On October 19, 2022 VIB, Flanders’ leading life sciences institute, and Surface Oncology (Nasdaq: SURF), a clinical-stage immuno-oncology company developing next-generation immunotherapies that target the tumor microenvironment, reported jointly the publication of a study entitled, "Structural basis of activation and antagonism of receptor signaling mediated by interleukin-27: Cell Reports," in Cell Reports, a leading scientific journal. The study was a collaborative research effort between the Unit for Structural Biology at the VIB-University of Ghent Center for Inflammation Research and Surface Oncology (Press release, Surface Oncology, OCT 19, 2022, View Source [SID1234622180]).
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"In this study, we have shown how the IL-27 heterodimer is formed, and how the cytokine uniquely docks with its receptor to form the IL-27 signaling complex, providing new insights into IL-27 cytokine biology," said Savvas Savvides, Professor and Group Leader at Ghent University and the VIB Center for Inflammation Research. "The elucidation of the structure of IL-27 and its complex with its signaling receptor provides invaluable data to support the ongoing mechanistic interrogation, engineering, and therapeutic targeting of IL-27."
"SRF388 is a fully human anti-IL-27 antibody designed to inhibit the activity of this immunosuppressive cytokine, and this study provides important structural evidence that the antibody directly competes with the IL-27 receptor to prevent downstream signaling of the cytokine," said Vito Palombella, Chief Scientific Officer at Surface Oncology. "IL-27 has been implicated as an immunosuppressive cytokine in several tumor microenvironments and understanding the mechanistic basis of SRF388’s inhibitory activity will help inform its ongoing clinical development."
Summary of key data:
IL-27 is comprised of p28 and EB13 subunits which are uniquely organized into a heterodimeric assembly distinct from other members of the IL-12 family of cytokines.
The elucidated crystal structure of IL-27 and its receptor reveals the presence of at least 4 different sites that are important for the assembly of the signaling complex and which potentially can be used as targeting sites to disrupt IL-27’s structure and subsequently its immunosuppressive function.
Analyses reveal that SRF388 and the IL-27 receptor contend for the same binding epitope on IL-27, with SRF388 competitively inhibiting IL-27 receptor activity, providing structural evidence for SRF388’s potent antagonistic properties.
Details on the study by Katarzyna Składanowska, Yehudi Bloch et al. can be found in the October 18 issue of Cell Reports [VOLUME 41, ISSUE 3, 111490, View Source(22)01340-7. Additional authors include Daniel Aldridge and Christopher Hunter, Ph.D., chair of the Department of Pathobiology at the University of Pennsylvania School of Veterinary Medicine and a member of the Surface Oncology Scientific Advisory Board.
About SRF388
SRF388 is a fully human anti-IL-27 antibody designed to inhibit the activity of this immunosuppressive cytokine. Surface Oncology has identified particular tumor types, including liver, kidney and lung cancer, where IL-27 appears to play an important role in the immunosuppressive tumor microenvironment and may contribute to resistance to treatment with checkpoint inhibitors. SRF388 targets the rate-limiting p28 subunit of IL-27, and preclinical studies have shown that treatment with SRF388 blocks the immunosuppressive biologic effects of IL-27, resulting in immune cell activation in combination with other cancer therapies including anti-PD-1 therapy, as well as potent anti-tumor effects as a monotherapy. Furthermore, Surface Oncology has identified a potential biomarker associated with IL-27 that may be useful in helping to identify patients most likely to respond to SRF388. In November 2020, Surface announced that SRF388 was granted Orphan Drug designation and Fast Track designation for the treatment of refractory hepatocellular carcinoma from the FDA.