Abstract Background: Aberrant glycosylation and elevated expression of MUC1 are common in non-small cell lung cancer (NSCLC), in which the two domains of the MUC1 heterodimer—MUC1-N, the shed extracellular subunit, and MUC1-C, the membrane-anchored oncogenic subunit—serve as therapeutically relevant yet biologically distinct targets. PankoMab-Dxd (DS-3939a analog) is an antibody-drug conjugate (ADC) directed against MUC1-N glycoepitopes, whereas XYA02 is a next-generation ADC targeting the transmembrane MUC1-C subunit that remains tumor anchored and is involved in numerous tumor survival signaling pathways. A direct comparison of these two targeting strategies reveals unique insights into the relative potency of drugs aimed at different MUC1 domains. Methods: We assessed antigen density, internalization, in vitro cytotoxicity and in-vivo antitumor efficacy of NSCLC cell lines. ADCs (XYA02 and DS-3939a analog) were evaluated using proliferation assays, apoptosis induction, and in vivo tumor growth inhibition studies. Safety of XYA02 in nude mice was assessed by monitoring the body weight, CBC, hematologic parameters and vital organ histology. Results: High-affinity binding of anti-MUC1-C monoclonal antibody (MAb)* was observed across multiple NSCLC cell lines endogenously expressing MUC1. At 4°C, robust cell-surface binding was detected, and shifting to 37°C resulted in efficient receptor internalization, consistent with productive ADC trafficking. Incubation of NSCLC cell lines with increasing concentrations of the MUC1-C-targeting ADC (XYA02) produced potent, dose-dependent cytotoxicity with low-nanomolar IC values. In contrast, treatment of the same models with a DS-3939a analog, which targets the shed MUC1-N subunit, resulted in markedly higher IC values.In vivo, XYA02 achieved durable tumor regressions in both NSCLC CDX and PDX models, whereas the DS-3939a analog produced variable responses. Both ADCs were well tolerated; however, XYA02 demonstrated a superior therapeutic index, with greater efficacy at comparable administered doses. Conclusions: Our findings demonstrate that targeting the membrane-tethered MUC1-C subunit with XYA02 provides superior antitumor efficacy compared with MUC1-N-directed DS-3939a analog in preclinical NSCLC models. Enhanced efficacy appears to be driven by uniform antigen binding and potential avoidance of MUC1-N-mediated antigen sink effects. These data support prioritizing MUC1-C-selective ADCs for clinical development in NSCLC and other MUC1-driven malignancies.* https://patents.google.com/patent/US20230265208A1/en Citation Format: Surender Kharbanda, Rehan Ahmad, Changchuin Mao, Sourav Choudhary, Brian Lawney, Govind Panchamoorthy, Ravi Jasuja. Comparative efficacy of MUC1-C (XYA02) and MUC1-N (PankoMab, DS-3939a analog) antibody-drug conjugates in preclinical NSCLC abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3175.
Kharbanda et al. (Fri,) studied this question.