577 Non-clinical efficacy, pharmacokinetics, and pharmacodynamics of a novel bi-functional anti-CD73-TGFβRII-trap molecule in combination with immune checkpoint therapy

作者：Susanna Stinson, Jianhua He, Kyung-Hoon Kim, Becky Yang, Marianna Zavodovskaya, Ping Yi, Federico Campigotto, Monika Sobczyk, Rutwij A. Dave, Brian Carr, In Kyoung Mah, Shiva Zaboli, Jens Brodbeck, Scott Turner, Vivian Barry, Kelli L. Boyd, Valeria R. Fantin · 发表于：Regular and Young Investigator Award Abstracts · 年份：2021 · DOI：10.1136/jitc-2021-sitc2021.577 · 被引用次数：1 · 研究领域：Adenosine and Purinergic Signaling、Radiopharmaceutical Chemistry and Applications、Peptidase Inhibition and Analysis

Background A novel murine bi-functional molecule, G04-trap, comprised of an anti-CD73 antibody fused to the extracellular domain of TGFβ receptor II, is designed to potently antagonize two prominent immunosuppressive and pro-tumorigenic pathways present across a variety of cancer types. Inhibition of both CD73-adenosine and TGFβ pathways is expected to create favorable conditions within the tumor microenvironment and restore antitumor immune responses. Methods G04-trap was evaluated in Detroit562, MC38, and Hepa1-6 efficacy tumor models. Tumor growth inhibition (TGI) was determined when >/=9 animals were alive in each group. Tumor-bearing mice received isotype control (200 microgram), G04-trap (246 microgram), anti-PD-(L)1 (200 microgram) or G04-trap + anti-PD-(L)1 twice per week for 3 weeks. Pharmacokinetic (PK) and pharmacodynamic (PD) assessment was performed on MC38 tumor-bearing mice dosed with 3 mg/kg, 10 mg/kg, or 30 mg/kg G04-trap. Plasma and tumor PK, CD73 target occupancy on T cells, plasma TGFβ, plasma free-sCD73, and tumor CD73 activity were measured after a single dose administration of G04-trap Results Administration of G04-trap to mice harboring TGFβ-dependent human pharyngeal Detroit562 xenograft tumors led to a dose-dependent anti-tumor response (83% TGI, at 246 microgram vs. isotype control on day 21). In addition, treatment with G04-trap in combination with immune checkpoint inhibition showed anti-tumor activity in MC38 and Hepa1-6 syngeneic mouse m...