Methods for dna-dependent targeting of a cell permeant antibody

Abstract

The invention provides methods for selective targeting of live cells, which have undergone or are undergoing radiation or chemotherapy, at a site of interest with a cell-penetrating polypeptide. In one embodiment of the invention, the method comprises contacting the live cells with a cell-penetrating polypeptide comprising cell-penetrating determinants so that the cell-penetrating polypeptide binds extracellular DNA near or around the live cells so as to form a complex or association therewith such that the complex or associated polypeptide-DNA so bound bind the live cells and penetrates the live cells thereby selectively targeting live cells at a site of interest with a cell-penetrating polypeptide.

What is claimed is: 
     
         1 . A method for selectively targeting live cells at a site of interest with a cell-penetrating polypeptide comprises:
 (a) introducing or producing extracellular DNA and its degradation product(s) near or around the live cells at the site of interest;   (b) introducing the cell-penetrating polypeptide comprising cell-penetrating determinants near or around the live cells, before, after or concurrently with the DNA of step (a);   (c) contacting the extracellular DNA or its degradation product with the cell-penetrating polypeptide so that the cell-penetrating polypeptide binds the extracellular DNA or its degradation product near or around the live cells so as to form a complex;   (d) contacting one of the live cells with the complex in (c) so as to bind and penetrate the live cell; and   (e) permitting additional complexes to form as in (c) and contacting additional cells with said complexes so as to bind and penetrate additional live cells at the site of interest;   thereby, selectively targeting live cells at the site of interest with a cell-penetrating polypeptide.   
     
     
         2 . A method for selective targeting of live cells at a site of interest, which site of interest has undergone or is undergoing radiation or chemotherapy so that the cells at the site of interest generates extracellular DNA or its degradation product, with a cell-penetrating polypeptide, the method comprising:
 (a) contacting a live cell at the site of interest with a cell-penetrating polypeptide comprising cell-penetrating determinants so that the cell-penetrating polypeptide binds extracellular DNA or its degradation product so as to form a complex;   (b) contacting one of the live cells at the site of interest with the complex in (a) so as to bind and penetrate the live cell;   (c) permitting additional complexes to form as in (a) and contacting additional cells with said complexes so as to bind and penetrate additional live cells at the site of interest;   thereby, selectively targeting live cells at the site of interest, which has undergone or is undergoing radiation or chemotherapy, with a cell-penetrating polypeptide.   
     
     
         3 . A method for inhibiting cellular injury in a subject comprising:
 (a) administering directly to the live cells at or near a site of cellular injury of the subject a cell-penetrating polypeptide comprising cell-penetrating determinants joined to a therapeutic agent;   (b) contacting extracellular DNA or its degradation product with the cell-penetrating polypeptide so that the cell-penetrating polypeptide binds extracellular DNA or its degradation product near or around the live cells so as to form a complex;   (c) contacting one of the live cells with the complex in (b) so as to bind and penetrate the live cell; and   (d) permitting additional complexes to form as in (b) and contacting additional cells with said complexes so as to bind and penetrate additional live cells at the site of cellular injury;   thereby, inhibiting cellular injury in the subject.   
     
     
         4 . A method for inducing cell death in a subject comprising:
 (a) administering directly to the live cells at or near a site of injury of the subject a cell-penetrating polypeptide comprising cell-penetrating determinants joined to a therapeutic agent;   (b) contacting extracellular DNA or its degradation product near or around the live cells with the cell-penetrating polypeptide so that the cell-penetrating polypeptide binds extracellular DNA or its degradation product near or around the live cells so as to form a complex;   (c) contacting one of the live cells with the complex in (b) so as to bind and penetrate the live cell which induces cell death; and   (d) permitting additional complexes to form as in (b) and contacting additional cells with said complexes so as to bind and penetrate additional live cells inducing additional cell death at the site of injury;   thereby inducing cell death at or near a site of injury with the cell-penetrating polypeptide.   
     
     
         5 . The method of  claim 2 ,  3  or  4  further comprising administering DNA to the site in an extracellular space to facilitate selective targeting at the site. 
     
     
         6 . A method for selective targeting of live cells at or near a site of cellular injury with a cell-penetrating polypeptide which comprises cell-penetrating determinants joined to a therapeutic agent, the method comprising: (a) contacting the live cells with a composition comprising (i) a cell-penetrating polypeptide which comprises cell-penetrating determinants joined to a therapeutic agent and (ii) extracellular DNA or its degradation product so that the cell-penetrating polypeptide binds extracellular DNA or its degradation product near or around the live cells so as to form a complex such that the complex so formed binds one of the live cells and penetrates the live cell; and (b) permitting additional complexes to form as in (a) and contacting additional cells with said complexes so as to bind and penetrate additional live cells at the site of cellular injury, thereby selectively targeting live cells at a site of cellular injury with a cell-penetrating polypeptide. 
     
     
         7 . A method for inhibiting a tumor associated with ischemia, cellular/tissue necrosis or cellular/tissue apoptosis by selective targeting of live cells at a site of interest by the method of  claim 1 ,  2 ,  3 ,  4  or  6 . 
     
     
         8 . A method for enhancing the effects of chemotherapy or radiation therapy by selectively targeting live cells by the method of  claim 1 ,  2 ,  5  or  6 . 
     
     
         9 . The method of  claim 1 ,  2 ,  3 ,  4  or  6  which is an adjunct therapy to a chemotherapy or a radiation therapy. 
     
     
         10 . The method of  claim 2 , wherein the chemotherapy or the radiation therapy is administered concurrently or before the method for selective targeting of live cells. 
     
     
         11 . The method of  claim 1  or  2 , wherein the cell-penetrating polypeptide is conjugated to a therapeutic agent. 
     
     
         12 . The method of  claim 1 ,  2 ,  3 ,  4  or  6 , wherein the cells are cells of an ischemic tissue. 
     
     
         13 . The method of  claim 1 ,  2 ,  3 ,  4  or  6 , wherein the cell-penetrating polypeptide is an anti-DNA antibody. 
     
     
         14 . The method of  claim 13 , wherein the anti-DNA antibody binds double-stranded DNA. 
     
     
         15 . The method of  claim 13 , wherein the anti-DNA antibody is selected from the group consisting of 3E10 antibody, 5C5 antibody, 5C6 antibody, 4H2 antibody, H7 antibody, H9 antibody, H72 antibody, H205 antibody, H317 antibody F14-6 antibody, SN22 antibody, SN50 antibody, SN111 antibody, SN112 antibody, SN575 antibody, SN604 antibody, SN608 antibody, F4.1 antibody, J20.8 antibody, F14.6 antibody, and 9D7 antibody or a fragment or variant thereof. 
     
     
         16 . The method of  claim 15 , wherein the anti-DNA antibody is a 3E10 antibody or a fragment or variant thereof. 
     
     
         17 . The method of  claim 16 , wherein the 3E10 antibody has a binding specificity of an antibody as produced by a hybridoma having ATCC accession number PTA 2439 or a fragment or variant thereof. 
     
     
         18 . The method of  claim 16 , wherein the 3E10 antibody is produced by a hybridoma having ATCC accession number PTA 2439 or a fragment or variant thereof. 
     
     
         19 . The method of  claim 16 , wherein the variant of 3E10 antibody is or comprises an amino acid substitution of 3E10 variable heavy chain at amino acid 31 from an aspartic acid to an asparagine (D31N). 
     
     
         20 . The method of  claim 16 , wherein the 3E10 antibody is a humanized variant of an antibody produced by the hybridoma having ATCC accession number PTA 2439 or a variant thereof. 
     
     
         21 . The method of  claim 16 , wherein the fragment is a single chain Fv (scFv) fragment of mAb 3E10 antibody. 
     
     
         22 . The method of  claim 16 , wherein the 3E10 antibody or a fragment or variant thereof is joined to an amino acid sequence AGIH at its amino terminus. 
     
     
         23 . The method of  claim 16 , wherein the 3E10 antibody or a variant thereof is joined to or comprises a peptide linker which in turn comprises a portion of an immunoglobulin heavy chain constant domain CH1 and a swivel sequence, and optionally, the 3E10 antibody or a variant thereof comprises an amino acid sequence AGIH at its amino terminus. 
     
     
         24 . The method of  claim 16 , wherein the variant has a change in the amino acid sequence of a 3E10 scFv, wherein the change in the amino acid sequence does not abolish or prevent cell penetration. 
     
     
         25 . The method of  claim 16 , wherein the variant has a change in the amino acid sequence of a 3E10 scFv, wherein the change in the amino acid sequence enhances cell penetration. 
     
     
         26 . The method of  claim 25 , wherein the change in the amino acid sequence enhancing cell penetration is an amino acid substitution of 3E10 variable heavy chain at amino acid 31 from an aspartic acid to an asparagine (D31N). 
     
     
         27 . The method of  claim 14 ,  15  or  16 , wherein cell penetration is dependent on a salvage pathway. 
     
     
         28 . The method of  claim 27 , wherein the salvage pathway is a nucleoside salvage pathway. 
     
     
         29 . The method of  claim 28 , wherein the nucleoside salvage pathway is a pathway mediated by equilibrative nucleoside transporters (ENTs) or SLC29 family of integral membrane proteins. 
     
     
         30 . The method of  claim 29 , wherein the equilibrative nucleoside transporter (ENT) or a member of the SLC29 family of integral membrane proteins is a transporter for purine and pyrimidine nucleosides and nucleobases or a metabolite thereof. 
     
     
         31 . The method of  claim 30 , wherein the transporter for purine and pyrimidine nucleosides and nucleobases or a metabolite thereof is an equilibrative nucleoside transporter ENT2. 
     
     
         32 . The method of  claim 15 , wherein the anti-DNA antibody is an isolated monoclonal antibody 5C5 or a fragment or variant thereof. 
     
     
         33 . The method of  claim 14 , wherein the anti-DNA antibody is an isolated monoclonal antibody 5C6 or a fragment or variant thereof. 
     
     
         34 . The method of  claim 14 , wherein the anti-DNA antibody is an isolated monoclonal antibody 4H2 or a fragment or variant thereof. 
     
     
         35 . The method of  claim 1 ,  2 ,  3 ,  4  or  6 , wherein the cells or tissue are as present in a mammal or derived from a mammal. 
     
     
         36 . The method of  claim 1 ,  2 ,  3 ,  4  or  6 , wherein the extracellular DNA is single-stranded, double-stranded, triple-stranded, or four-stranded or a combination thereof. 
     
     
         37 . The method of  claim 1 ,  2 ,  3 ,  4  or  6 , wherein the extracellular DNA comprises a phosphodiester bond, a phosphorothioate bond or a methylphosphonate bond or a combination thereof. 
     
     
         38 . The method of  claim 1 ,  2 ,  3 ,  4  or  6 , wherein the extracellular DNA comprises a 5′-to-3′ linkage, an inverted 5′-to-5′ linkage or an inverted 3′-to-3′ linkage or a combination thereof. 
     
     
         39 . The method of  claim 1 ,  2 ,  3 ,  4  or  6 , wherein the extracellular DNA comprises an artificial DNA. 
     
     
         40 . The method of  claim 39 , wherein the artificial DNA comprises a DNA mimetic. 
     
     
         41 . The method of  claim 40 , wherein the DNA mimetic comprises a pseudopeptide backbone. 
     
     
         42 . The method of  claim 41 , wherein the pseudopeptide backbone comprises an ethylglycine, a propylglycine, an ethyl-β-alanine, a propionyl linker, a retro inverso linker, a (S,S)-cyclohexyl linker, a (R,R)-cyclohexyl linker, an L-ornithine, a 2-me-ethyl-glycine, an ethyl-lysine, a L-proline, a n-proline, a glycine backbone/ethyl linker, a L-4-trans-amino proline, a L-4-cis-amino proline, a D-4-trans-amino proline, a β-alanine/proline, a glycylglycine/ethyl linker, a glycine/ethyl linker, a proline-glycine, a β-amino-alanine, E-OPA, Z-OPA, APNA, a serinol-ethyl-methyl linker, a serinol-ethyl-ethyl linker, an α-methyl-serinol-ethyl-ethyl linker, an aminopentan, a hydroxyethyl phosphono glycine, an aminoethyl phosphono glycine, a lysine, an aminoethyl prolyl or a serinyl methylene or a combination thereof. 
     
     
         43 . The method of  claim 1 ,  2 ,  3 ,  4  or  6 , wherein the cell-penetrating polypeptide is or comprises a therapeutic agent. 
     
     
         44 . The method of  claim 1  or  2 , wherein the site of interest is an injury site. 
     
     
         45 . The method of  claim 44 , wherein the site of interest where the extracellular DNA is so introduced is directly in the injury site. 
     
     
         46 . The method of  claim 44 , wherein an injury in the injury site is an intracranial injury, brain injury, myocardial infarction, skin injury, liver injury, gastrointestinal injury, lung injury, eye injury, kidney injury, pancreas injury, peritoneal injury, bone injury, nasopharyngeal injury, uterine injury, cervical injury, breast injury, organ injury, tissue injury, burn or radiation injury. 
     
     
         47 . The method of  claim 3 ,  4  or  6 , wherein the injury site is an intracranial injury, brain injury, myocardial infarction, skin injury, liver injury, gastrointestinal injury, lung injury, eye injury, kidney injury, pancreas injury, peritoneal injury, bone injury, nasopharyngeal injury, uterine injury, cervical injury, breast injury, organ injury, tissue injury, burn or radiation injury. 
     
     
         48 . The method of  claim 44 , wherein an injury in the injury site is an acute renal failure, acute organ failure, liver injury, bowel infarction, peripheral vascular disease, pulmonary failure or a cancer. 
     
     
         49 . The method of  claim 3 ,  4  or  6 , wherein the injury is an acute renal failure, acute organ failure, liver injury, bowel infarction, peripheral vascular disease, pulmonary failure or a cancer. 
     
     
         50 . The method of  claim 44 , wherein an injury in the injury is a brain injury, heart injury, skin injury or radiation injury. 
     
     
         51 . The method of  claim 3 ,  4  or  6 , wherein the injury is a brain injury, heart injury, skin injury or radiation injury. 
     
     
         52 . The method of  claim 50 , wherein the brain injury is a brain trauma, spinal cord injury, peripheral nerve injury, or stroke. 
     
     
         53 . The method of  claim 51 , wherein the brain injury is a brain trauma, spinal cord injury, peripheral nerve injury, or stroke. 
     
     
         54 . The method of  claim 50 , wherein the heart injury is a myocardial infarction. 
     
     
         55 . The method of  claim 51 , wherein the heart injury is a myocardial infarction. 
     
     
         56 . The method of  claim 50 , wherein the skin injury is a wound, burn, or decubitus ulcer. 
     
     
         57 . The method of  claim 51 , wherein the skin injury is a wound, burn, or decubitus ulcer. 
     
     
         58 . The method of  claim 50 , wherein the radiation injury is a burn or poison. 
     
     
         59 . The method of  claim 51 , wherein the radiation injury is a burn or poison. 
     
     
         60 . The method of  claim 44 , wherein the injury site is created through the use of a cell-damaging agent. 
     
     
         61 . The method of  claim 3 ,  4  or  6 , wherein the injury site is created through the use of a cell-damaging agent. 
     
     
         62 . The method of  claim 44 , wherein the cell-damaging agent is a radioisotope, cytotoxic agent or radiation. 
     
     
         63 . The method of  claim 3 ,  4  or  6 , wherein the cell-damaging agent is a radioisotope, cytotoxic agent or radiation. 
     
     
         64 . The method of  claim 62 , wherein the radioisotope is selected from the group consisting of  46 Sc,  47 Sc,  48 Sc,  67 Cu,  67 Ga,  72 Ga,  73 Ga,  90 Y,  67 Cu,  109 Pd,  111 Ag,  111 In,  125 I,  131 I,  149 Pm,  153 Sm,  166 Ho,  177 Lu,  186 Re,  188 Re,  211 At,  211 Bi,  212 Bi,  212 Pb,  213 Bi,  214 Bi, and  225 Ac. 
     
     
         65 . The method of  claim 63 , wherein the radioisotope is selected from the group consisting of  46 Sc,  47 Sc,  48 Sc,  67 Cu,  67 Ga,  72 Ga,  73 Ga,  90 Y,  67 Cu,  109 Pd,  111 Ag,  111 In,  125 I,  131 I,  149 Pm,  153 Sm,  166 Ho,  177 Lu,  186 Re,  188 Re,  211 At,  211 Bi,  212 Bi,  212 Pb,  213 Bi,  214 Bi, and  225 Ac. 
     
     
         66 . The method of  claim 62 , wherein the cytotoxic agent is selected from the group consisting of ricin, ricin A-chain, doxorubicin, daunorubicin, paclitaxel, taxol, ethidium bromide, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, dihydroxy anthracenedione, actinomycin D, diphtheria toxin,  Pseudomonas  exotoxin (PE) A, PE40, abrin, abrin A chain, modeccin A chain, alpha-sarcin, gelonin, mitogellin, restrictocin, phenomycin, enomycin, curcin, crotin, calicheamicin,  Saponaria officinalis  inhibitor, maytansinoids, and glucocorticoid. 
     
     
         67 . The method of  claim 63 , wherein the cytotoxic agent is selected from the group consisting of ricin, ricin A-chain, doxorubicin, daunorubicin, paclitaxel, taxol, ethidium bromide, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, dihydroxy anthracenedione, actinomycin D, diphtheria toxin,  Pseudomonas  exotoxin (PE) A, PE40, abrin, abrin A chain, modeccin A chain, alpha-sarcin, gelonin, mitogellin, restrictocin, phenomycin, enomycin, curcin, crotin, calicheamicin,  Saponaria officinalis  inhibitor, maytansinoids, and glucocorticoid. 
     
     
         68 . The method of  claim 62 , wherein the radiation is selected from the group consisting of microwave, infrared, ultraviolet, X-ray, gamma ray, alpha particle radiation, beta ray and ionizing radiation. 
     
     
         69 . The method of  claim 63 , wherein the radiation is selected from the group consisting of microwave, infrared, ultraviolet, X-ray, gamma ray, alpha particle radiation, beta ray and ionizing radiation. 
     
     
         70 . The method of  claim 1 ,  2 ,  3 ,  4  or  6 , wherein the cell-penetrating polypeptide is further linked or bound to an imaging agent or detectable marker. 
     
     
         71 . The method of  claim 70 , wherein the imaging agent or detectable marker is selected from the group consisting of a radioisotope, a fluorophore, a fluorescent quencher, an enzyme, a luminescent compound, a chemiluminescent compound, a bioluminescent compound, a photon emitter, a heavy metal, a ferromagnetic agent, a contrast agent, a metal chelator, and an epitope. 
     
     
         72 . The method of  claim 48 , wherein the cancer is selected from the group consisting of colorectal cancer, osteosarcoma, non-small cell lung cancer, breast cancer, ovarian cancer, glial cancer, solid tumors, metastatic tumor, acute lymphoblastic leukemia, acute myelogenous leukemia, adrenocortical carcinoma, Kaposi sarcoma, lymphoma, anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain tumor, breast cancer, bronchial tumor, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancers, ductal carcinoma in situ, endometrial cancer, esophageal cancer, eye cancer, intraocular, retinoblastoma, metastatic melanoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors, glioblastoma, glioma, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, hepatoma, Hodgkin lymphoma, hypopharyngeal cancer, Langerhans cell histiocytosis, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ, lung cancer, non-small cell lung cancer, small cell lung cancer, lymphoma, AIDS-related lymphoma, Burkitt lymphoma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, melanoma, squamous neck cancer, mouth cancer, multiple myeloma, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oral cavity cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic carcinoma, papillary carcinomas, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal parenchymal tumors, pineoblastoma, pituitary tumor, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell cancer, salivary gland cancer, sarcoma, Ewing sarcoma, soft tissue sarcoma, squamous cell carcinoma, Sezary syndrome, skin cancer, Merkel cell carcinoma, testicular cancer, throat cancer, thymoma, thymic carcinoma, thyroid cancer, urethral cancer, endometrial cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms tumor. 
     
     
         73 . The method of  claim 49 , wherein the cancer is selected from the group consisting of colorectal cancer, osteosarcoma, non-small cell lung cancer, breast cancer, ovarian cancer, glial cancer, solid tumors, metastatic tumor, acute lymphoblastic leukemia, acute myelogenous leukemia, adrenocortical carcinoma, Kaposi sarcoma, lymphoma, anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain tumor, breast cancer, bronchial tumor, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancers, ductal carcinoma in situ, endometrial cancer, esophageal cancer, eye cancer, intraocular, retinoblastoma, metastatic melanoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors, glioblastoma, glioma, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, hepatoma, Hodgkin lymphoma, hypopharyngeal cancer, Langerhans cell histiocytosis, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ, lung cancer, non-small cell lung cancer, small cell lung cancer, lymphoma, AIDS-related lymphoma, Burkitt lymphoma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, melanoma, squamous neck cancer, mouth cancer, multiple myeloma, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oral cavity cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic carcinoma, papillary carcinomas, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal parenchymal tumors, pineoblastoma, pituitary tumor, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell cancer, salivary gland cancer, sarcoma, Ewing sarcoma, soft tissue sarcoma, squamous cell carcinoma, Sezary syndrome, skin cancer, Merkel cell carcinoma, testicular cancer, throat cancer, thymoma, thymic carcinoma, thyroid cancer, urethral cancer, endometrial cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms tumor. 
     
     
         74 . The method of  claim 7 , wherein the tumor is associated with a cancer selected from the group consisting of colorectal cancer, osteosarcoma, non-small cell lung cancer, breast cancer, ovarian cancer, glial cancer, solid tumors, metastatic tumor, acute lymphoblastic leukemia, acute myelogenous leukemia, adrenocortical carcinoma, Kaposi sarcoma, lymphoma, anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain tumor, breast cancer, bronchial tumor, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancers, ductal carcinoma in situ, endometrial cancer, esophageal cancer, eye cancer, intraocular, retinoblastoma, metastatic melanoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors, glioblastoma, glioma, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, hepatoma, Hodgkin lymphoma, hypopharyngeal cancer, Langerhans cell histiocytosis, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ, lung cancer, non-small cell lung cancer, small cell lung cancer, lymphoma, AIDS-related lymphoma, Burkitt lymphoma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, melanoma, squamous neck cancer, mouth cancer, multiple myeloma, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oral cavity cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic carcinoma, papillary carcinomas, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal parenchymal tumors, pineoblastoma, pituitary tumor, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell cancer, salivary gland cancer, sarcoma, Ewing sarcoma, soft tissue sarcoma, squamous cell carcinoma, Sezary syndrome, skin cancer, Merkel cell carcinoma, testicular cancer, throat cancer, thymoma, thymic carcinoma, thyroid cancer, urethral cancer, endometrial cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms tumor. 
     
     
         75 . The method of  claim 74 , wherein the tumor is a glioma. 
     
     
         76 . The method of  claim 7 , wherein the cellular/tissue necrosis or cellular/tissue apoptosis is associated with an ischemia, a chemical burn, a fire, radiation, hypothermia, freezing, a physical trauma, hypoxia, a poison, a chemotherapeutic agent, a cell damaging agent, a tumor or a cancer. 
     
     
         77 . The method of  claim 43 , wherein the therapeutic agent is selected from the group consisting of a cell-penetrating polypeptide comprising cell-penetrating determinants free of any additional active agent, a cell-penetrating polypeptide comprising cell-penetrating determinants coupled to a radioisotope, a cell-penetrating polypeptide comprising cell-penetrating determinants coupled to a cytotoxic agent, and a cell-penetrating polypeptide comprising cell-penetrating determinants coupled to a component with a cell protecting property. 
     
     
         78 . The method of  claim 77 , wherein a cell-penetrating polypeptide comprising cell-penetrating determinants free of any additional active agent is selected from the group consisting of 3E10 mAb, 3E10 scFv, a variant or a fragment thereof. 
     
     
         79 . The method of  claim 78 , wherein the variant is D31N variant of 3E10 mAb or 3E10 scFv. 
     
     
         80 . The method of  claim 77 , wherein the radioisotope is selected from the group consisting of  46 Sc,  47 Sc,  48 Sc,  67 Cu,  67 Ga,  72 Ga,  73 Ga,  90 Y,  67 Cu,  109 Pd,  111 Ag,  111 In,  125 I,  131 I,  149 Pm,  153 Sm,  166 Ho,  177 Lu,  186 Re,  188 Re,  211 At,  211 Bi,  212 Bi,  212 Pb,  213 Bi,  214 Bi, and  225 Ac. 
     
     
         81 . The method of  claim 77 , wherein the cytotoxic agent is selected from the group consisting of ricin, ricin A-chain, doxorubicin, daunorubicin, paclitaxel, taxol, ethidium bromide, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, dihydroxy anthracenedione, actinomycin D, diphtheria toxin,  Pseudomonas  exotoxin (PE) A, PE40, abrin, abrin A chain, modeccin A chain, alpha-sarcin, gelonin, mitogellin, restrictocin, phenomycin, enomycin, curcin, crotin, calicheamicin,  Saponaria officinalis  inhibitor, maytansinoids, and glucocorticoid. 
     
     
         82 . The method of  claim 77 , wherein a component with a cell protecting property is selected from the group consisting of hsp90, hsp84, hsp70, hsp27, hsp20, GRP78 and alpha B crystallin and portions thereof. 
     
     
         83 . A method for detecting an area or zone of cellular turnover comprising (a) contacting cells at a potential area or zone of cellular turnover with a cell-penetrating polypeptide comprising 3E10 scFv or cell-penetrating determinants of a lupus autoantibody or a fragment or variant thereof so that the cell-penetrating polypeptide binds extracellular DNA or its degradation product present at an area or zone of cellular turnover; (b) permitting cellular uptake of the cell-penetrating polypeptide of (a) at the area or zone of cellular turnover; and (c) detecting the presence of the cell-penetrating polypeptide inside the cell body, thereby detecting an area or zone of cellular turnover. 
     
     
         84 . The method of  claim 83  further comprising identifying a center of cellular turnover wherein the center marked by presence of a lysed cell produces a gradient of extracellular DNA such that (a) presence of greatest amount of extracellular DNA near the center results in greatest uptake of the cell-penetrating polypeptide by live cells near the center of cellular turnover and (b) presence of lesser amount of extracellular DNA away from the center results in lower uptake of the cell-penetrating polypeptide by live cells away from the center of cellular turnover, thereby identifying the center of cellular turnover. 
     
     
         85 . The method of  claim 35 , wherein the mammal is selected from mouse, rat, hamster, cat, dog, rabbit, bovine, pig, sheep, goat, horse, monkey or human. 
     
     
         86 . A method for increasing uptake and enhancing efficacy of a cell-penetrating polypeptide comprising an anti-DNA antibody or a fragment or a variant thereof in targeting tumor or cancer cells comprising (a) inducing additional extracellular DNA release at or near the tumor or cancer cells through the use of a cell-damaging agent or introducing additional extracellular DNA or artificial DNA at or near the tumor or cancer cells; (b) administering the cell-penetrating polypeptide; (c) allowing the cell-penetrating polypeptide to form additional complexes with the additional extracellular DNA or artificial DNA; and (d) permitting the additional complexes in (c) to contact the tumor or cancer cells, thereby increasing uptake and enhancing efficacy of a cell-penetrating polypeptide comprising an anti-DNA antibody or a fragment or a variant thereof in targeting tumor or cancer cells. 
     
     
         87 . A method for diagnosing or identifying a site of cell or tissue injury, an ischemic site with necrotic or apoptotic cells, a tumor site with necrotic or apoptotic cells, a cancer site with necrotic or apoptotic cells, or a site of cellular turnover comprising: (a) administering a cell-penetrating polypeptide comprising cell-penetrating determinants so as to interrogate one or more sites with the cell-penetrating polypeptide; (b) detecting the presence of the cell-penetrating polypeptide within the nucleus of a live cell; and (c) determining if a cluster of live cells with the cell-penetrating polypeptide is present at the interrogated sites, wherein presence of a cluster of live cells with the cell-penetrating polypeptide is indicative of a site of cell or tissue injury, an ischemic site with necrotic or apoptotic cells, a tumor site with necrotic or apoptotic cells, a cancer site with necrotic or apoptotic cells, or a site of cellular turnover, thereby, diagnosing or identifying a site of cell or tissue injury, an ischemic site with necrotic or apoptotic cells, a tumor site with necrotic or apoptotic cells, a cancer site with necrotic or apoptotic cells, or a site of cellular turnover. 
     
     
         88 . A method for increasing or enhancing cytoprotection at an ischemic site comprising:
 (a) administering DNA to the site in an extracellular space so as to permit increased targeting of a cell-penetrating polypeptide comprising 3E10 scFv or cell-penetrating determinants of a lupus autoantibody or a fragment or variant thereof, and a cytoprotective agent;   (b) administering the cell-penetrating polypeptide of (a);   (c) contacting the extracellular DNA of (a) or its degradation product at an ischemic site with a cell-penetrating polypeptide of (a) so that the cell-penetrating polypeptide binds extracellular DNA or its degradation product at an ischemic site so as to form a complex;   (d) contacting a live cell at an ischemic site with the complex in (c) so as to bind and penetrate the live cell; and   (e) permitting additional complexes to form as in (c) and contacting additional live cells with said complexes so as to bind and penetrate additional live cells at an ischemic site;   thereby, delivering additional cytoprotective agent to a cell and delivering cytoprotective agent to more cells at an ischemic site, thus, increasing or enhancing cytoprotection at an ischemic site.   
     
     
         89 . The method of  claim 88 , wherein the cytoprotective agent is a heat shock protein, stress protein or chaperone protein. 
     
     
         90 . The method of  claim 89 , wherein the heat shock protein, stress protein or chaperone protein is selected from a group consisting of Hsp-70, HspA1A, HspA1B, HspA1L, HspA2, HspA5, HspA6, HspA7, HspA8, HspA9, HspA12A, HspA12B, HspA13, HspA14, HspH1, HspH2, HspH3, and HspH4, Hsp40, DNAJA1, DNAJA2, DNAJA3, DNAJA4, DNAJB1, DNAJB2, DNAJB3, DNAJB4, DNAJB5, DNAJB6, DNAJB7, DNAJB8, DNAJB9, DNAJB11, DNAJB12, DNAJB13, DNAJB14, DNAJC1, DNAJC2, DNAJC3, DNAJC4, DNAJC5B, DNAJC5G, DNAJC6, DNAJC7, DNAJC8, DNAJC9, DNAJC10, DNAJC11, DNAJC12, DNAJC13, DNAJC14, DNAJC15, DNAJC16, DNAJC17, DNAJC18, DNAJC19, DNAJC20, DNAJC21, DNAJC22, DNAJC23, DNAJC24, DNAJC25, DNAJC26, DNAJC27, DNAJC28, DNAJC30, HSPB1, HSPB2, HSPB3, HSPB4, HSPB5, HSPB6, HSPB7, HSPB8, HSPB9, HSPB10, HSPB11, hsp90, hsp84, hsp27, hsp20, GRP78, alpha B crystallin, hsp60, hsp100, GRP94, GRP170, AIPL1, FKBP1A, FKBP1B, FKBP2, FKBP3, FKBP5, FKBP6, FKBP7, FKBP8, FKBP9, FKBP9L, FKBP10, FKBP11, FKBP12, FKBP14, FKBP15, FKBP38, FKBP52 and LOC541473. 
     
     
         91 . The method of  claim 88 , wherein the ischemic site is associated with a condition selected from the group consisting of cardiac ischemia, myocardial infarction, ischemic colitis, mesenteric ischemia, brain ischemia, acute ischemic stroke, transient ischemic attack, vascular dementia, stroke, acute limb ischemia, cyanosis, gangrene, an embolism, a thrombosis, an atherosclerosis artery, a trauma, venous outflow obstruction, acute arterial ischemia, an aneurysm, mitral valve disease, chronic atrial fibrillation, cardiomyopathies, an occlusion, pulmonary embolus, acute arterial occlusion, peripheral arterial disease, a thromboembolism, a compression, a shearing, a laceration, arterial dissection, iatrogenic arterial injury, thoracic outlet syndrome, atherosclerosis, hypoglycemia, tachycardia, hypotension, septic shock, heart failure, superior mesenteric artery syndrome, sickle cell disease, induced g-force, frostbite, improper cold compression therapy, tourniquet application, increased glutamate receptor stimulation, arteriovenous malformation, peripheral artery occlusive disease, rupture of significant blood vessel, anemia, cardiac arrhythmia, cardiorespiratory arrest, subarachnoid hemorrhage, intracerebral hemorrhage, cerebral infarction, focal brain ischemia, global brain ischemia, pulmonary infarction, lung infarction, splenic infarction, limb infarction, deep vein thrombosis, phlebitis, skeletal muscle infarction, diabetes mellitus, avascular necrosis, testicular torsion, testicular infarction, central retinal artery infarction, sepsis, antiphospholipid syndrome, giant-cell arteritis, hemia, volvulus, hepatic ischemia, dehydration and infection. 
     
     
         92 . The method of  claim 88 , wherein the cell-penetrating polypeptide comprising 3E10 scFv or cell-penetrating determinants of a lupus autoantibody or a fragment or variant thereof, and a cytoprotective agent is a fusion protein. 
     
     
         93 . The method of  claim 92 , wherein the fusion protein is a single chain polypeptide. 
     
     
         94 . The method of  claim 2 , wherein the cell penetrating polypeptide is introduced after step (a). 
     
     
         95 . A composition comprising (a) a cell-penetrating polypeptide which comprises cell-penetrating determinants, (b) extracellular DNA or artificial DNA and (c) a pharmaceutically acceptable carrier. 
     
     
         96 . The composition of  claim 95 , wherein (a) and (b) are the sole therapeutic agents in the composition.