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Novel immunotherapies to combine with PD-1/PD-L1 treatment

With an international approach to open innovation, ImmuneOncia Therapeutics was established in 2016 as a joint venture between Sorrento Therapeutics, Inc., an antibody-centric biopharmaceutical company based in the US, and Yuhan Corporation, one of the largest pharmaceutical companies in South Korea. ImmuneOncia benefits from Sorrento’s leading immunotherapy product portfolio. Yuhan, meanwhile, has committed substantial resources for the development of cancer immunotherapeutics. ImmuneOncia also benefits from Yuhan’s experience in research and development (R&D), as well as the history of excellence and efficiency in drug development among South Korean companies.

From its base in South Korea, ImmuneOncia operates virtually by forging collaborations with contract research organizations and utilizes the well-developed clinical trial infrastructure in South Korea. “Early clinical development requires rigorous scientific proof-of-concept studies, and the hospitals in Korea are able to support this,” said Yun Jeong Song, CEO and CMO at ImmuneOncia.

Thanks to investment from the Korean government, the Global Centers of Excellence Program for early-phase clinical development was set up, which focuses on specialized therapeutic areas or unmet needs in R&D; there are 5 top university hospital consortia ranked by Korean authorities that form core investigative sites in South Korea, as well as 184 qualified clinical trial sites with world-class infrastructure and medical care. The sites have among the fastest study start-up times, with well-defined regulatory and review processes, and have access to highly educated medical and research staff (details available at kcc.konect.or.kr).

Anti-PD-L1, a future backbone therapy

ImmuneOncia’s portfolio includes immune checkpoint (IC) antibodies that target both hematological malignancies and solid tumors. The most advanced molecules in its pipeline target the IC proteins CD47, a ligand of signal-regulatory protein-α (SIRPα), and PD-L1, a ligand of programmed cell death protein 1 (PD-1) (Fig. 1).

Fig. 1 | ImmuneOncia’s portfolio. IMC-001 blocks PD-L1 on tumor cells interacting with PD-1 on T cells, and boosts T cell activity. IMC-002 blocks CD47–SIRPα interactions between tumor cells and macrophages and promotes tumor phagocytosis by macrophages.

It is now well established that antibodies that block the interaction between PD-1 on T cells and PD-L1 on tumor cells can boost T cell activity and proliferation, leading to enhanced antitumor immunity. Clinical candidate IMC-001 is a fully human IgG1 monoclonal antibody against PD-L1 that retains antibody-dependent cell-mediated cytotoxic activity and shows robust efficacy in vitro and in vivo. The investigational new drug (IND) filing for IMC-001 was accepted in February 2018 and the results of a phase 1 trial are expected in Q2 of 2019. IMC-001 supports ImmuneOncia’s global vision of supplying innovative drugs to a wider population. “It is a high-quality, innovative drug, yet we also aspire to provide this drug at a lower cost than is typically associated with immunotherapies, which will be relevant for market access with our regional partners,” said Song.

ImmuneOncia is also positioning IMC-001 as a ‘first-to-market’ anti-PD-L1 antibody in certain rare cancers. “Although current PD-1/PD-L1-targeting treatments can achieve durable responses in many types of cancers, there are still many cancers where clinical benefit of these agents is not well understood,” said Song. “We are focusing our clinical development on these types of malignancies, incorporating biomarkers and combination strategies.”

Prioritizing the development of IMC-001 is part of the overarching strategy for ImmuneOncia. “With IMC-001—our backbone therapy—in place, we will be able to move quickly and explore a wide range of therapeutic options with various partnering technologies, including novel combinations with other IC-targeting antibodies in our pipeline,” said Song.

Anti-CD47 and beyond

Another advanced candidate in the pipeline targets CD47, which acts as a ‘don’t eat me’ signal that inhibits the phagocytosis of healthy cells by interacting with the SIRPα receptor on macrophages. Research shows that CD47 is often overexpressed on cancer cells, which protects tumors from phagocytosis but also presents an opportunity to develop drugs that restore the phagocytic activity of macrophages. Indeed, blockade of the CD47–SIRPα interaction has been shown to inhibit tumor growth in mouse xenograft models.

IMC-002 is a fully human IgG4 monoclonal antibody designed to block the CD47–SIRPα interaction in order to promote the phagocytosis of cancer cells by macrophages. It binds to human CD47 with an optimal affinity that maximizes efficacy, in terms of tumor phagocytosis and in vivo tumor growth suppression, without causing hemagglutination, which is linked to side effects seen in the clinic, such as anemia and thrombocytopenia. The IND filing for IMC-002 is expected in early 2020.

Recent evidence shows that tumor-associated macrophages also express PD-1, suggesting that PD-1/PD-L1 therapies may also have a direct effect on macrophages1. Combinatorial blockade of PD-L1 and CD47 has been shown to enhance antitumor effects in vivo1, which presents an interesting opportunity to combine IMC-001 and IMC-002 in the clinic.

The company is also in the early stages of developing a number of other IC-targeting antibodies, as well as bispecific antibody drug candidates. “We are building our pipeline in a way that ensures synergies between the different drug targets, and we also take the patent landscape very seriously,” said Song.

Partnering opportunities

ImmuneOncia is open to various partnering opportunities, including chemistry, manufacturing and control development, R&D collaborations and business alliances. Because it is a small biotech system run by industry experts and advisors, the company has a quicker decision-making process and more flexible mindset compared with a large pharmaceutical company. At the same time, ImmuneOncia will continue to make the most of its international joint venture in immuno-oncology by forging multinational and regional alliances, and networking with immunological and clinical experts worldwide.

References

  1. 1.

    Gordon, S. R. et al. Nature 545, 495–499 (2017).

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