Harnessing the Power of SGN-CD30C: A Promising Camptothecin ADC for CD30-Positive Malignancies

SGN-CD30C, an innovative CD30-targeting antibody-drug conjugate (ADC), features a potent camptothecin-based cytotoxic agent. It is designed to target the same antigen as brentuximab vedotin (BV), yet it operates through a distinct mechanism, inhibiting topoisomerase I rather than microtubules. Notably, this approach may circumvent the peripheral neuropathy observed with monomethyl auristatin E-based therapies.

In preclinical evaluations, SGN-CD30C exhibited robust monotherapy efficacy, leading to durable tumor regression across various lymphoma models and even curing BV-resistant tumors. It also demonstrated bystander cell killing, a trait attributed to BV, within CD30-heterogeneous tumor environments. The compound was found to be well-tolerated in non-human primate toxicology studies, showing a higher maximum tolerated dose (MTD) compared to BV. The primary side effect was anemia, attributed to bone marrow erythropoiesis suppression, with minimal impact on neutrophil counts and only slight platelet reductions. The absence of significant neutropenia with SGN-CD30C contrasts with BV, suggesting different dose-limiting toxicities.

A strategy combining a reduced BV dose with SGN-CD30C was hypothesized to provide a dual mechanism, potentially enhancing anti-tumor effects while reducing peripheral neuropathy risks. In a Karpas-299 xenograft model, the combination of SGN-CD30C and BV at sub-curative doses resulted in a higher number of durable complete responses (CRs) than either monotherapy, validating the synergistic anti-tumor potential.

Collectively, the data indicate SGN-CD30C as a promising treatment for CD30-positive cancers, with its potent anti-tumor activity and enhanced tolerability suggesting a beneficial therapeutic index. The unique mechanism and distinct toxicity profile also present an opportunity to combine SGN-CD30C with BV for a more favorable risk-to-benefit ratio.

The study was presented by Maureen Ryan et al. at the Annual Meeting of the American Association for Cancer Research in 2020, highlighting the potential of SGN-CD30C as a new CD30-directed camptothecin ADC with strong preclinical anti-tumor activity and superior tolerability.