Innate Pharma Presents Compelling Preclinical Data on Novel ADC Candidate IPH4502 Targeting Nectin-4 at AACR 2025
Innate Pharma SA (Euronext Paris: IPH; Nasdaq: IPHA), a biotechnology company specializing in the development of immunotherapies for cancer, has unveiled promising new preclinical results for its innovative antibody-drug conjugate (ADC) candidate, IPH4502, during a presentation at the American Association for Cancer Research (AACR) Annual Meeting 2025.
IPH4502 represents a next-generation ADC designed to selectively target Nectin-4, a cell surface protein overexpressed in a range of solid tumors. Leveraging a topoisomerase I inhibitor payload, IPH4502 is engineered to deliver potent cytotoxic activity while aiming to improve tolerability and overcome resistance mechanisms associated with first-generation Nectin-4 ADCs.
The new data underscore the differentiated potential of IPH4502 in both Nectin-4 high- and low-expressing tumors, as well as in tumors that have developed resistance to enfortumab vedotin (EV)—a currently approved ADC targeting the same antigen.
A Validated Target in Oncology: Nectin-4
Nectin-4 has become an increasingly attractive target for therapeutic development in oncology due to its high expression in several tumor types, most notably urothelial carcinoma (UC), as well as triple-negative breast cancer (TNBC), head and neck squamous cell carcinoma (HNSCC), and esophageal cancer.
The clinical success of enfortumab vedotin (EV), which employs a monomethyl auristatin E (MMAE) payload to induce cancer cell death via microtubule disruption, has validated Nectin-4 as a therapeutic target. However, EV’s use has been limited by several key factors, including:
- Treatment-limiting toxicity, leading to early discontinuation in some patients;
- Disease relapse following initial response;
- Ineligibility of patients due to comorbidities or prior treatment failures;
- Limited efficacy in tumors with low Nectin-4 expression;
- Resistance mechanisms, particularly the upregulation of multidrug resistance protein 1 (MDR1), which actively expels MMAE from cells.
These limitations create an urgent need for alternative Nectin-4-targeting ADCs with enhanced safety profiles, broader activity in diverse tumor types, and the ability to overcome acquired resistance.
IPH4502: A Differentiated ADC Platform with Enhanced Efficacy
Innate Pharma’s IPH4502 is a novel ADC that incorporates a topoisomerase I inhibitor payload rather than a microtubule inhibitor. This allows for a distinct mechanism of action that may circumvent known resistance pathways associated with MMAE-based ADCs like EV.
In a series of preclinical studies, IPH4502 demonstrated potent anti-tumor activity across multiple models, including:
- EV-resistant patient-derived xenograft (PDX) models of urothelial carcinoma with confirmed upregulation of MDR1. In these models, IPH4502 effectively inhibited tumor growth where EV failed, suggesting that it can retain efficacy in settings where MDR1-mediated drug efflux impairs MMAE-based treatments.
- Preclinical tumor models beyond urothelial cancer, including triple-negative breast cancer, head and neck squamous cell carcinoma, and esophageal cancer. These results point to a potential for broader clinical application across solid tumors that express Nectin-4 at varying levels.
Moreover, IPH4502 outperformed a clinical-stage Nectin-4-exatecan ADC in tumors with low Nectin-4 expression. This superior activity was attributed to several key properties of IPH4502:
- Higher internalization efficiency, allowing for more effective intracellular delivery of the cytotoxic payload.
- Increased inherent cytotoxicity of the topoisomerase I inhibitor compared to other payloads.
- Enhanced bystander killing effect, enabling IPH4502 to kill adjacent tumor cells regardless of their antigen expression, which is particularly valuable in heterogeneous tumors.
Taken together, these preclinical findings suggest that IPH4502 could offer a wider therapeutic window and increased efficacy, even in tumors with heterogeneous or low Nectin-4 expression—an area where EV has shown limited benefit.
Expert Commentary and Development Outlook
Commenting on the findings, Dr. Sonia Quaratino, Chief Medical Officer at Innate Pharma, said:
“We are highly encouraged by these preclinical data, which not only validate the mechanism of action of IPH4502 but also highlight its potential to address significant unmet medical needs in oncology. The ability to retain efficacy in EV-resistant settings and in tumors with low Nectin-4 expression positions IPH4502 as a promising next-generation therapeutic. These results support our rationale for progressing the molecule into clinical development, and we look forward to sharing initial clinical data in 2026.”
Clinical Development Underway: Phase 1 Trial in Solid Tumors
Innate Pharma has already initiated a Phase 1 first-in-human trial of IPH4502 in patients with advanced solid tumors known to express Nectin-4, including urothelial carcinoma, triple-negative breast cancer, and others. The trial, registered under ClinicalTrials.gov identifier NCT06781983, is designed to evaluate:
- Safety and tolerability of IPH4502 in a dose-escalation setting;
- Pharmacokinetics and pharmacodynamics;
- Preliminary anti-tumor activity in a biomarker-enriched population.
The study is currently enrolling patients at multiple sites across Europe and North America, with a focus on identifying a recommended Phase 2 dose and evaluating early signs of clinical efficacy.
Initial data from this trial are anticipated in 2026, potentially setting the stage for further development in both monotherapy and combination settings.
A Step Forward in ADC Innovation
The preclinical data presented by Innate Pharma at the AACR 2025 Annual Meeting reflect significant progress in the company’s mission to advance differentiated ADCs that improve outcomes for cancer patients. IPH4502’s strong performance in challenging tumor models—particularly those with EV resistance or low Nectin-4 expression—suggests that this novel compound could reshape the therapeutic landscape for Nectin-4-positive tumors.
As the clinical development of IPH4502 progresses, Innate Pharma continues to build on its expertise in tumor-targeted therapeutics and immuno-oncology, aiming to bring forward a new generation of treatment options for patients with difficult-to-treat cancers.
