Regression of established breast carcinoma xenografts with antibody-directed enzyme prodrug therapy against c-erbB2 p185.
The enzyme carboxypeptidase G2 (CPG2) was conjugated to the rat IgG2a monoclonal antibody (mAb) ICR12, which recognizes the external domain of the human c-erbB2 protooncogene product. The conjugate retained antigen-binding and enzyme activity. Radiolabeled conjugate localized efficiently and stably to MDA MB 361 breast carcinoma xenografts, which overexpress the c-erbB2 gene product p185. Radiotracer determinations and plasma enzyme activity studies in nu/nu mice gave conjugate blood clearance rate half-lives of approximately 4 days. In separate antibody-directed enzyme prodrug therapy regimes, one dose of the 4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl-L-glutamic acid prodrug was administered to nu/nu mice bearing established MDA MB 361 tumors (mean volume, 170-260 mm3). In mice which had received ICR12-CPG2 12-14 days previously, sustained dose-dependent tumor stasis or regressions were effected, which in some cases persisted throughout observation periods of up to 90 days. In control mice which had received the isotype-matched irrelevant mAb ICR16-CPG2 conjugate, tumors grew progressively, as did those in mice treated with prodrug alone, or treated simultaneously with ICR12-CPG2 and prodrug at the maximum tolerated dose. Control chemotherapy with conventional drugs proved toxic and induced only minimal growth delays.
Eccles
S A
SA
CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, United Kingdom.
Court
W J
WJ
Box
G A
GA
Dean
C J
CJ
Melton
R G
RG
Springer
C J
CJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000627:therapeutic use*; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D014183:Transplantation, Heterologous; D011623:gamma-Glutamyl Hydrolase / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D011355:Prodrugs; D018719:Erb-b2 Receptor Tyrosine Kinases; D011623:gamma-Glutamyl Hydrolase