Abstract 2968: A novel bispecific CD3/CDH19 antibody construct (CDH19 BiTE) directs potent killing of melanoma cells in vitro and in vivo and is enhanced by blockade of PD-L1

Abstract

Abstract CDH19 is an unconventional type 2 cadherin widely expressed in malignant melanoma with limited expression in normal tissues. RNAseq and immunohistochemical analysis of CDH19 in human samples confirmed its over-expression in >60% of melanoma, whereas normal expression primarily occurred in tissues derived from the neural crest such as nerve fibers and autonomic ganglia. CD3 based bi-specific T-cell engagers (BiTEs) were used to determine if redirected lysis of T-cells against CDH19 would drive anti-tumor efficacy. In vitro, the CDH19 BiTEs were high affinity binders to both human and cyno CDH19, and were able to induce specific T-cell activation and cytotoxicity against a panel of melanoma cell lines. In addition, soluble CDH19 levels were detected in human serum and the effects of BiTE cytotoxicity toward melanoma cells in the presence of soluble CDH19 was investigated. In vivo studies were conducted to confirm the specificity and activity of CDH19 BiTEs in xenograft models of melanoma. The CDH19 BiTE AMG-CDH19X was able to cause tumor growth inhibition in models expressing as few as 250 receptors per cell, and inhibition of tumor growth was enhanced by the addition of a blocking antibody against PD-L1. Immunohistochemical analysis of post-treatment xenograft samples suggested that anti-PD-L1 the persistence of tumor reactive T cells, and provided rationale for combining a BiTE against CDH19 with a PD-1 or PD-L1 blocking antibody in melanoma. In summary, targeting CDH19 presents a promising novel opportunity for BiTEs in the treatment of melanoma, both alone and in combination with current standard of care. Citation Format: Gordon E. Moody, Jodi Moriguchi, Shyun Li, Fei Lee, Brendon Frank, Amy Gilbert, Ryan Case, Khue Dang, Beth Hinkle, Suzanne Coberly, James Rottman, Kim Merriam, Julie Bailis, Pedro J. Beltran. A novel bispecific CD3/CDH19 antibody construct (CDH19 BiTE) directs potent killing of melanoma cells in vitro and in vivo and is enhanced by blockade of PD-L1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2968.