Preclinical characterization of a novel anti-CD39/TGFβ-trap bispecific antibody that aims to modulate tumor microenvironment.

• DOI: 10.1200/jco.2023.41.16_suppl.e14523
• Publication Date: 2023-06-04T15:12:51Z
• Authors: Hongtao Lu; Dawei Sun; Yehua Zhu; Jun Sun; Zhouwenli Meng; Quan Qiu; Yuting Qiu; Yanan Geng; Rui Gao; Yuanyuan Ho; Hongping Zhou; Zheng Song; Xiaoli Guo; Yefeng Lu; Liliang Xia; Shun Lu
• Keywords: Blocking antibody

e14523 Background: Adenosine and TGF-β are two key immune suppressors in tumor microenvironment (TME) that cause broad suppression resulting resistance to current CPI immunotherapies. Cancer cells, other cell types within TME, frequently express TGFβ, which inhibits CD8 + T Th1 cells promotes epithelial–mesenchymal transition. We have designed a bi-specific targeting molecules blocking the inhibitory pathways, aiming create an immune-friendly TME. Methods: created bifunctional antibody–ligand trap called ES014 comprises antibody CD39 fused TGFβ receptor II ectodomain sequence. molecule could simultaneously disable prevent extracellular ATP from degradation neutralize autocrine/paracrine vicinity of target cells. The immunological function was studied series vitro immuno-assays. vivo efficacy investigated human PBMC engrafted models. effects on were also analyzed using malignant pleural effusions (MPE) collected lung cancer patients. pharmacokinetics (PK), pharmacodynamics (PD) safety profile assessed cynomolgus monkeys after intravenous administration ES014. Results: bispecific antibody, exhibited synergistic activation Treg differentiation. activates dendritic macrophages natural killer by maintaining level neutralizing immune-suppressive TGFβ. Interestingly, demonstrated unique mechanism protecting effector induced death (AICD), not observed with or anti-CD39 alone, combination two. is effective inhibiting progression PD-1 antibody-unresponsive model. Treatment patients led switch M2 M1 macrophage as indicated increased CD86 expression decreased CD163 CD11b+ Importantly, more CD8+ maintained treatment MPE compared control, significant reduction number. well tolerated monkeys, phase I clinical study ongoing investigate safety, tolerability, PK, PD preliminary activity advanced solid tumors. Conclusions: first-in-class counteracts TGFβ-mediated differentiation Tregs adenosine-induced tolerance, protected AICD. resulted anti-tumor ex A single agent therefore expected trials.