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 population-based PDX clinical trial and retrospective biomarker analysis can provide correlates of activity and response to guide initial patient selection for first-in-human trials of HKT288. Cancer Discov; 7(9); 1030-45. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 920.
Highlights
Despite recent therapeutic advances in both ovarian and renal cancers, there remains significant unmet medical need for patients suffering from these malignancies, especially in advanced settings
Our work provides a framework for knowledge-based Antibody-drug conjugates (ADC) drug discovery, incorporating a hypothesis-driven target identification strategy, as well as the optimal design and preclinical evaluation of ADCs including broad assessment of efficacy across a heterogeneous population of patient-derived xenograft (PDX) models
CDH6 ranked in the top 0.3% of all surface protein genes for ovarian serous, renal clear cell, and papillary carcinoma based on expression differential between samples from a given tumor type and all available normal tissue samples, and requiring that maximum expression in normal tissues was in the lowest 25th percentile of expression values for all genes
Summary
Despite recent therapeutic advances in both ovarian and renal cancers, there remains significant unmet medical need for patients suffering from these malignancies, especially in advanced settings. Exemplifying this unmet need, most patients with ovarian cancer present with advanced-stage disease (70%) and face an associated low 5-year survival rate of 28% [1]. ADCs typically utilize a cytotoxic agent, such as monomethyl auristatin E (MMAE), maytansinoids (DM1 and DM4), calicheamicin, or a pyrrolobenzodiazepine dimer (PBD), linked to a targetspecific mAb. There are two approved ADCs: brentuximab vedotin, a MMAE-based ADC targeting CD30 in lymphoma [2, 3], and ado-trastuzumab emtansine (T-DM1), a DM1-. Multiple additional ADCs are currently in clinical development (reviewed in refs. 5–7)
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