Abstract 5443: IPH4502, a differentiated Nectin-4 exatecan antibody-drug conjugate
Authors: Romain Remark, Cécile Bonnafous, Laura Chiossone, Caroline Soulas, Cyril Perrier, Sivan Bokobza, Rachel Courtois, Julie Lopez, Grégory Fenaux, Olivier Benac, Barbara Carrette, Robin Letay-Drouet, Raja Bonifay, Marion Gaudin, Séverine Augier, Léa Simon, Agnès Represa, Ariane Morel, Eric Vivier, Yannis Morel, Nicola Beltraminelli, Carine Paturel
Journal: Cancer Research (2025)

Abstract Background: Nectin-4 is a cell-adhesion molecule expressed in many solid tumors. Enfortumab vedotin (EV, PADCEV®), an antibody-drug conjugate (ADC) targeting Nectin-4 with a monomethyl auristatin E (MMAE) payload, is approved for the treatment of urothelial cancer (UC), which exhibits the highest Nectin-4 expression among all solid tumor types. To address the unmet medical need of UC patients who discontinue EV due to toxicity, lack of efficacy, or ineligibility for this approved therapy, and to expand Nectin-4 targeting in tumor indications with lower Nectin-4 expression beyond UC, we have developed IPH4502, a differentiated anti-Nectin-4 ADC conjugated to exatecan with a cleavable hydrophilic linker, and a drug-to-antibody ratio of 8. Methods: Nectin-4 immunohistochemistry (IHC) was performed on formalin-fixed, paraffin-embedded tissue-microarrays. Internalization was evaluated in vitro, and bystander effect was evaluated in vivo. In vivo studies were also conducted to evaluate anti-tumor activity using syngeneic mouse models, cell line-derived xenografts, and patient-derived xenografts (PDXs) from various indications. Results: IHC revealed that Nectin-4 is overexpressed in tumor tissues from several cancer types including but not limited to UC, esophageal cancer, triple-negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and prostate cancer. IPH4502 demonstrates strong bystander killing effect in vivo, and high internalization efficiency in vitro in comparison to other Nectin-4 ADCs. These attributes contribute to enhanced anti-tumor activity in comparison to EV, across a spectrum of Nectin-4 expression levels, ranging from low to high expression, in PDX models. Moreover, IPH4502 shows efficacy in an in vivo model with primary resistance to MMAE due to MDR1 transporter expression and demonstrates anti-tumor activity in a PDX model of UC that acquired resistance to EV. Finally, IPH4502 shows activity in PDX models from indications beyond UC. Conclusion: The strong internalization and bystander effect of IPH4502 enable an efficient anti-tumor activity in Nectin-4 positive tumor models independent of Nectin-4 expression levels. In addition, IPH4502 shows efficacy in models resistant to EV, indicating that IPH4502 has potential for UC patients relapsing or refractory to EV treatment, as well as for cancer patients treated with MMAE-based ADCs. Finally, IPH4502 shows anti-tumor activity in various preclinical cancer models, including PDX models from different indications, supporting its development beyond UC. Citation Format: Romain Remark, Cécile Bonnafous, Laura Chiossone, Caroline Soulas, Cyril Perrier, Sivan Bokobza, Rachel Courtois, Julie Lopez, Grégory Fenaux, Olivier Benac, Barbara Carrette, Robin Letay-Drouet, Raja Bonifay, Marion Gaudin, Séverine Augier, Léa Simon, Agnès Represa, Ariane Morel, Eric Vivier, Yannis Morel, Nicola Beltraminelli, Carine Paturel. IPH4502, a differentiated Nectin-4 exatecan antibody-drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5443.