OncoC4
Breaking Drug Resistance with Next-Gen Immunotherapy

Dr. Liu is recognized internationally for his research on immune recognition of cancer and activation of lymphocytes, the main immune defender against cancer. He has also received numerous awards for his pioneering contribution to innate immunity, T cell costimulation, and cancer immunology. After having led several cancer immunology programs in academic institutions in the United States for over three decades and having founded and led OncoImmune, Inc, which was acquired by Merck in 2020, Dr. Liu laid the foundation for OncoC4, a biotech company unveiling novel biologics for cancer treatment with a pipeline of first-in-class and bestin- class immunotherapy product candidates to overcome the most daunting challenges faced by the cancer immunotherapy market.

Cancer immunotherapy (or immuno-oncology), which has emerged in the last decade is, without question, the single most important advancement in cancer treatment in more than eighty years. While a large number of host immune pathways have shown promise as targets for cancer immunotherapy, only two, those mediated by PD(L)1 and CTLA-4, have been successfully targeted. Of these two, most clinical benefit has been achieved by targeting PD(L1), with CTLA4-targeting drugs yet to fulfil their promise.

Unfortunately, most patients do not benefit much from PD(L)1 targeting drugs, because their cancers do not respond to these drugs or because their cancers have acquired resistance to these drugs. OncoC4’s mission is to change the status quo by releasing the untapped potential of the CTLA-4 pathway and by unveiling new targets for cancer immunotherapy.

ONC-392: a best-in-class drug candidate leading the way to break PD(L)1 resistance

Most experts in the immune oncology field agree that CTLA-4 plays a major role in cancer evasion of host immunity because it is the molecule, or checkpoint, that confers suppressor activity to the immune cells that regulate cancer immunity. But, for the same reason, CTLA-4 also keeps our immune system from attacking our own normal tissues-hence the toxicity associated with CTLA-4-targeting drugs. The reason that CTLA-4 targeting antibodies have not made as great an impact in cancer is because the toxicity has prevented sufficient dosing of the drug to patients. Based on decades of fundamental research on immunotherapy, OncoC4’s founders have demonstrated that the cancer immunotherapeutic effect and associated toxicity, known as immunotherapy-related adverse events, can be mediated by distinct mechanisms and thus uncoupled through antibody engineering. The company developed a next-gen anti- CTLA-4 antibody named ONC- 392 that aims to reduce the toxicity associated with immunotherapy with an innovative process, where the CTLA-4 immune checkpoint is preserved outside of the cancer tissues, in contrast to the current first generation anti-CTLA-4 drugs used in the clinic that inactivate the immune protective function of CTLA- 4. In the tumor microenvironment, ONC-392 uses CTLA-4 as the target to selectively eliminate regulatory immune cells which suppress tumor killing by other immune cells. The selectivity allows ONC-392 to spare the regulatory cells that suppress immune killing on normal tissues.

Our preclinical studies showed that, compared with other commercial and clinical stage anti-CTLA-4 antibodies, ONC-392 has more robust cancer immunotherapeutic effect but dramatically lower immunotherapyrelated adverse events in preclinical models,” says Dr. Yang Liu, CEO, OncoC4.

The better safety window has allowed us to dose more drug and for longer in the clinic, resulting in very promising therapeutic activity in our preliminary readout of the Phase I clinical trial.” said Dr. Pan Zheng, the Chief Medical Officer and Co-founder of OncoC4.

OncoC4 has recently completed the first part of the Phase I trial for ONC-392 to determine its pharmacokinetics, safety, and efficacy as a single agent in advanced solid tumors and in combination with the anti-PD-1 standard of care in nonsmall cell lung cancer. The drug was shown to be well tolerated at the clinical doses tested and can be administered at a higher dose and longer duration than the CTLA- 4 drug on the market. In addition, of the ten patients enrolled in the monotherapy, six were reported to show positive clinical activities. Out of these, one with non-small cell lung cancer and one with ovarian cancer showed complete responses (with all tumor lesions eliminated). Thus, a safe and efficacious profile of ONC- 392 has begun to emerge showing promising clinical benefits.

Most notably, three of the ten enrolled patients were Stage 4 non-small cell lung cancer patients who previously received PD-(L)1 therapy and developed resistance for it later. The drug showed clinical and biological activity in all three of them: one had complete response; one show very significant reduction in tumor volume; and one had stable disease for extended period. Since the PD(L)1 resistant patients are the most difficult to treat, PD(L)1 resistance is considered the most challenging problem in immune oncology field. The early hopeful sign from OncoC4’s clinical data encourage them to focus on PD(L)1 resistance in their future clinical development, aiming to make a major dent in this challenging field.

Compared With Other Commercial And Clinical Stage Anti-Ctla-4 Antibodies, Onc-392 Has The Promise Of More Robust Cancer Immunotherapeutic Effect But Dramatically Lower Immunotherapyrelated Adverse Events Based On Preclinical Models

A pipeline of first-inclass preclinical assets moving into clinic

In their previous life as leading academic researchers, Dr. Liu and Zheng’s laboratories discovered an innate immune checkpoint mediated by the interaction of CD24 and Siglec-10. Their previous company, OncoImmune, Inc., has successfully explored this pathway to treat disorders caused by uncontrolled inflammation, such as COVID-19. Based on the promising clinical data of their lead drug, CD24Fc, OncoImmune was acquired by Merck in December of 2020. This led to the formation of OncoC4 whose focus is on the utility of targeting this pathway for cancer treatment for giving quotes inside description.

CD24 is elevated in nearly 70% of all human cancers, and the higher the level on cancer cells, the worse the clinical outcome. One of the explanations for this indictment is provided by scientists at Stanford University who reported that CD24 binds to Siglec-10 on the immune cells, macrophages, and tells them not to eat the surrounding tumor cells.

Accordingly, they dubbed this CD24-Siglec-10 pathway a “do-noteat- me” signal. Having confirmed the work and found that this pathway can also allow cancer to evade other mechanisms of immune attack, OncoC4’s team has developed a pipeline of five preclinical assets targeting either Siglec-10 or CD24.

In developing the anti-Siglec-10 antibody, called ONC-841, OncoC4 scientists have found that Siglec-10 does a lot more than blocking its binding to CD24 and telling macrophages not to eat cancer cells, raising the hope that the drug may have a significant and broad impact in the immune oncology field. This novel discovery prompted OncoC4 to expedite ONC-841 development and the drug candidate is now in INDenabling studies with a first-in-human clinical study planned within this year.

Because of wide-spread expression of CD24 in human cancers, there is a long-standing interest to target this molecule for cancer therapy. However, progress has been slow because the molecule is also present in normal tissues, making it risky to target. The secret sauce of OncoC4’s four CD24- targeting assets is a unique anti-CD24 antibody called ONC-781 that only targets CD24 on cancer cells.

The proprietary ONC-781 antibody recognizes a novel antigenic glyco-epitope broadly expressed on cancer cells but essentially absent in normal tissues. The systemic characterization of the proprietary target through cancer biology research reveals that the epitope is encoded by an over-expressed gene and is fundamentally important for cancer cell growth and metastasis. Based on this novel tumor-targeting approach, OncoC4 is developing engineered CAR-T cells (ONC-782), bi-specific antibodies (ONC-783), and antibodydrug conjugates (ONC-784) to expand the cancer immunotherapy pipeline. Laboratory testing showed a broad reactivity of these drug candidates to hepatocellular carcinoma, breast cancer, ovarian cancer, cervical cancer, neuroblastoma, prostate cancer, lung cancer, and essentially all types of malignant brain tumors.

With a rich product development pipeline, spurring out of extensive research, OncoC4 is making way for effective treatments for all major types of cancer. “We are constantly pushing the new frontier in cancer immunotherapy by introducing firstin- class immunotherapy products into our pipeline” concludes Liu.