OncoImmune’s lead compound is CD24Fc, a first-in-class recombinant fusion protein that targets a novel immune pathway checkpoint. CD24Fc has demonstrated efficacy in animal models of GVHD, multiple sclerosis and rheumatoid arthritis, and safety in a Phase I trial in healthy human subjects. We recently completed a Phase II study and initiated the Phase III trials for the prophylactic treatment of graft-versus-host disease (GVHD) for leukemia patients undergoing hematopoietic stem cell transplantation and are expanding into additional indications including metabolic disorders and immunotherapy-related adverse effect in multiple planned clinical trials. More importantly, as a part of the global effort to confront COVID-19, OncoImmune has launched and is near completion of Phase III clinical trial using CD24Fc to treat severe and critical COVID-19.
Pattern recognition receptors, such as Toll or Toll-like receptors (TLRs), recognize pathogens (Pathogen-Associated Molecular Patterns, or PAMPs) or components of injured cells (Danger-Associated Molecular Patterns, or DAMPs), and trigger activation of the innate immune system. On the other hand, Siglecs are a distinct class of pattern recognition receptors that down-regulate cellular responses. As reported by our Founders in Science (2009) and Nature Biotech (2011), CD24 interacts with DAMPs as well as a pattern recognition receptor, which is called Siglec G in mice and Siglec 10 in human, to selectively regulate host responses to DAMPs.
Specifically, the CD24-Siglec-G (or its human homologue, Siglec 10) interaction negatively regulates the activity of NFkB via intracellular ITIM domains that are associated with SHP-1. Accordingly, binding of CD24 to Siglec G/10 suppresses TNF-α, IL-1β and IL-6, which are all major targets of autoimmune diseases and cancer. Furthermore, CD24 binds to several DAMPs and represses host response to these DAMPs.
Therefore, CD24Fc has a dual mechanism of action:
- CD24Fc binds DAMPs, trapping the inflammatory stimuli to prevent their interaction with TLR receptors
- CD24Fc binds Siglec G/10 and regulates host response to tissue injuries Siglec G/10-associated SHP1 inhibitory signaling
Our founders have established that the CD24-Siglec G axis regulates the severity of GVHD and that CD24Fc prevents GVHD in animal models of GVHD by interacting with Siglec G. Importantly, CD24Fc does not suppress PAMP-mediated or antigen-specific immune responses, which suggests that CD24Fc will not increase the risk of infection, a major limitation of other approaches such as T cell depletion. Furthermore, CD24Fc prevents GVHD but preserves GVL, making it an ideal drug for GVHD prophylaxis in leukemia patients.
We have recently completed a randomized, placebo-controlled Phase II trial to evaluate the addition of CD24Fc to standard of care acute GVHD prophylaxis in cancer patients undergoing allogeneic myeloablative hematopoietic stem cell transplantation (HCT). Overall, CD24Fc was found to be safe and well tolerated in the phase II study. The clinical evidence from the phase II study suggests that CD24Fc, administered in combination with methotrexate and tacrolimus, greatly improves outcomes in leukemia patients undergoing myeloablative allo-HCT by reducing both the likelihood of severe aGVHD (grades III – IV) and the likelihood of leukemia relapse as well as overall survival and conditioning toxicity.
CD24Fc is also in a Phase III clinical trial testing the safety and efficacy of CD24Fc for the treatment of hospitalized COVID-19 patients. The COVID-19 Phase III trial has been initiated in 17 medical centers nationwide and is enrolling severe and critical COVID-19 patients that either require supplemental oxygen support or high flow oxygen non-invasive ventilation, in addition to ICU patients requiring invasive mechanical ventilation. The trial plans to enroll over 270 patients and is near its enrollment target with topline readouts expected soon.
Beyond GVHD and COVID-19, genetic analysis of a variety of autoimmune disease in human, including multiple sclerosis, systemic lupus erythromatosus, rheumatoid arthritis, and giant cell arthritis, showed significant association between CD24 polymorphism and risk of autoimmune diseases. In mice, CD24Fc reduces the production of multiple cytokines involved in the pathogenesis of RA and is highly effective in treating disease in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. CD24Fc also has the potential to prevent and treat immune-related adverse events (irAE) associated with cancer immunotherapies.
CD24Fc has also initiated a new Phase II clinical trial called CALIBER to test its efficacy in reducing late effects of HIV infection, such as inflammatory abnormalities and cardiovascular disease.
CD24Fc protects against viral pneumonia in simian immunodeficiency virus-infected Chinese rhesus monkeys.
Tian R, Zhang M, Liu M, Fang X, Li D, Zhang L, Zheng P, Zheng Y & Liu Y. 2020. Cellular & Molecular Immunology 17: 887-888.
CD24 and Fc fusion protein protects SIVmac239-infected Chinese rhesus macaque against progression to AIDS.
Tian RR, Zhang MX, Zhang LT, Zhang P, Ma JP, Liu M, Devenport M, Zheng P, Zhang XL, Lian XD, Ye M, Zheng HY, Pang W, Zhang GH, Zhang LG, Liu Y, Zheng YT. Antiviral Res. 2018 Sep;157:9-17.
Siglec-G-CD24 axis controls the severity of graft-versus-host disease in mice.
Toubai T, Hou G, Mathewson N, Liu C, Wang Y, Oravecz-Wilson K, Cummings E, Rossi C, Evers R, Sun Y, Wu J, Choi SW, Fang D, Zheng P, Liu Y, Reddy P. Blood. 2014;123(22):3512-23.
Broad and direct interaction between TLR and Siglec families of pattern recognition receptors and its regulation by Neu1.
Chen GY, Brown NK, Wu W, Khedri Z, Yu H, Chen X, van de Vlekkert D, D'Azzo A, Zheng P, Liu Y. Elife. 2014 Sep 3;3:e04066. doi: 10.7554/eLife.04066.
Amelioration of sepsis by inhibiting sialidase-mediated disruption of the CD24-SiglecG interaction.
Chen GY, Chen X, King S, Cavassani KA, Cheng J, Zheng X, Cao H, Yu H, Qu J, Fang D, Wu W, Bai XF, Liu JQ, Woodiga SA, Chen C, Sun L, Hogaboam CM, Kunkel SL, Zheng P, Liu Y. Nat Biotechnol. 2011 May;29(5):428-35
CD24 and Siglec-10 Selectively Repress Tissue Damage-Induced Immune Responses.
Chen GY, Tang J, Zheng P, Liu Y. Science. 2009;323:1722-5.
CD24-Siglec G/10 discriminates danger- from pathogen-associated molecular patterns.
Liu Y, Chen GY, Zheng P. Trends Immunol. 2009 Dec;30(12):557-61. doi: 10.1016/j.it.2009.09.006. Epub 2009 Sep 26.