736 Background: Pancreatic cancer is an aggressive tumors resistant to standard therapies, due to lack of early detection tools and effective treatments. The current 1L SOC is combination chemotherapy, most often FOLFIRINOX or gemcitabine plus nab-paclitaxel. The relapse rate ranges between 70-90%, typically within the first 1-2 years, and the 5-year survival rate is approximately 13%. Recently, antibody-drug conjugate (ADC) promises an emerging modality for effective treatment of solid tumors, targeting Her2, TROP2, and CLDN18.2, etc. Cadherin-17 (CDH17) is a novel GI cancer target we recently identified that was highly expressed in about 70% in clinical tumor samples tested. This study investigates the safety and druggability of CDH17-ADC, ARB1002, for treating pancreatic adenocarcinoma (PDAC). Methods: A monoclonal antibody selected from a library of 300 hybridoma generated again human CDH17, ARB1002, is conjugated linker-payload, MC-VC-PAB-MMAE. Binding affinity of ARB1002 was measured by BLA and FACS; internalization and cytotoxicity assays were determined using pancreatic cancer cell lines, AsPC1 and HPAFII, as well as other GI cancer cell lines. By-stander effect and cross-reactivities with other cadherin family members were also determined. PK and safety profiles of ARB1002 were evaluated in nonhuman primates. Results: ARB1002 demonstrated highly selective binding to CDH17-expressing cancer cells with sub nM affinity in FACS-based assay, while exhibited efficient internalization and potent cytotoxicity against various CDH17-positive GI cancer cells. The drug also mediated antibody-dependent cellular cytotoxicity, complement-mediated cytotoxicity, and bystander killing, enabling effective eradication of tumors with heterogeneous CDH17 expression. In PDAC xenograft mouse model, it achieved significant tumor growth inhibition without adverse effects, and notably, showed robust antitumor killing in gemcitabine-resistant pancreatic xenografts. In a NPH toxicity study up to 10mpk repeated dosing, ARB1002 displayed a favorable pharmacokinetic profile and improved tolerability compared to other ADCs with the same payload. Furthermore, ARB1002 also demonstrated good CMC production yield and long-term stability for IND-enabling application. Conclusions: ARB1002, promises to be a potential first-in-class/best-in-class ADC for treating advanced pancreatic cancers refractory to 1L gemcitabine chemotherapy.
Luk et al. (Sat,) studied this question.