Cell-penetrating anti-DNA antibodies and uses thereof inhibit DNA repair
Inventors
Hansen, James E. • Glazer, Peter M. • Weisbart, Richard H. • Nishimura, Robert N. • Chan, Grace
Assignees
Yale University • US Department of Veterans Affairs • University of California San Diego UCSD
Publication Number
US-9701740-B2
Publication Date
2017-07-11
Expiration Date
2032-04-02
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Abstract
Antibodies that penetrate cell nuclei and inhibit DNA repair or interfere with DNA metabolism are provided for treatment of cancer (both directly and by sensitizing cancer cells to DNA-damaging treatments) or inhibiting or preventing viral infection, proliferation or metabolism. The method involves treating cells with a composition containing cell-penetrating anti-DNA antibodies or derivatives thereof, alone or in combination with treatment that induces DNA damage such as DNA-damaging chemotherapy or radiation. The impact of the cell-penetrating anti-DNA antibodies or derivatives thereof is potentiated in cancer cells that are deficient in DNA repair, and the cell-penetrating anti-DNA antibodies or derivatives thereof are synthetically lethal to cancer cells with DNA repair deficiencies.
Core Innovation
The invention provides cell-penetrating anti-DNA antibodies and derivatives thereof that inhibit DNA repair and interfere with DNA metabolism, for use in treating cancer by directly killing cancer cells or by sensitizing them to DNA-damaging treatments such as chemotherapy or radiation. These antibodies can penetrate the nuclei of cells and inhibit DNA repair pathways, particularly targeting cancer cells with pre-existing DNA repair deficiencies, leading to synthetic lethality in such cells.
The invention addresses the problem that current monoclonal antibodies used in cancer therapy lack the ability to penetrate into cancer cells and target intracellular components, limiting their efficacy to cell surface antigens. Many tumor-specific targets reside inside cells and nuclei, and cancers deficient in DNA repair are particularly vulnerable to inhibition of DNA repair. Therefore, there is a need to develop cell-penetrating antibodies that inhibit DNA repair and sensitize or selectively kill cancer cells with DNA repair defects.
The invention includes methods of treating cancers or infected cells by administering compositions containing cell-penetrating anti-DNA antibodies, alone or combined with DNA-damaging therapies. The antibodies can be selected based on the identification of mutations or aberrant expression of DNA repair genes in tumors, such as BRCA1 or BRCA2 mutations. Notably, the monoclonal anti-DNA antibody 3E10 or its single chain variable fragment (3E10 scFv) is a preferred example, which penetrates cells and inhibits DNA repair pathways including base excision repair and homologous recombination through inhibition of RAD51-mediated strand exchange. The antibodies are also synthetically lethal to cancer cells deficient in DNA repair and can potentiate chemo- and radiotherapy.
Claims Coverage
The patent contains multiple independent claims focused on methods of inhibiting DNA repair and treating cancers or virally transformed cells using cell-penetrating anti-DNA antibodies, primarily monoclonal antibody 3E10 or its derivatives. The main inventive features relate to the use of specific cell-penetrating anti-DNA antibodies to impair DNA repair pathways, their selective toxicity and sensitization effects, and their administration in combination with other therapies.
Use of cell-penetrating unconjugated monospecific anti-DNA antibodies to inhibit DNA repair
Administering to neoplastic or virally transformed cells a pharmaceutical composition comprising effective amounts of monoclonal antibody 3E10 or cell penetrating antigen binding fragments thereof, without conjugation, to impair DNA repair pathways in the target cells.
Selective targeting of DNA repair-deficient or therapy-resistant cells
Utilizing the antibodies to treat cancer cells that are radiation or chemotherapy resistant, or that have intrinsic defective or deficient DNA repair, including mutations or abnormal expression in a defined set of DNA repair or tumor suppressor genes such as BRCA1 and BRCA2.
Combination with other therapeutic agents to enhance efficacy
Administering these cell-penetrating anti-DNA antibodies in combination with radiosensitizers, DNA-damaging chemotherapeutic drugs, radiation therapy, or therapeutic monoclonal antibodies to increase sensitivity of cancer cells to treatment and improve therapeutic outcomes.
Cellular uptake and nuclear localization of antibodies without carriers
The antibodies or antigen binding fragments are transported into the nucleus of cells without the aid of carriers or conjugates, enabling direct interference with nuclear DNA repair processes.
Synthetic lethality with DNA repair deficiencies
The antibodies are not directly cytotoxic to DNA repair-proficient cells but exhibit synthetic lethality toward DNA repair-deficient cancer cells, selectively killing those cells.
The claims cover methods of using the monoclonal anti-DNA antibody 3E10 or humanized forms thereof, alone and in combination with other therapies, to inhibit DNA repair in cancer or virally transformed cells, specifically targeting cells with DNA repair deficiencies or therapy resistance, thereby enhancing therapeutic efficacy and providing selective toxicity.
Stated Advantages
The antibodies selectively inhibit DNA repair, making them synthetically lethal to DNA repair-deficient cancer cells, offering targeted cancer therapy.
They sensitize cancer cells to DNA-damaging chemotherapy and radiation therapy, potentially lowering required doses and associated toxicities.
The antibodies can penetrate cell nuclei without carriers, allowing access to intracellular targets inaccessible to conventional antibodies.
They offer a novel mechanism of action distinct from existing monoclonal antibodies that only target cell surface antigens.
Documented Applications
Treatment of cancers including carcinomas, gliomas, sarcomas, lymphomas, and other tumors that are resistant to radiation or chemotherapy or have DNA repair deficiencies such as BRCA1 or BRCA2 mutations.
Enhancement of efficacy of DNA-damaging chemotherapy or radiation therapy by sensitizing cancer cells to these treatments.
Selective killing of cancer cells with pre-existing DNA repair defects, including tumors arising from familial cancer syndromes.
Inhibition and prevention of viral infection, proliferation, or metabolism in virally transformed or infected cells, including cells infected with oncoviruses or lentiviruses such as HIV, by interfering with host DNA repair pathways required for viral life cycles.
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