NANTES, France—Late last year, OSE Immunotherapeutics presented preclinical efficacy data for OSE-230 at the 2020 Federation of Clinical Immunology Societies (FOCIS) Annual Meeting. OSE-230 is a novel agonist monoclonal antibody against ChemR23, also known as chemerin chemokine-like receptor 1 (CMKLR1), a G-protein coupled receptor (GPCR) expressed on myeloid immune cells known to modulate inflammation.
Persistent inflammation is a characteristic feature of all chronic inflammatory or autoimmune diseases. If it isn’t controlled or resolved, it can lead to further tissue damage and tissue fibrosis. Most anti-inflammatory agents use a mechanism that blocks pro-inflammation pathways. In contrast, OSE Immunotherapeutics is developing OSE-230 as a first-in-class therapeutic that could potentially resolve chronic inflammation by causing the affected tissues to complete the inflammation program and restore tissue integrity.
“OSE-230 represents a disruptive concept in the resolution of inflammation, a failed process in potentially all chronic inflammatory diseases,” said Nicolas Poirier, chief scientific officer of OSE Immunotherapeutics. “The data presented show that OSE-230 is the first monoclonal antibody triggering the activation of specialized receptors of resolution to restore tissue homeostasis, integrity, and functions. Our findings provide strong evidence for the therapeutic potential of OSE-230 to be developed in various chronic inflammation and autoimmune pathologies and reinforce OSE’s position in the immunotherapy field targeting myeloid cells in autoimmune and chronic inflammatory diseases, and in immuno-oncology.”
“The resolution of inflammation is an emerging field and a completely new paradigm in the management of inflammation. We’ve learned over the last years that inflammation is a natural process with an initiation, a middle, and a resolution phase. It doesn’t just peter out, but instead the body actively shuts it down using specific resolution signals that researchers hope to transform into therapies,” Poirier tells DDN. “OSE-230 is a monoclonal antibody agonist for one of the key receptors of the resolution of inflammation pathways. It demonstrated strong potential to trigger resolution in situations where this process is known to be blocked or deficient such as in severe and chronic inflammatory disease (e.g. Crohn’s disease) or autoimmune diseases (multiple sclerosis, type 1 diabetes).”
“The current standard of care for the management of severe and chronic inflammation is a variety of anti-inflammatory drugs which aim at pushing back inflammation by blocking signals that initiate the process, meaning a return to the past. The novel approach under development by OSE is to actively push on resolution pathways using agonist monoclonal antibodies to mimic natural signals that induce the resolution cascade and promote a return of tissue homeostasis, and avoid loss of function and fibrosis in affected tissues,” he explains.
The FOCIS presentation showed efficacy results for OSE-230 in chronic inflammatory preclinical models and ex-vivo human models. OSE-230 accelerates inflammation resolution in acute inflammatory preclinical models by triggering pro-resolutive programs in macrophages and neutrophils at the site of inflammation. The therapy triggers efficient resolution of inflammation in chronic colitis models which spontaneously do not resolve, with a significant decrease in leukocyte infiltrates, tissue lesions, fibrosis, and inflammation-driven tumors. Preclinical studies have also demonstrated resolution of inflammation in type 1 diabetes and multiple sclerosis models.
“OSE-230 demonstrated strong preclinical efficacy as a monotherapy in various in-vivo experimental models,” states Poirier. “However, due to its completely different mechanism of action and novel pathways targeted, OSE-230 is also potentially a complementary approach to current anti-inflammatory drugs and combination might be envisaged in the future.”
The natural resolution of inflammation is elicited by pro-resolving lipids which activate GPCRs to induce neutrophil apoptosis, reduce neutrophil tissue recruitment, and promote macrophage efferocytosis. Using transcriptional analyses of up to 300 chronic colitis patients, OSE’s R&D team identified ChemR23 as a GPCR receptor of the resolution program overexpressed in the inflamed tissues of patients who were not responsive to anti-TNFα or anti-α4β7 therapies. In these patients, treatment resistance was strongly associated with bowel mucosal neutrophil accumulation. The ChemR23 receptor is mainly expressed by resident tissue macrophages and neutrophils only under inflammatory (TNF, IL-6, LPS) conditions.
Poirier reports that OSE-230 is undergoing manufacturing development, and the company plans to begin a Phase 1 clinical trial in the first half of 2022.
“Using an agonist monoclonal antibody modality to switch on completely novel and as-of-yet non-targeted pathways of the resolution of inflammation opens a new therapeutic avenue to fight drug resistance seen in some patients to certain types of anti-inflammatory agents, such as anti-TNF non-response. It also has the potential to re-invent the future on the next management of severe and chronic inflammation,” he concludes.
