Discovery and Optimization of HKT288, a Cadherin-6–Targeting ADC for the Treatment of Ovarian and Renal Cancers

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 () 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 , including 40% of models on the PCT, and features a preclinical safety profile supportive of progression toward clinical evaluation. 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. .

Modulation of Macropinocytosis-Mediated Internalization Decreases Ocular Toxicity of Antibody–Drug Conjugates

“…Interestingly, both, an anti-CDH6 sulfo-SPDB-DM4 as well as an IgG 1 sulfo-SPDB-DM4 control induced corneal toxicities in cynomolgus monkeys, suggesting that the toxicity was caused by the linker-payload and not by engagement of the target in the cornea or by the attributes of the antibody (17). Consistent with this conclusion, an IgG 2 antibody conjugated to a similar druglinker, SPDB-DM4, had an IC 50 of 11.6 nmol/L in the HCEC proliferation assay, whereas when conjugated to mcMMAF, it was 136.6 nmol/L, approximately 10-fold less cytotoxic.…”

“…8), CD19 (9), CD70 (10), HER2 (11,12), mesothelin (13), folate receptor (14), CA9 (7), and 5T4 (15), none of which is known to be expressed in the cornea, except HER2 (16). More recently, corneal toxicities were observed in non-human primates (NHP) treated with an ADC against CDH6 containing an N-Succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB) linker-payload (17). Interestingly, most of these ADCs contain either monomethyl auristatin F (MMAF) or N2'-Deacetyl-N2'-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4), suggesting a relationship with the drug linker.…”

Cadherin-6 mediates thrombosisin vivo

“…Tumor cells can activate platelets to promote tumor growth, invasion, and immune evasion. [20] Cadherin-6 overexpression has been identified in ovarian and renal cancers [21,22], inciting the possibility that tumor-expressed cadherin-6 mediates tumor-platelet crosstalk. Treatment of colorectal cancer or melanoma cells with an antibody targeting the cadherin-17 RGD motif reduced their metastatic potential in vivo.…”

Extracellular domains of E-cadherin determine key mechanical phenotypes of an epithelium through cell- and non-cell-autonomous outside-in signalling

“…Models of juxtaposed domains at the hybrid interfaces were built using the web-based interface of SWISS-MODEL 34 and existing protein structures as templates: 2A62, 3Q2V, 3Q2W, 1L3W and 5VEB 5,9,47,54 . Calcium ions were placed by hand and sidechains angles were orientated to coordinate the ions in Coot 55 .…”