CO-1: A Novel Bifunctional CD47 Antibody for the Treatment of Hematologic Malignancies

CD47 is an immune checkpoint receptor that is expressed in most human cells and functions as an essential part of the innate immune system through interaction with signal regulatory protein alpha (SIRPα) expressed on macrophages. CD47/SIRPα interactions induces an immune response that inhibits cell phagocytosis which is known as the "do not eat me"-signal. Blocking the CD47-SIRPα interaction has been shown to stimulate the phagocytic activity of macrophages and other innate immune cells to cancer cells. Hence, anti-CD47 antibodies that block the interaction between CD47 and SIRPα have gained increasing attention in immunotherapy. However, clinical studies have shown only blocking CD47-SIRPα interactions does not provide a sufficient efficacy response. Therefore, additional cytotoxic mechanisms have to be triggered to obtain clinically meaningful treatment responses to anti-CD47 antibodies.

Here we introduce a novel IgG4 anti-CD47 antibody, called CO-1, that not only enhances the macrophage phagocytosis activity but also induces a unique and fast form of programmed cell death (PCD) in cancer cells directly through ligation of CD47. In our in vitro study, CO-1 induces rapid (within 3 hours) and potent (≥40%) PCD at low concentrations in several cell lines derived from hematologic malignancies (Jurkat, MOLT-4 and REH). In addition, CO-1 shows other interesting therapeutic properties as it has low binding to red blood cells (RBC) and induces no hemagglutination to RBC at desired therapeutic concentrations. To validate our in vitro findings, we established a pilot experiment with a xenograft model of human B cell precursor acute lymphoblastic leukemia in NOD-scid IL2Rγ^null (NSG) mice. We found that the animals were rapidly cured of cancer even after only two injections of CO-1 as monotherapy. The potency of CO-1 towards killing cancer cells through multiple modes of action would classify CO-1 as a promising treatment option for patients suffering from hematological cancers.

Matar:Caedo Oncology: Current Employment. Skah:Caedo Oncology: Current Employment. Pettersen:Caedo Oncology: Consultancy, Current equity holder in private company. Hestdal:Caedo Oncology: Consultancy, Current equity holder in private company. Richartz:Caedo Oncology: Consultancy, Current Employment.