As part of global effort to confront COVID-19, OncoImmune also completed a Phase III clinical trial, SAC-COVID, which showed that CD24Fc significantly improved clinical recovery while reducing disease progression to death or respiratory failure of severely and critically ill COVID-19 patients.

After the successful phase 3 trial of CD24Fc above, the company was acquired by Merck for an upfront payment of $425 million, undisclosed milestones and royalties, coupled with a $50 million investment leading to the creation of OncoC4, Inc. a spinout that is focused on developing the oncology pipeline assets.

In December 2020, after the Merck acquisition and with Merck’s investment, Dr. Liu cofounded OncoC4 and serves as its Chairman, Chief Executive Officer and Chief Scientific Officer.  Based in Rockville, Maryland, OncoC4 is a privately-held, clinical-stage biotech company that is actively engaged in the discovery and development of novel biologics for cancer treatment based on the scientific discoveries by Dr. Liu and his team.  As a spinout of OncoImmune, OncoC4 retains the original assets except for the CD24Fc and was infused with additional funds from Merck to invigorate its product development pipeline focusing on best-in-class and first-in-class immunotherapies for oncology.

As a leading cancer immunologist, Dr. Yang Liu has made pioneering contributions to adaptive and innate immune checkpoints responsible for cancer immune evasion. On the adaptive immune checkpoint, CTLA-4, Dr. Liu’s laboratory was the first to identify the major CTLA-4 ligand, which was later called CD86. His decades of dedicated work on ligand recognition and biology of CTLA-4 led to OncoC4’s nextgen anti-CTLA-4 antibodies that differentiate from other CTLA-4 antibody products in that they selectively eliminate the evasive immune function of CTLA-4 by killing the high CTLA-4-expressing immune-suppressor cells (called regulatory T cells) reside in the tumors but preserve immune tolerance function of CTLA-4 in the normal tissues.  

To test this concept, OncoC4 has sponsored the first-in-human study to assess the safety, pharmacokinetics, and efficacy of ONC-392 as a single agent in advanced solid tumors and in combination with anti-PD(L)1 standard of care in cancer patients (PRESERVE-001, NCT04140526).  Recently released data from OncoC4 showed that ONC-392 appears to have better safety and higher clinical activity than other anti-CTLA-4 antibodies. In particular, promising clinical activities were observed in lung cancer patients who are resistant to current immunotherapy.

The New Innate Immune Checkpoint

Dr. Liu’s laboratory identified CD24-Siglec 10 innate immune checkpoint. This pathway was initially identified as a negative regulator for inflammation initiated by tissue injury, but its significance has been extended to several innate and adaptive immune effectors.  In particular, this pathway helps cancer cells to evade innate immunity in the tumor microenvironment by preventing cancer cells from eating by macrophages and/or killed by other innate and adaptive immune effector cells.  OncoC4, Inc. has embarked on IND-enabling studies and is on track to move their anti-Siglec 10 antibody drug to clinical testing later this fall.

Wholesome Research

Beyond the contribution to fundamental biology that is being translated in clinical trials, Dr. Liu has also impacted the process of bridging basic and translational research to clinical developments.  For instance, in the late 1990s, his group was the first to use human gene knock-in mice to test immuno-oncology drugs in animal models.  This method has become an industrial standard in assessing activity and selecting immuno-oncology drugs that target human molecules before testing them in humans.   Separately, Dr. Yang Liu identified the most sensitive mouse tumor models for cancer immunotherapy, which have since become the models of choice for immuno-oncology drug development to study the anti-tumor responses.

True to its root of original research, OncoC4, Inc is building state-of-the-art research infrastructure. This allows them to be more adept, productive, and faster with their scientific advancements. They have also developed extensive collaborations with major academic centers around the world to stay at the cutting edge of immune-oncology research and are building a multi-center clinical trial network with leading institutes and hospitals, including international and national key opinion leaders as our clinical investigators for their clinical trials.  The unmet medical needs for cancer patients who are resistant to other immune therapy treatments on the market or lack of effective immune therapy option propel Dr. Liu’s OncoC4 team to continue making advances in transforming their innovative immunotherapies into standard of care for cancer.

OncoC4, Inc’s lead product ONC-392 is a good example of a best-in-class product.  CTLA-4 targeting agent was the first approved immuno-oncology drug, but it has met with an enormous challenge in the market because of its high toxicity, which also prevents patients from receiving effective dosing. Their original research revealed that toxicity and efficacy were due to separate properties of the anti-CTLA-4 drug in the market: toxicity was due to reduction of CTLA-4 molecules on the lymphocyte cell surface, which triggers the destruction of an important immune tolerance checkpoint.  On the other hand, anti-cancer activity is attributed to the killing of regulatory T cells in the tumor microenvironment.  ONC-392 prevents CTLA-4 from lysosomal degradation, thus reducing toxicity.  Remarkably, avoiding lysosomal degradation also increased the efficacy of the antibody in tumor rejection.  The lower toxicity and higher efficacy make ONC-392 best-in-class based on reported preclinical and clinical data. A number of competitors are all chasing the same mechanisms but have not paid sufficient attention to the biology of the target, which makes ONC-392 drug truly differentiated by this unique mode of action.

Towards the Future

The first-in-class drugs are OncoC4, Inc’s large pipeline targeting the CD24-Siglec 10 innate immune checkpoint which Dr. Liu’s team discovered. They have accumulated unique antagonists for this pathway, respectively, against CD24 and Siglec-10. Their pipeline includes anti-Siglec 10 antibody (ONC-841) that promotes both phagocytosis and killing of tumor cells by the host’s innate immune system, engineered cancer-specific anti-CD24 antibodies (ONC-781), chimeric antigen receptor CAR-T (ONC-782), T cell-engaging bispecific antibodies (ONC-783), and antibody-drug conjugates (ONC-784).