Bialucha, Carl, Collins, Scott, Li, Xiao, Saxena, Parmita, Zhang, Xiamei, Duerr, Clemens, Shim, Yeonju, Mosher, Rebecca, Ostrom, Lance, Hu, Tiancen, Bilic, Sanela, Liric Rajlic, Ivana, Capka, Vladimir, Sharp, Fiona, Antonakos, Brandon, Wagner, Joel, Elliott, Ginell, Veloso, Artur, Piel, Jessica, Xu, Jian, Flaherty, Meghan, Mansfield, Keith, London, Anne, Kurz, Markus, Nguyen, Duc, Meyer, Matthew, Faris, Jason, Janatpour, Mary, Chan, Vivien, Yoder, Nicholas, Catcott, Kelly, McShea, Molly, Sun, Xiuxia, Gao, Hui, Williams, Juliet, Hofmann, Francesco, Engelman, Jeffrey, Ettenberg, Seth, Sellers, William and Lees, Emma (2017) Discovery and optimization of HKT288, a cadherin-6-targeting ADC for the treatment of ovarian and renal cancers. Cancer Discovery, 7 (9). pp. 1030-1045. ISSN 21598290

Abstract

Despite an improving therapeutic landscape, significant challenges remain in treating the majority of patients with advanced ovarian or renal cancer. We identified the cell-cell adhesion molecule cadherin-6 (CDH6) as a lineage gene having significant differential expression in ovarian and kidney cancers. HKT288 is an optimized CDH6-targeting DM4-based antibody-drug conjugate (ADC) developed for the treatment of these diseases. Our study provides mechanistic evidence supporting the importance of linker choice for optimal antitumor activity and highlights CDH6 as an antigen for biotherapeutic development. To more robustly predict patient benefit of targeting CDH6, we incorporate a population-based patient-derived xenograft (PDX) clinical trial (PCT) to capture the heterogeneity of response across an unselected cohort of 30 models-a novel preclinical approach in ADC development. HKT288 induces durable tumor regressions of ovarian and renal cancer models in vivo, including 40% of models on the PCT, and features a preclinical safety profile supportive of progression toward clinical evaluation. SIGNIFICANCE: We identify CDH6 as a target for biotherapeutics development and demonstrate how an integrated pharmacology strategy that incorporates mechanistic pharmacodynamics and toxicology studies provides a rich dataset for optimizing the therapeutic format. We highlight how a populationbased PDX clinical trial and retrospective biomarker analysis can provide correlates of activity and response to guide initial patient selection for fi rst-in-human trials of HKT288.

Item Type:	Article
Date Deposited:	14 Nov 2017 00:45
Last Modified:	25 Jan 2019 00:45
URI:	https://oak.novartis.com/id/eprint/31781