Next-generation tumor-specific anti-CD30 ADC as a new therapy in hemato-oncology

Abstract Context. CD30 is a type I transmembrane protein widely expressed in various lymphomas, such as B-cell Hodgkin lymphoma. Its receptor has been shown to undergo ectodomain shedding to generate sCD30, an 85 kDa soluble form released in the circulation. The sCD30 has been detected in culture supernatants of CD30+ cell lines and in the sera of patients harboring CD30+ tumors, such as Hodgkin's lymphoma and anaplastic large-cell lymphoma. Moreover, recent LYSA clinical studies (O. Tournilhac, Blood Advances 2025) demonstrated that high circulating sCD30 levels were associated with poor prognosis in patients treated with Brentuximab Vedotin (BV). In this context, median survival was 8 months in the high sCD30 group versus 30.3 months in the low sCD30 group. This result suggests that sCD30 may act as a decoy and directly impact BV efficacy. This potential limitation gives a unique opportunity to develop a next-generation anti-CD30 ADC therapy. Methods. Due to high lymphoma metabolic status, we took advantage of lymphoma tumor microenvironment acidification to generate a pH-sensitive anti-CD30 ADC targeting only the tumor-specific CD30 and not the circulating form. Thanks to phage-yeast display AI-assisted technology and unique proprietary human antibody libraries, we discovered and characterized a first pH-sensitive anti-CD30 antibody (18D03), which has been further conjugated with DAR4-MMAE with lead name MQI-181. Results. 18D03 antibody demonstrated a strong affinity and pH-sensitive interaction with human CD30 as determined by Bio Layer Interferometry and crossreactivity with cynomolgus CD30 counterpart. We explored antigen-antibody interaction and identified 18D03 unique epitope, distinct from the one recognized by BV. We further assessed in vitro functionality on Hodgkin lymphoma CD30+ cell lines by validating 18D03 pH-sensitive binding, internalization capacity, and strong cytotoxic potency in ADC format. By In vivo studies we explored its antitumoral efficacy in L540 xenografted mouse model. We confirmed that MQI-181 reached the tumor site and induced complete tumor regression in the lymphoma model. More interestingly, in the context of sCD30, we demonstrated MQI-181 superiority over BV. Indeed, following sCD30 injection, BV efficacy was strongly reduced by circulating CD30, whereas MQI-181 efficacy was fully preserved. We could explain this difference by the presence of sCD30-BV complex in the circulation, whereas no complex was detected following MQI-181 injection. Conclusion. MQI-181 is a next-generation anti-CD30 therapy with high clinical potential, able to specifically target the tumor site while avoiding its capture by circulating CD30. In vivo, MQI-181 demonstrated complete tumor regression in a preclinical lymphoma cancer model and superiority over BV in the presence of soluble CD30. The Phase I trial is now under planification.