Product Pipeline Overview

OncoImmune’s founders have identified a novel pathway that is a checkpoint for the development of a number of disease indications. Our lead molecule, CD24Fc, targets this pathway and efficiently modulate the immune response in animal models of GVHD, multiple sclerosis and rheumatoid arthritis.  We have completed phase II clinical trial for GVHD and is launching a pivotal phase III clinical trial for the indication.

In addition to our in-house flagship program on CD24Fc, OncoImmune is developing a pipeline of unique product candidates in immuno-oncology, inflammatory and autoimmune diseases.


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 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.

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:

  • First, CD24Fc binds DAMPs, trapping the inflammatory stimuli to prevent their interaction with TLR receptors
  • Second, CD24Fc binds Siglec G/10 and regulates host response to tissue injuries Siglec G/10-associated SHP1 inhibitory signaling

Both mechanisms likely act in concert to modulate immune responses.

Endogenous CD24 Inhibits Inflammatory Responses

CD24Fc Mimics/Augments Endogenous CD24 Activity

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/ 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.


CTLA-4 was commercially validated as the first target to correct immune defects in cancer patients through antibody-based immunotherapy.  However, CTLA-4-targeting drugs currently in clinical use cause immunotherapy-related adverse events (irAE) in 75-90% of cancer patients.  The laboratory of Drs. Liu and Zheng have developed an in vivo model to investigate molecular and immunological mechanisms for irAE and cancer immunotherapeutic effect (CITE).  Their work established that irAE and CITE are mediated by distinct mechanisms and thus can be uncoupled through in vivo screening and engineering for antibodies with stronger CITE but minimal irAE.  ONC-392 is such an antibody that targets CTLA-4 in a unique way to selectively eliminate tumor-infiltrating regulatory T cells (Treg) without affecting T cell activation in the peripheral T cells.  Compared with the commercial and clinical stage anti-CTLA-4 antibodies, ONC-392 has more robust CITE but dramatically lower irAE.  This drug is currently in pre-clinical testing to support and IND filing and clinical testing in 2019.


How Does an Anti-CTLA-4 Antibody Promote Cancer Immunity?

Liu Y, Zheng P.

Trends Immunol. 2018 Dec;39(12):953-956. doi: 10.1016/

Uncoupling Therapeutic from Immunotherapy-related Adverse Effects for Safer and Effective Anti-CTLA-4 Antibodies in CTLA4 Humanized Mice.

Du X, Liu M, Su J, Zhang P, Tang F, Ye P, Devenport M, Wang X, Zhang Y, Liu Y, Zheng P.

Cell Res. 2018 Apr;28(4):433-447. doi: 10.1038/s41422-018-0012-z. Epub 2018 Feb 20.

A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy.

Du X, Tang F, Liu M, Su J, Zhang Y, Wu W, Devenport M, Lazarski CA, Zhang P, Wang X, Ye P, Wang C, Hwang E, Zhu T, Xu T, Zheng P, Liu Y.

Cell Res. 2018 Apr;28(4):416-432. doi: 10.1038/s41422-018-0011-0. Epub 2018 Feb 22.

Human CTLA-4-knock-in mice unravel the quantitative link between tumor immunity and autoimmunity induced by anti-CTLA-4 antibodies.

Lute KD, May KF Jr, Lu P, Zhang H, Kocak E, Mosinger B, Wolford C, Phillips G, Caligiuri MA, Zheng P, Liu Y.

Blood. 2005 Nov 1;106(9):3127-33. Epub 2005 Jul 21.


Echinomycin has been used unsuccessfully in the treatment of solid tumors but not previously evaluated in the patients with haematological malignancies. OncoImmune’s founders have demonstrated that echinomycin is highly effective at selectively targeting leukemia stem cells (LSCs) and we are developing novel formulations of Echinomycin for the treatment of leukemia and solid tumors, including acute myeloid leukemia (AML). 

AML is a fast-growing form of cancer of the blood and bone marrow, and the most common type of acute leukemia. Treatment of AML is usually divided into 2 chemotherapy (chemo) phases: Remission Induction which is aimed at getting rid of as many leukemia cells as possible, and Consolidation (post-remission therapy) which aims to destroy any remaining leukemia cells and prevent a relapse. However, while current therapy can result in complete remission (CR) in the majority of AML cases, relapsed AML (rAML) occurs in >50% patients within two years of CR.  Among them, more than 60% succumb to AML within two years of relapse and is generally resistant to chemotherapy. Recent studies suggest that leukemia stem cells (LSC) are highly resistant to conventional chemotherapy and thus likely responsible for relapse.  Therefore, therapeutic elimination of LSC may offer a new strategy for the treatment of rAML.

Echinomycin is a DNA intercalating cyclic peptide which belongs to a member of quinoxaline antibiotics originally isolated from Streptomyces echinatus. Because of its anti-neoplastic activities against murine tumors, echinomycin was brought into clinical development for solid tumors by the National Cancer Institute (NCI) in multiple phase I and phase II studies. However,  the dose-limiting toxicity (DLT) in all trials, regardless of schedule, was severe and often protracted and echinomycin was not consistently effective for adult patients with solid tumors. Accordingly, clinical development of echinomycin was discontinued.

Using a transgenic mouse model of lymphoma/leukemia, OncoImmune’s founders identified a subset of cells with stem cell like self renewing properties. This cell population was found to be particularly susceptible to the HIF-1a inhibitor, echinomycin, whereas inhibitors of other pathways had little to no effect on cell viability. Furthermore, the lymphoma CSCs were approximately 100-fold more sensitive than normal hematopoeitic progenitor cells (HPCs) and echinomycin treatment results in long-lasting elimination of lymphoma CSCs as demonstrated by a complete lack of recurrence in treated mice. The HIF-1a -Notch pathway was determined to be essential for the maintenance of these cancer stem cells (CSCs) in hematological malignancies under normoxia.

Leukemia stem cells (LSCs) from AML display a similar increase in HIF-1a expression. The inhibitory effect of echinomycin was demonstrated in 7 independent primary AML samples taken from the bone marrow (BM) or peripheral blood (PB). In the xenogeneic model of human AML, short-term treatment by echinomycin prevented serial transplantation of AML, supporting the use of echinomycin as a therapeutic agent for AML.

The major limitation of echinomycin as a drug product, is the narrow therapeutic window due to its short half life. OncoImmune is developing new formulations of echinomycin with increased half life and we have received orphan drug designation from the FDA for the treatment of AML.

With the support of Nanotechology Characterization Laboratory of the National CancerInstitute, OncoImmune has developed a novel nanoformulation of Echinomycin. With much improved therapeutic index, the new formulation of Echinomycin has been shown to be highly effective in a number of solid tumor models, including both primary and metastatic lesions of breast cancer and glioblastoma.


Echinomycin protects mice against relapsed acute myeloid leukemia without adverse effect on hematopoietic stem cells.

Wang Y, Liu Y, Tang F, Bernot KM, Schore R, Marcucci G, Caligiuri MA, Zheng P, Liu Y.

Blood. 2014 Aug 14;124(7):1127-35. doi: 10.1182/blood-2013-12-544221.

Targeting HIF1α eliminates cancer stem cells in hematological malignancies.
Wang Y, Liu Y, Malek SN, Zheng P, Liu Y.
Cell Stem Cell. 2011 Apr 8;8(4):399-411. doi: 10.1016/j.stem.2011.02.006.


A major advance in immunotherapy is to targeting T cell to cancer cells through either bi-specific antibodies or chimeric antigen receptors for T cells (CAR-T).  While this approach has been transformative for some hematological malignancies, its impact on solid tumors has been very limited, in part due to the lack of appropriate target and targeting agents that are specific for cancer cells.  Our ONC-781 program is based on a novel antigenic glyco-epitope that is broadly expressed on cancer tissues but essentially absent in normal tissues. We have developed a novel monoclonal antibody that binds to this novel glycoform and demonstrated that it binds to all major types of cancer tissues but not normal tissues. Subsequently, we have developed bispecific antibodies and CAR-T cells using this novel antibody that show broad reactivity to hepatocellular carcinoma, breast cancer, ovarian cancer, cervical cancer, neuroblastoma, prostate cancer, lung cancer and essentially all types of malignant brain tumors (see Figure B).  Our systemic characterization of the proprietary target reveal that the epitope is encoded by a gene that is over-expressed and fundamentally important for cancer cell growth and metastasis.  It is shielded in normal cells by a specific glycosylation.   Since the antigenic epitope is on an oncogene that is critical for cancer growth and metastasis, it is anticipated that cancer cells would be hard-pressed to lose the antigen to evade ONC-781-based immunotherapy.

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