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Development of AO-176, a Next-Generation Humanized Anti-CD47 Antibody with Novel Anticancer Properties and Negligible
Robyn J Puro1, Myriam N Bouchlaka1, Ronald R Hiebsch1
1Arch Oncology, Inc., St. Louis, Missouri.
Abstract:
Inhibitors of adaptive immune checkpoints have shown promise as cancer treatments. CD47 is an innate immune checkpoint receptor broadly expressed on normal tissues and overexpressed on many tumors. Binding of tumor CD47 to signal regulatory protein alpha (SIRPα) on macrophages and dendritic cells triggers a "don't eat me" signal that inhibits phagocytosis enabling escape of innate immune surveillance. Blocking CD47/SIRPα interaction promotes phagocytosis reducing tumor burden in numerous xenograft and syngeneic animal models. We have developed a next-generation humanized anti-CD47 antibody, AO-176, that not only blocks the CD47/SIRPα interaction to induce tumor cell phagocytosis, but also induces tumor cytotoxicity in hematologic and solid human tumor cell lines, but not normal noncancerous cells, by a cell autonomous mechanism (not ADCC). AO-176 also binds preferentially to tumor versus many normal cell types. In particular, AO-176 binds negligibly to RBCs in contrast to tumor cells, even at high concentrations up to 200 μg/mL and does not agglutinate RBCs up to 1 mg/mL in vitro These properties are expected not only to decrease the antigen sink, but also to minimize on-target clinical adverse effects observed following treatment with other reported RBC-binding anti-CD47 antibodies. When tested in cynomolgus monkeys, AO-176 was well tolerated with no adverse effects. Finally, we show that AO-176 demonstrates dose-dependent antitumor activity in tumor xenograft models. Taken together, the unique properties and antitumor activity of our next-generation anti-CD47 antibody, AO-176, distinguishes it from other CD47/SIRPα axis targeting agents in clinical development.
Insights
A novel anti-CD47 antibody, AO-176, effectively blocks the CD47/SIRPα interaction to enhance tumor cell phagocytosis and induce cytotoxicity. This next-generation antibody shows reduced binding to red blood cells, minimizing side effects and demonstrating significant antitumor activity in preclinical models.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Adaptive immune checkpoint inhibitors are promising cancer therapeutics.
- CD47 acts as an innate immune checkpoint, preventing phagocytosis by macrophages and dendritic cells.
- Blocking the CD47/SIRPα interaction can enhance phagocytosis and reduce tumor burden.
Purpose of the Study:
- To develop and characterize a next-generation humanized anti-CD47 antibody, AO-176.
- To evaluate AO-176's ability to block CD47/SIRPα interaction and induce tumor cell phagocytosis and cytotoxicity.
- To assess AO-176's safety profile, particularly its binding to red blood cells and its in vivo antitumor activity.
Main Methods:
- Development of a humanized anti-CD47 antibody (AO-176).
- In vitro assessment of AO-176's ability to block CD47/SIRPα interaction, induce phagocytosis, and cause tumor cell cytotoxicity.
- Evaluation of AO-176's binding affinity to tumor cells versus normal cells, including red blood cells (RBCs).
- In vivo testing in cynomolgus monkeys for safety and in tumor xenograft models for antitumor activity.
Main Results:
- AO-176 blocks CD47/SIRPα interaction, inducing phagocytosis and cytotoxicity in hematologic and solid tumor cell lines, but not normal cells.
- AO-176 exhibits preferential binding to tumor cells over normal cells, with negligible binding and no agglutination of RBCs.
- AO-176 was well-tolerated in cynomolgus monkeys with no observed adverse effects.
- AO-176 demonstrated dose-dependent antitumor activity in preclinical tumor xenograft models.
Conclusions:
- AO-176 is a next-generation anti-CD47 antibody with unique properties, including potent antitumor activity and an improved safety profile due to minimal RBC binding.
- These characteristics distinguish AO-176 from other CD47/SIRPα targeting agents, suggesting its potential as a novel cancer therapeutic.
- AO-176's cell-autonomous cytotoxicity and preferential tumor binding offer a promising approach to cancer treatment with potentially reduced clinical adverse effects.
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