Antibody-mediated FOXP3 protein therapy induces apoptosis in cancer cells in vitro and inhibits metastasis in vivo.
In addition to its immune suppressive function in T-regulatory cells, the nuclear transcription factor, FOXP3, has been identified as a tumor suppressor. To evaluate the clinical efficacy of monoclonal antibody (mAb) 3E10 Fv antibody-mediated FOXP3 protein therapy of cancer, the Fv-FOXP3 fusion protein produced in Pichia pastoris was tested on breast, ovarian, and colon cancer cells in vitro, and with colon cancer cells in vivo in a mouse model of colon cancer metastasis to liver. Treatment with Fv-FOXP3 resulted in dose-dependent cell death of cancer cells in vitro. Apoptosis was established as a mechanism of cell death by demonstrating increased production of the p17 activated fragment of caspase-3 by cancer cells in response to Fv-FOXP3 and inhibition of cell killing by the caspase inhibitor, Z-VAD-FMK. Fv-FOXP3 treatment resulted in clinically significant reduction in tumor burden in a syngeneic model of colon cancer metastasis to liver in Balb/c mice. These results represent the first demonstration of effective full-length FOXP3 protein therapy and emphasize the clinical potential of mAb 3E10 as an intracellular and intranuclear delivery vehicle of FOXP3 for prevention and treatment of cancer metastasis.
Heinze
Emil
E
Veterans Affairs Greater Los Angeles Health Care System, Sepulveda, CA,91393, USA.
Baldwin
Scott
S
Chan
Grace
G
Hansen
James
J
Song
Jason
J
Clements
Douglas
D
Aragon
Robert
R
Nishimura
Robert
R
Reeves
Mark
M
Weisbart
Richard
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D004305:Dose-Response Relationship, Drug; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D007128:Immunoglobulin Fragments / Q000235:genetics / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D014162:Transfection
D000911:Antibodies, Monoclonal; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018796:Immunoconjugates; D007128:Immunoglobulin Fragments; D011993:Recombinant Fusion Proteins; C505407:CASP3 protein, human; D053148:Caspase 3