Abstract B109: ASN004, a novel 5T4-targeted Dolaflexin ADC, causes complete and durable tumor regression in a variety of tumor xenograft models

Abstract

Abstract The 5T4 oncofetal antigen (trophoblast glycoprotein) is expressed in a wide range of malignant tumors, while showing very limited expression in normal adult tissues. This selective pattern of expression establishes 5T4 as an attractive therapeutic target for the Antibody-Drug Conjugate (ADC) strategy. ASN004 is an anti-5T4 ADC that incorporates a novel single-chain homo-dimer antibody, Fleximer® linker technology (Mersana Therapeutics), and cytotoxic dolastatin (auristatin) analog warheads, with a drug/antibody ratio of ~15:1. ASN004 shows high affinity for the 5T4 antigen (Kd < 30 pM), with selective binding and internalization to 5T4-expressing tumor cells. Potent, selective cytotoxicity has been determined for a diverse panel of tumor cell lines. ASN004 provides complete and durable tumor regression in multiple tumor xenograft models, derived from human lung, breast, cervical, and gastric tumor cell lines having a range of 5T4 expression levels. Tumor-free survivors could be achieved in tumor models with a single dose of ASN004, as low as 1 mg/kg iv. The broad, superior activity of ASN004 was demonstrated in a head-to-head study against trastuzumab-DM1, in a low-5T4/high-HER2 expressing tumor model. Finally, efficacy of ASN004 in patient-derived tumor xenograft (PDX) models will be presented. In summary, ASN004 has been established as a promising ADC therapeutic for multiple tumor types, encompassing a wide range of 5T4-expression levels. IND-enabling studies are ongoing in preparation for advancement to clinical development. Citation Format: Roger A. Smith, David J. Zammit, Sanjeeva P. Reddy. ASN004, a novel 5T4-targeted Dolaflexin ADC, causes complete and durable tumor regression in a variety of tumor xenograft models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B109.