Long-term Tumor Regression Induced by an Antibody-Drug ConjugateThatTargets5T4,anOncofetalAntigenExpressed on Tumor-Initiating Cells

Antibody–drug conjugates (ADC) represent a promising therapeutic modality for the clinical management of cancer. We sought to develop a novel ADC that targets 5T4, an oncofetal antigen expressed on tumorinitiating cells (TIC), which comprise the most aggressive cell population in the tumor. We optimized an anti5T4ADC(A1mcMMAF)bysulfydryl-basedconjugationofthehumanizedA1antibodytothetubulininhibitor monomethylauristatin F (MMAF) via a maleimidocaproyl linker. A1mcMMAF exhibited potent in vivo antitumor activity in a variety of tumor models and induced long-term regressions for up to 100 days after thelastdose.Strikingly,animalsshowedpathologiccompleteresponseineachmodelwithdosesaslowas3mg antibody/kgdosedevery4days.Inanon–smallcelllungcancerpatient-derivedxenograftmodel,inwhich5T4 is preferentially expressed on the less differentiated tumor cells, A1mcMMAF treatment resulted in sustained tumor regressions and reduced TIC frequency. These results highlight the potential of ADCs that target the most aggressive cell populations within tumors, such as TICs. In exploratory safety studies, A1mcMMAF exhibited no overt toxicities when administered to cynomolgus monkeys at doses up to 10 mg antibody/kg/ cycle � 2 and displayed a half-life of 5 days. The preclinical efficacy and safety data established a promising therapeutic index that supports clinical testing of A1mcMMAF. Mol Cancer Ther; 12(1); 38–47. � 2012 AACR.