Preclinical characterization of MC339: A novel radiotherapeutic agent for DLL3 expressing cancers

BackgroundNeuroendocrine neoplasms (NENs), including small cell lung cancer (SCLC) and treatment-emergent neuroendocrine prostate cancer (NEPC), commonly exhibit upregulated surface expression of the atypical notch Delta-like ligand 3 (DLL3), a protein expressed almost exclusively by tumor cells. MC339 is a novel macrocyclic peptide binder to DLL3 designed to achieve high, rapid uptake and retention into tumor tissue and fast clearance of the unbound compound via the renal route. MC339 complexed with radioisotopes can be used for therapy or imaging. The purpose of these preclinical studies was to characterize in vitro and in vivo properties of MC339.MethodsBinding affinity and selectivity were characterized using surface plasmon resonance (SPR). Cell binding and internalization was determined in a cell-based assay in cell lines expressing DLL3 (SHP-77, CT26.DLL3). Cytotoxicity was evaluated in SHP-77 cells using a Cell Titer Glow assay. In vivo biodistribution and anti-tumor activity was assessed in a subcutaneous cell-derived xenograft (CDX) SCLC model.ResultsMC339 binds rapidly and selectively to human DLL3 with picomolar affinity. A SHP-77 cell-based assay demonstrated high uptake (67%) and internalization (34%) of Lu-MC339. Similarly, there was high uptake (49%) and internalization (27%) in CT26 cells engineered to express DLL3. Conversely there was minimal binding in CT26.WT cells, indicating specificity of binding to DLL3. Dose-dependent cytotoxicity was also demonstrated using MC339. Biodistribution studies of Lu-MC339 in a mouse CDX model (SHP-77) demonstrated rapid radionuclide tumor uptake, persistent tumor retention throughout the study (12.2%IA/g at 24h) and favorable tumor:kidney ratio (5:1). Kidneys had the highest uptake of Lu-MC339 in healthy tissue suggesting that the major route of elimination was renal excretion. In the same model, a single dose of Ac-MC339 (0.35-1.4 μCi) resulted in robust and sustained tumor regression and prolonged survival.ConclusionsTaken together, these studies support further investigation of the novel therapeutic MC339 as a treatment for patients with DLL3-expressing solid tumors.Legal entity responsible for the studyMariana Oncology Inc.FundingMariana Oncology Inc.DisclosureA. Savinainen, L. Wu, T. Bruton, A. Chonkar, J. Cupido, J. Dearling, C. Huang, K. Lee, Z. Ma, H. Mok, K. Nabi, A. Salih, A. Sutton, L. Tavera, M. Wan, Z. Wang, X. Xu, J. Xu, A. Zidell, A. Ricardo: Financial Interests, Personal, Full or part-time Employment: Mariana Oncology Inc.