Abstract 2530: Long-term tumor regression induced by a novel antibody drug conjugate that targets 5T4, an oncofetal antigen expressed on tumor-initiating cells

Abstract Antibody-drug conjugates (ADCs) represent a promising therapeutic modality for the clinical management of cancer. We have developed a novel ADC that targets 5T4 (also known as TPBG), a tumor-associated antigen that rapidly internalizes. In preclinical models of NSCLC, 5T4 was identified as a marker of undifferentiated tumorigenic cells that express properties of tumor-initiating cells (TICs) and was associated with a highly proliferating (Ki67 positive) cell phenotype. Based on the biological properties of 5T4, we designed the ADC by conjugating an internalizing humanized anti-5T4 antibody (Ab), A1, to the tubulin inhibitor monomethylauristatin F via a maleimidocaproyl (mc) linker (A1mcMMAF) with a drug/antibody ratio of ∼ 4. The A1 Ab has a Kd of 0.9 nM against the 5T4 antigen, binds to a broad range of 5T4 expressing cell lines, and rapidly internalizes (66% internalized within 4h). As an ADC, A1mcMMAF retains similar properties to the unconjugated Ab. In vitro, A1mcMMAF exhibited potent and target-specific cytotoxic activity against a panel of 5T4+ cell lines with an IC50 of 5 ng Ab/ml against high 5T4 expressing cells. In vivo, A1mcMMAF exhibited potent anti-tumor activity in all five tumor models tested (with a broad range of 5T4 expression) and caused long-term regressions monitored up to 100 days after the last dose. Strikingly, animals were cured of disease in every model with doses as low as 3 mg Ab/kg Q4d x 4. In a lung cancer patient-derived xenograft in which 5T4 is not uniformly expressed, but instead is preferentially expressed on the less differentiated sub-population of tumor cells, A1mcMMAF treatment resulted in sustained tumor regression. This result highlights the clinical potential of ADCs that target aggressive cell subpopulations such as TICs. In exploratory safety studies, A1mcMMAF exhibited no overt toxicities when administered at 10 mg Ab/kg/cycle x 2 to cynomolgus monkeys and had a half-life of ∼5 days. The encouraging efficacy and safety data of the conjugate resulting in high therapeutic index in preclinical models warrants further clinical testing of this ADC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2530. doi:1538-7445.AM2012-2530