Cell-penetrating anti-dna antibodies and uses thereof inhibit dna repair

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.

1 . A method of inhibiting DNA repair in a neoplastic cell, comprising contacting the cell with a pharmaceutical composition comprising cell-penetrating unconjugated monospecific anti-DNA antibodies or cell-penetrating unconjugated antigen binding fragments thereof, wherein the cell-penetrating unconjugated monospecific anti-DNA antibodies or cell-penetrating unconjugated antigen binding fragments thereof consist of monoclonal antibody 3E10 produced by ATCC Accession No. PTA 2439 hybridoma, or a cell penetrating antigen binding fragment or humanized form thereof. 
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the cell is radiation resistant. 
     
     
         4 . The method of  claim 1 , wherein the cell is resistant to chemotherapy. 
     
     
         5 . The method of  claim 1 , wherein the cell has intrinsic defective or deficient DNA repair. 
     
     
         6 .- 10 . (canceled) 
     
     
         11 . The method of  claim 1  wherein the antibodies are administered in combination with a radiosensitizer. 
     
     
         12 .- 15 . (canceled) 
     
     
         16 . The method of  claim 1 , wherein the cell-penetrating anti-DNA antibodies are derived from a subject or an animal with systemic lupus erythematous, or an animal model thereof. 
     
     
         17 .- 18 . (canceled) 
     
     
         19 . The method of claim, wherein the cell-penetrating unconjugated antigen binding fragments comprise a single chain variable fragment of 3E10 (3E10 scFv) or a humanized form thereof. 
     
     
         20 . (canceled) 
     
     
         21 . A dosage unit comprising cell-penetrating anti-DNA antibodies or fragments thereof in a pharmaceutically acceptable excipient, wherein the antibodies are present in an amount effective to inhibit DNA repair in cancer or virally infected cells with or without intrinsic deficiency in DNA repair. 
     
     
         22 . The dosage unit of  claim 21 , further comprising an antineoplastic or radiosensitizing agent. 
     
     
         23 . The dosage unit of  claim 22 , wherein the antineoplastic agent is selected from the group consisting of cisplatin, cytoxan, doxorubicin, methotrexate, mitomycin c, nitrogen mustard, hydroxyurea, tirapazamine, temozolomide, camptothecin, PARP inhibitors, carboplatin, epirubicin, ribonucleotide reductase inhibitors, ifosphamide, cetuximab, rituximab, sunitinib, streptozocin, sorafenib, actinomycin D, procarbazine, DTIC, 8-MOP, pemetrexed, everolimus, vincristine, vinblastine, bleomycin, dacarbazine, etoposide, Gliadel, alkylating agents nucleoside or nucleotide analogs and combinations thereof. 
     
     
         24 . The dosage unit of  claim 22 , wherein the radiosensitizer is selected from the group consisting of cisplatin, doxorubicin, gemcitabine, 5-fluorouracil, PARP1 inhibitors, histone deacetylase inhibitors, proteasome inhibitors, epidermal growth factor receptor (EGRF) inhibitors, insulin-like growth factor-1 (IGF-1) receptor inhibitors, CHK1 inhibitors, mTOR inhibitors, pentoxifylline, vinorelbine misonidazole, mitomycin C, alkylating agents, nucleoside analogs, and nucleotide analogs. 
     
     
         25 .- 32 . (canceled) 
     
     
         33 . A method of determining a subject's sensitivity to a DNA damaging therapy, comprising assaying a sample obtained from the subject for levels of cell-penetrating anti-DNA antibodies, wherein an increase in cell-penetrating anti-DNA antibodies in the sample compared to a control indicates that the subject is sensitive to the DNA damaging therapy. 
     
     
         34 . The method of  claim 33 , wherein the subject has cancer. 
     
     
         35 . The method of  claim 1 , wherein the subject has a cancer that has intrinsic defective or deficient DNA repair.