Graft-versus-host disease (GVHD) is a life threatening condition that occurs when the immune competent cells in a tissue graft mount an immune attack against the host. GVHD is most commonly associated with hematopoietic stem cell transplantation (HSCT) for the treatment of hematologic malignancies. Activated donor T cells attack host epithelial cells following an inflammatory cascade that begins with the preparative myeloablative regimen.
Host tissue injuries caused by HSCT conditioning regimens, including high-dose chemotherapy and/or total body irradiation (TBI), is considered to be the first step in the development of acute GVHD and leads to the release of proinflammatory cytokines, such as TNF-α, IL-1β and IL-6, as well as the release of DAMPs and PAMPs. Both DAMPs and PAMPs can activate host antigen-presenting cells (APCs), such as dendritic cells (DCs), which are critical for the activation of the donor T cells and the development of acute GVHD.
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 conducted 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 preliminary clinical evidence from the phase II study strongly suggests that CD24Fc, administered in combination with methotrexate and tacrolimus, greatly improves outcomes in leukemia patients undergoing myeloablative allo-HCT. CD24Fc reduces the likelihood of severe aGVHD (grades III – IV) and leukemia relapse. CD24Fc also reduced transplantation conditioning toxicity and shows a positive trend in improvement of overall survival and leukemia free survival.
OncoImmune has received orphan drug designation for CD24Fc in both the US and Europe
Beyond GVHD, 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.
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.
Siglec-G represses DAMP-mediated effects on T cells
Toubai T, Rossi C, Oravecz-Wilson K, Zajac C, Liu C, Braun T, Fujiwara H, Wu J, Sun Y, Brabbs S, Tamaki H, Magenau J, Zheng P, Liu Y, Reddy P. JCI Insight 2017, 2(14): e92293.