Antibody-mediated p53 protein therapy prevents liver metastasis in vivo.
To evaluate the clinical efficacy of monoclonal antibody (mAb) 3E10 Fv antibody-mediated p53 protein therapy, an Fv-p53 fusion protein produced in Pichia pastoris was tested on CT26.CL25 colon cancer cells in vitro and in vivo in a mouse model of colon cancer metastasis to the liver. In vitro experiments showed killing of CT26.CL25 cells by Fv-p53 but not Fv or p53 alone, and immunohistochemical staining confirmed that Fv was required for transport of p53 into cells. Prevention of liver metastasis in vivo was tested by splenic injection of 100 nmol/L Fv-p53 10 min and 1 week after injection of CT26.CL25 cancer cells into the portal vein of BALB/c mice. Mice were sacrificed 1 week after the second injection of Fv-p53 and assigned a quantitative metastasis score. Control mice had an average metastasis score of 3.3 +/- 1.3, whereas mice treated with Fv-p53 had an average metastasis score of 0.8 +/- 0.4 (P = 0.004). These results indicate that Fv-p53 treatment had a profound effect on liver metastasis and represent the first demonstration of effective full-length p53 protein therapy in vivo. mAb 3E10 Fv has significant clinical potential as a mediator of intracellular and intranuclear delivery of p53 for prevention and treatment of cancer metastasis.
Hansen
James E
JE
Medical Center, Veterans Affairs Greater Los Angeles Healthcare System, 16111 Plummer Street, Sepulveda, CA 91343, USA.
Fischer
Laurice K
LK
Chan
Grace
G
Chang
Sophia S
SS
Baldwin
Scott W
SW
Aragon
Robert J
RJ
Carter
Jacqueline J
JJ
Lilly
Michael
M
Nishimura
Robert N
RN
Weisbart
Richard H
RH
Reeves
Mark E
ME
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy; D005260:Female; D006801:Humans; D007128:Immunoglobulin Fragments / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D007128:Immunoglobulin Fragments; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53