Therapeutic Potential of AO-176, a Next Generation Humanized CD47 Antibody, for Hematologic Malignancies

Autor: Robyn J Puro, Prabir Chakraborty, Daniel S. Pereira, Karr Robert W, Ronald R. Hiebsch, Vicki Sung, Pamela T. Manning, Alun Carter, Ben J Capoccia, W. Casey Wilson, Michael J. Donio, Myriam N. Bouchlaka
Rok vydání: 2018
Předmět:
Zdroj: Blood. 132:4180-4180
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood-2018-99-118456
Popis: Inhibitors of adaptive immune checkpoints have shown promise as cancer treatments. CD47 is an innate immune checkpoint receptor broadly expressed on normal tissues and over-expressed on several tumors. Binding of tumor CD47 to signal regulatory protein alpha (SIRPalpha) 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/SIRPalpha interaction and induces phagocytosis of hematologic and solid tumor cells, but also exhibits several unique functional properties. The first property is the ability of AO-176 to induce direct tumor cytotoxic cell death in hematologic (ex. Jurkat, Raji and Molt-4) as well as solid human tumor cell lines by a cell autonomous mechanism (not ADCC). Secondly, AO-176 exhibits preferential binding to tumor versus normal cells, including red blood cells (RBCs), T cells, endothelial cells, skeletal muscle cells and epithelial cells. A0-176 also does not affect the function of any of these primary cells when assayed ex vivo. The negligible binding of AO-176 to RBCs versus hematologic (ex. Jurkat, Raji or Molt-4) or solid tumor cells is particularly profound and different from other reported anti-CD47 antibodies. AO-176 also does not induce hemagglutination of RBCs. 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. Consistent with this attribute, AO-176 was well tolerated in cynomolgus monkeys with no adverse effects in general nor with respect to RBCs which was consistent with ex vivo results. A third novel property of AO-176 is its enhanced binding to tumor cells at acidic pH. Because the microenvironment of leukemic bone marrow and solid tumors has an acidic pH, this enhanced binding of AO-176 at low pH has the potential added advantage of tumor-specific targeting. Lastly, we show that AO-176 demonstrates dose-dependent anti-tumor activity in hematologic and solid tumor xenograft models. Taken together, the unique properties and anti-tumor activity of our next generation anti-CD47 antibody, AO-176, distinguishes it from other CD47/SIRPalpha axis targeting agents as it progresses to clinical development. Disclosures No relevant conflicts of interest to declare.
Databáze: OpenAIRE
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