody or antigen binding fragment can be a humanized antibody or a chimeric antibody, retaining the same defined CDR sequences for both heavy and light chains.
Exclusion of mouse IgG2a-k monoclonal antibody form
The antibody or antigen binding fragment thereof is not an IgG2a-k mouse monoclonal antibody.
The claims collectively cover pharmaceutical compositions containing cell-penetrating nucleolytic antibodies or their fragments with defined CDR sequences, including humanized and chimeric forms, optionally combined with established antineoplastic or radio-sensitizing agents, formulated for injection, and exclude the original mouse monoclonal antibody form.
Stated Advantages
The antibodies selectively kill or sensitize DNA repair-deficient cancer cells while sparing DNA repair-proficient cells, enabling targeted therapy with reduced side effects.
The cell-penetrating nucleolytic antibodies facilitate delivery of DNA-damaging agents directly into the cell nucleus overcoming prior therapeutic limitations.
Use of these antibodies increases cancer cell sensitivity to radiation therapy and chemotherapy by greater than 10%, enhancing treatment efficacy.
Documented Applications
Targeted therapy for DNA repair-deficient malignancies including breast, ovarian, pancreatic, colon, endometrial, brain cancers, leukemias, genitourinary system cancers, nervous system cancers, head and neck cancers, lung cancers, gynecologic cancers, gastrointestinal cancers, skin cancers, and pediatric cancers.
Treatment of cancers that are resistant to radiotherapy or chemotherapy, by increasing cancer cell sensitivity to such treatments.
Use in combination therapies with established chemotherapeutic or radiotherapeutic agents to enhance anti-cancer effects.
Prevention or treatment of cancer in subjects at risk due to mutations in DNA repair genes such as ATM, ATR, BRCA1, BRCA2, FANCD2, MLH1, MRE11, MSH2, PALB2, or PMS2.
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