AO-176’s differentiated Mechanisms of Action

Proposed Mechanisms of Action

Anti-CD47 therapies block the CD47/SIRPα interaction, the “don’t eat me” mechanism for macrophages. AO-176 is a humanized anti-CD47 IgG2 monoclonal antibody with a potential best-in-class profile. Beyond blocking, AO-176 has several additional mechanisms of action that make this a highly-differentiated therapy among agents in this class.

Blocking CD47/SIRPα Interaction & Inducing Phagocytosis

Lower Binding to Normal Cells

First, AO-176 demonstrates lower binding to the CD47 receptor on normal cells, including negligible binding to red blood cells (RBCs). Despite high CD47 expression on RBCs, AO-176 does not cause hemagglutination.

Puro RJ et al, Mol Cancer Ther 2020;19:835–46
Wilson WC et al, Mol Cancer Ther 2019; 18 (12 Suppl): Abstract nr B100

Preferential Binding to CD47 at Acidic vs. Physiologic pH

In addition, AO-176 has enhanced binding in low pH conditions, such as the tumor microenvironment. Since normal cells also reside in more neutral pH environments, we believe AO-176 will show lower CD47 receptor occupancy in the periphery, sparing normal cells, and potentially higher receptor occupancy in tumor cells.

MFI = Mean Fluorescence Intensity

Anti-AO-176 IHC: Complete Xenograft Tumor Cell Surface Staining

Direct Killing and DAMP Induction

Other effects of AO-176 treatment on tumor cells include direct killing through programmed cell death type III and induction of damage-associated molecular patterns (DAMPs), resulting in immunogenic cell death. These mechanisms highlight AO-176’s promising potential as a novel anti-CD47 therapy for treating cancer.

Direct Tumor Cell Killing by Programmed Cell Death Type III

Capoccia BJ et al, J ImmunoTherapy of Cancer (2018) 6 (Suppl 1) 115

Enhanced Tumor Cell Killing by DAMP Induction

Zitvogel, K et al. Nat Rev Immunol, 2016; Puro R et al, Cancer Res 2018; 78 (13 Suppl): Abstract nr 1765; Capoccia BJ et al, J ImmunoTherapy of Cancer (2018) 6 (Suppl 1) 115