Abstract 2889: SGN-CD30C, a new CD30-directed camptothecin antibody-drug conjugate (ADC), shows strong anti-tumor activity and superior tolerability in preclinical studies

Abstract

Abstract SGN-CD30C, a new CD30-directed ADC, utilizes a potent camptothecin derivative as the cytotoxic payload. SGN-CD30C targets the same antigen as brentuximab vedotin (BV), though the payload has a different mechanism of action, namely inhibiting topoisomerase I rather than disrupting microtubules. Unlike monomethyl auristatin E, camptothecin-based therapies do not cause peripheral neuropathy clinically, suggesting that SGN-CD30C may have the potential to avoid one of the most common adverse events associated with BV. In preclinical studies, SGN-CD30C demonstrated strong monotherapy activity, inducing durable tumor regressions in multiple lymphoma models and eliciting cures in a BV-resistant tumor model. Furthermore, bystander killing of antigen-negative tumor cells, which is thought to be an important attribute of BV, was confirmed in vivo using CD30-heterogeneous tumors. SGN-CD30C was well-tolerated in non-human primate (NHP) toxicology studies and demonstrated ~6-fold higher maximum tolerated dose (MTD) when compared to BV. The primary toxicity for SGN-CD30C in NHP studies was anemia due primarily to bone marrow suppression of erythropoiesis. SGN-CD30C had no effect on neutrophil counts and caused only minimal to mild decreases in platelets. The lack of significant neutropenia seen with SGN-CD30C contrasts with BV, indicating the two antibody-drug conjugates may have non-overlapping dose limiting toxicities. We theorized using a reduced dose of BV in combination with SGN-CD30C could provide a dual mechanism of action to retain or enhance anti-tumor activity while decreasing the incidence of non-overlapping toxicities (i.e. peripheral neuropathy). To test this hypothesis preclinically, we evaluated the anti-tumor activity of BV and SGN-CD30C at sub-curative doses in a Karpas-299 xenograft model. The results show the combination of SGN-CD30C + BV generated a higher number of durable CRs compared to the equivalent monotherapy doses, thereby confirming strong anti-tumor activity by using a lower dose of each ADC in combination. In summary, our data show SGN-CD30C is a compelling therapeutic candidate for CD30-positive malignancies. The strong anti-tumor activity and superior tolerability suggest SGN-CD30C has a favorable therapeutic window. Furthermore, the distinct mechanism of action and non-overlapping toxicity profile offers the potential to combine SGN-CD30C with BV for enhanced risk/benefit. Citation Format: Maureen Ryan, Ryan Lyski, Lauren Bou, David Meyer, Steven Jin, Jessica Simmons, Dennis Benjamin, Peter Senter, Scott Jeffrey. SGN-CD30C, a new CD30-directed camptothecin antibody-drug conjugate (ADC), shows strong anti-tumor activity and superior tolerability in preclinical studies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2889.