Abstract ND08: Discovery and development of a CD30 dual-payload ADC that combines MTI and Top1i to overcome drug resistance

Abstract Since the 1960s combination therapy has been practiced to address drug resistance in cancer patients. Initially utilizing multiple chemotherapeutic agents, approaches have evolved to include chemotherapeutics combined with a biologic or, more recently, multi-biologic regimens. Despite the potential of delivering multiple mechanisms for tumor cell killing, the clinical efficacy of these strategies has been constrained by off-target toxicities, varying pharmacokinetics and limited receptor availability. Dual-payload antibody-drug conjugates (dpADCs) offer great promise to provide targeted co-delivery of two therapeutics to tumor cells, enhancing tolerability and ensuring optimized drug exposure to overcome the variable mechanisms of drug resistance in heterogeneous tumor biology. We have employed non-natural amino acid conjugation technology to engineer an anti-CD30 dpADC that combines clinically validated microtubule inhibitor monomethylauristatin E (MMAE) with a proprietary topoisomerase one inhibitor (Top1i). In a classical Hodgkin’s lymphoma preclinical xenograft model (L428), a single intravenous administration of the CD30 dpADC induced a significant tumor growth inhibition (TGI) of 92.5% at 2.4mg/kg and 76.5% at 1.2mg/kg. In an anaplastic large-cell lymphoma (ALCL) preclinical xenograft model (DEL), a single dose of the CD30 dpADC resulted in complete tumor regression at a dose as low as 0.6mg/kg. High expression of ABCB1 (formerly known as the MDR1 gene, encoding P-glycoprotein, PgP) has been shown to be related to MMAE resistance in brentuximab vedotin-treated patients. In a preclinical DEL xenograft model engineered to overexpress PgP, we observed complete loss of efficacy by brentuximab vedotin. However, the CD30 dpADC maintained robust anti-tumor killing consistent with the efficacy observed in the parental model, indicating that the dpADC approach could prove advantageous in combating drug resistance. Furthermore, nonclinical safety studies have revealed an acceptable tolerability profile compared to the current approved industry standard, brentuximab vedotin. Together, these findings highlight the CD30 dpADC’s potential for chemo-free/chemo light treatment of classical Hodgkin’s lymphoma. Citation Format: Megan Rice, Francesca Casano, Wenting Zhang, Pan Pan, Vivanna Taylor, Frances Anne Tosto, Bala NN Rao Attili, Catherine Rodger, Reecha Shah, Paul Santacroce, John Hood, Mahua Roy, Chao Gong, Virginie Cerec, Cedric Dos Santos, Marcello Marelli, Jim Christie, Krista Kinneer, Arthur Shaffer, John Kellie, Elaine Hurt, Anas Younes, Puja Sapra. Discovery and development of a CD30 dual-payload ADC that combines MTI and Top1i to overcome drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr ND08.