Researchers have described Siglec-15 (S15) as a new target for immunotherapy in a paper published in Nature Medicine.
"Our focus is on discovering next-generation immunomedicines that normalise the immune system. Different from immune checkpoint blockade, cancer immunotherapy based on normalisation aims to restore an impaired immune system to a healthy state, so it detects and destroys cancerous cells and avoids harming healthy cells," stated Prof Chen, Scientific Founder of NextCure, United Technologies Corporation Professor in Cancer Research and Professor of Immunobiology, of Dermatology and of Medicine (Medical Oncology) at the Yale University School of Medicine and the Co-Director of the Cancer Immunology Program at Yale Cancer Center.
"Using a new technology platform called genome-scale T-Cell Activity Array (TCAA), we identified S15 as a major immune suppressor in B7-H1 (PD-L1) negative tumours, which are resistant to currently approved anti-PD cancer therapies. We hope S15 will be the first in a series of novel targets for immunomedicines to help patients not responding to current immunotherapy drugs." Prof Chen also added.
The study, led by Prof Chen, revealed that S15 is upregulated on human cancer cells and M2 macrophages in the tumour microenvironment and suppresses tumour immunity.
Furthermore, the study showed that S15 knock-out mice did not develop autoimmune or other diseases, suggesting that S15 inhibition may not be associated with adverse effects on normal cells.
"We are very excited about this publication and demonstration that S15 is an important target for drug development. We recently initiated the first-in-human Phase 1/2 clinical trial for NC318, a monoclonal antibody against S15," said Sol Langermann, Ph.D., CSO of NextCure. "In addition to our NC318 and NC410 cancer programs, our FIND-IO™ platform, an expanded and industrialised form of the TCAA, continues to identify novel targets for cancer and immune-related diseases, as well as other indications. We look forward to advancing immunomedicines against these novel targets."
NC318 is a first-in-class immunomedicine against S15, a novel immunomodulatory target found on a restricted set of myeloid cells in the tumour microenvironment and on certain tumour types including lung, ovarian and head and neck cancers.
In preclinical research, it was observed that S15 promoted the survival and differentiation of suppressive myeloid cells and negatively regulated T cell function, allowing cancer to avoid immune destruction.
In preclinical studies, NC318 blocked the negative effects of S15.
NC318 has the potential to treat multiple cancer types.