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-10961301-B2
Publication Date
2021-03-30
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 or derivatives thereof that penetrate cell nuclei and inhibit DNA repair or interfere with DNA metabolism. These antibodies are utilized for treatment of cancer by directly killing cancer cells or by sensitizing them to DNA-damaging treatments such as chemotherapy or radiation. The method involves administering compositions containing these cell-penetrating anti-DNA antibodies alone or in combination with DNA-damaging therapies. The antibodies are particularly effective in cancer cells deficient in DNA repair pathways and are synthetically lethal to such cancer cells.
The problem addressed is the limitation of most cancer therapies by significant side effects due to non-specific tissue toxicity and the lack of antibodies capable of penetrating cancer cells to target intracellular tumor-specific targets. Current approved antibodies for cancer therapy cannot penetrate cancer cells and are limited to targeting cell surface molecules. Additionally, many tumor-specific targets are inside cells and nuclei, and certain cancers are vulnerable to treatments that inhibit DNA repair. Therefore, there is a need for cell-penetrating antibodies that inhibit DNA repair to selectively target cancer cells and improve the efficacy and specificity of cancer therapy.
The invention also addresses the need for compositions increasing cancer cells' sensitivity to radiation therapy and chemotherapy. It provides cell-penetrating antibodies and derivatives selectively toxic to cancer cells or other undesirable cells with pre-existing deficiencies in DNA repair caused by mutations or silencing of DNA repair genes. Furthermore, the invention extends to inhibiting or preventing viral infection, proliferation, or metabolism through perturbation of host DNA repair by these antibodies, thus providing a novel approach for treating virally transformed or infected cells.
Claims Coverage
The claims include one main independent claim related to a dosage unit comprising cell-penetrating anti-DNA antibodies or fragments and DNA-damaging or DNA repair-inhibiting agents, and further define cancer cells, viral infected cells, antibody forms, and combination therapies.
Combination dosage unit containing cell-penetrating anti-DNA antibodies and antineoplastic or radiosensitizing agents
A dosage unit comprising cell-penetrating unconjugated monospecific anti-DNA antibodies or antigen binding fragments and an antineoplastic or radiosensitizing agent that damages DNA or inhibits DNA repair in a pharmaceutically acceptable carrier, present in an amount effective to inhibit DNA repair in cancer or virally infected cells. The antibodies include monoclonal antibody 3E10 or humanized forms thereof.
Selection of DNA-damaging or DNA repair inhibiting agents for combination therapy
The antineoplastic or radiosensitizing agent can be selected from a group including cisplatin, cytoxan, doxorubicin, mitomycin c, nitrogen mustard, tirapazamine, temozolomide, camptothecin, PARP inhibitors, carboplatin, epirubicin, ifosphamide, streptozocin, sorafenib, actinomycin D, procarbazine, DTIC, 8-MOP, everolimus, bleomycin, dacarbazine, etoposide, carmustine, chlorambucil, cyclophosphamide, daunorubicin, misonidazole, idarubicin, ifosfamide, lomustine, mechlorethamine, mitoxantrone, oxaliplatin, valrubicin, pentoxifylline, CHK1 inhibitors, histone deacetylase inhibitors, proteasome inhibitors, kinase inhibitors, and combinations thereof.
Cancer cell types targeted
The dosage unit is effective against cells from cancers including sarcomas, lymphomas, leukemias, carcinomas, adenocarcinomas, blastomas, germ cell tumors, gliomas, neuroendocrine tumors, melanomas, rhabdoid tumors, embryonal tumors, neuroectodermal tumors, carcinoid tumors, craniopharyngiomas, histiocytomas, medulloepitheliomas, mesotheliomas, multiple myelomas, chronic myeloproliferative disease, primitive neuroectodermal tumors, salivary gland tumors, thymomas, thymic carcinoma, thyroid cancer, and Wilms tumor, including breast cancer and glioblastoma cells.
Targeting resistant and DNA repair-deficient cells
Targets resistant cancer cells including radiation-resistant and chemotherapy-resistant cells and cells with intrinsically defective or deficient DNA repair, including those with mutations or abnormal expression in numerous specified DNA repair genes or tumor suppressor genes such as BRCA1 or BRCA2. Also targets cells in hypoxic tumors.
Forms of anti-DNA antibodies
The antibodies or antigen binding fragments consist of monoclonal antibody 3E10 or derivatives such as single chain variable fragments (scFv) or divalent single-chain variable fragments (di-scFv), or humanized forms thereof, and are not directly cytotoxic to DNA repair proficient cells.
Application to virally infected cells
The dosage unit targets cells infected with viruses causing DNA repair defects or dependent on host DNA repair pathways, including lentiviruses.
The claims collectively cover a dosage unit combining cell-penetrating anti-DNA antibodies derived from monoclonal antibody 3E10 or its fragments with DNA-damaging or DNA repair inhibiting agents, directed at treating various cancers including resistant and DNA repair-deficient tumors, as well as virally infected cells dependent on DNA repair, utilizing multiple antibody forms and combination therapies.
Stated Advantages
The antibodies selectively kill cancer cells deficient in DNA repair while sparing DNA repair-proficient cells.
They increase sensitivity of cancer cells to DNA-damaging chemotherapy and radiation, potentially allowing lower doses of toxic therapies.
The cell-penetrating anti-DNA antibodies can overcome resistance to chemotherapy and radiotherapy in cancer cells.
These antibodies can inhibit DNA repair pathways directly, including base excision repair and homologous recombination, providing a novel mechanism to target cancer cell survival.
The antibodies also have potential to inhibit viral infection, integration, and replication by perturbing host DNA repair, offering a method to treat virally transformed or infected cells.
Documented Applications
Treatment of cancer, including breast, ovarian, pancreatic, gliomas, lymphomas, leukemias, carcinomas, and others, especially those with impaired DNA repair or resistance to radiotherapy or chemotherapy.
Sensitization of cancer cells to radiation therapy and DNA-damaging chemotherapy, including use in combination with agents such as doxorubicin, cisplatin, and PARP inhibitors.
Targeted therapy for cancers with inherited or sporadic DNA repair deficiencies, including tumors with BRCA1 or BRCA2 mutations.
Treatment of viral infections and virally transformed cells by inhibiting viral replication, infection, integration, or metabolism dependent on host DNA repair mechanisms, including lentivirus (HIV) infections.
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