45P - Discovery of CBO-212, a first-in-class drug Fc-conjugate (DFC), targeting CD73 in cancer

Background

CD73 contributes to immune evasion in solid tumors by producing immune-suppressive adenosine in the tumor microenvironment. Herein, we describe CBO-212, a first-in-class CD73 targeting DFC, comprising a multi-valent conjugate of a novel small molecule CD73 inhibitor to a proprietary immune-silent hIgG1 Fc. CBO-212 combines the strengths of small molecule inhibitors and monoclonal antibodies targeting CD73 currently in clinical development with potential best-in-class activity.

Methods

Inhibition of CD73 was evaluated in cell-free and cell-based assays. Functional activity was measured in a PBMC rescue assay in the presence of AMP and binding to cancer cells was measured in the presence and absence of AMP by flow cytometry. CD73 internalization was determined using MDA-MB-231 cells. Pharmacokinetic (PK) studies were conducted in Balb/c mice. Plasma concentrations were measured using an anti-hIgG in combination with CD73 capture ELISA. Efficacy of CBO-212 was evaluated in syngeneic mouse models with established CT26.WT tumors.

Results

CBO-212 is a potent, AMP-competitive CD73 inhibitor. In cell-free and cell-based CD73 inhibition assays, CBO-212 IC₅₀s were single digit nM, making them comparable or superior to small molecule inhibitors and anti-CD73 mAbs in clinical development. Unlike most anti-CD73 mAbs, CBO-212 demonstrated complete enzyme inhibition. Furthermore, CBO-212 demonstrated an EC₅₀ in a human PBMC rescue assay of 6 nM, which was equivalent to small molecule inhibitor controls and approximately 100-fold more potent than anti-CD73 mAb controls. Additionally, CBO-212 triggered CD73 internalization, similar to some anti-CD73 mAbs. CBO-212 demonstrates long half-life and stability in mice. In a syngeneic mouse colon cancer model, a single 20 mg/kg dose of CBO-212 resulted in 37.9% tumor growth inhibition (TGI) relative to vehicle (P=0.0152).

Conclusions

CBO-212 demonstrated high potency in CD73 enzyme inhibition and functional PBMC rescue assays. The in vitro potency and favorable PK of CBO-212 translated to significant TGI in a syngeneic model with a single dose. Based on these results CBO-212 is being advanced as a clinical development candidate for the treatment of solid cancers.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Cidara Therapeutics.

Funding

Cidara Therapeutics.

Disclosure

J. Levin, S. Döhrmann, N. Dedeic, A. Almaguer, D. Zuill, E. Abelovski, R. Grewal, J. Fortier, Q. Zhao, M. Hernandez, K. Amundson, M. Moniz, H. Chen, D. Panickar, T. Lam, T. Brady, A. Borchardt: Financial Interests, Personal, Full or part-time Employment, Shareholder: Cidara Therapeutics.