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2089 SGN-CD30C, an Investigational CD30-Directed Camptothecin Antibody-Drug Conjugate (ADC), Shows Strong Anti Tumor Activity and Superior Tolerability in Preclinical StudiesClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 625. Lymphoma: Pre-Clinical—Chemotherapy and Biologic Agents: Poster II
Hematology Disease Topics & Pathways:
Biological, antibodies, Diseases, Lymphoma (any), Animal models, Therapies, Biological Processes, Lymphoid Malignancies, Study Population, immune mechanism
Sunday, December 6, 2020, 7:00 AM-3:30 PM

Maureen Ryan*, Ryan Lyski*, Lauren Bou*, Ryan Heiser*, Bryan Grogan*, Dave Meyer*, Steven Jin*, Jessica Simmons*, Melissa Conerly*, Peter Senter, PhD* and Scott Jeffrey*

Seattle Genetics, Inc., Bothell, WA

SGN-CD30C, an investigational CD30-directed ADC, utilizes a potent novel 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‑resistance tumor model (Figure 1). Moreover, SGN-CD30C exhibits many of the desirable attributes associated with BV, notably, bystander activity and CD30+ T regulatory cell (Treg) depletion. Using an admixed model of CD30+ and CD30‑tumor cells, SGN‑CD30C demonstrated robust anti-tumor activity in vivo, confirming SGN‑CD30C can induce bystander killing of antigen-negative tumor cells in CD30-heterogeneous tumors. Additionally, SGN‑CD30C depleted CD30+ Treg cells in vitro (Figure 2), suggesting it has the potential to exert activity through multiple mechanisms of action.

SGN-CD30C was well-tolerated in non-human primate toxicology studies and demonstrated ~6-fold higher maximum tolerated dose when compared to BV. The primary toxicity for SGN-CD30C in non‑human primates (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 ADCs may have non‑overlapping dose limiting toxicities. Hematology parameters show SGN-CD30C is tolerated at a 10‑fold higher dose than BV with weekly dosing, suggesting SGN‑CD30C may offer the potential for increased dose density.

In summary, our data show SGN-CD30C is a compelling therapeutic candidate for CD30-positive malignancies. The distinct mechanism of action, strong anti-tumor activity, and enhanced tolerability provide a strong rationale to clinically investigate SGN-CD30C across the CD30-expressing lymphoma landscape. A Phase 1 clinical trial is planned to investigate SGN-CD30C in relapsed and refractory lymphoma.

Disclosures: Heiser: Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Grogan: Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Jin: Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Conerly: Seattle Genetics: Current Employment, Current equity holder in publicly-traded company.

*signifies non-member of ASH