A French study has demonstrated that the novel agonist anti-human ChemR23 monoclonal antibody (MAb) designated OSE-230 accelerated recovery from acute inflammation and triggered resolution of chronic inflammation in mice chronic colitis models, preventing fibrosis and reducing tumor development.

"This is the first study describing not only an agonist anti-ChemR23 MAb that is effective in accelerating resolution of inflammation, but also the first agonist pro-resolutive MAb," said study leader Nicolas Poirier, chief scientific officer at OSE Immunotherapeutics in Nantes.

"This was shown in vivo in chronic inflammatory models, in which the animals treated with OSE-230 showed significant decreased inflammation-driven tumor development and nearly complete abrogation of tissues fibrosis in chronic colitis," Poirier told BioWorld Science.

These are significant findings, as they open up a new therapeutic approach to developing a new class of drugs to reinstate the efficient resolution of chronic inflammation in diseases such as inflammatory bowel disease (IBD), the authors reported in the April 2, 2021, edition of Science Advances.

IBDs, including ulcerative colitis (UC) and Crohn's disease (CD), are increasingly common chronic relapsing gastrointestinal disorders, which have major impacts on quality of life and working ability.

Conventional anti-inflammatory treatments involve gradual administration of agents including steroids and biological agents targeting tumor necrosis factor (TNF) or gut-specific alpha4beta7 integrin, particularly for refractory and severe disease.

However, this approach often fails to induce remission and relapse occurs in primary responders, with fibrotic complications developing in many patients.

Hence the need to identify novel mechanisms and signaling networks implicated in preventing inflammation and in turning off inflammatory chronicity.

Inflammation resolution is actively governed partly by endogenous mediators, notably lipidic specialized proresolving mediators (SPMs) and proteins promoting inflammatory infiltrate clearance, restoring normal function.

Failed resolution occurs when an excessive protective acute inflammation response progresses to chronic inflammation, as seen in many organ-specific diseases.

SPMs resolve inflammation by targeting distinct G protein-coupled receptors (GPCRs) expressed by immune cells, particularly phagocytes.

SPMs also stop neutrophil transmigration and trigger their apoptosis, while promoting phagocytosis of cellular debris (efferocytosis), including apoptotic neutrophils.

These functions are critical for inflammation resolution, as excessively recruited neutrophils can collaterally damage tissues.

In IBD, delayed neutrophil apoptosis and neutrophil-mediated damage are associated with UC and CD development. Moreover, activated neutrophil recruitment correlates with disease severity in CD, whereas complete mucosal neutrophil resolution improves long-term clinical outcomes in UC.

Furthermore, SPM production is reduced in UC patients' colonic mucosa, although increased SPM expression in UC colonic tissue is associated with remission and mucosa homeostasis.

Notably, exogenous resolvin E1 (RvE1) treatment has been shown to accelerate resolution of colon inflammation in acute, spontaneously resolving UC mouse models.

RvE1 triggers extracellular signal-regulated kinase (ERK) and Akt signaling via activation of ChemR23 GPCRs expressed by myeloid cells including.

The RvE1/ChemR23 axis has been reported to decrease inflammatory TNF-alpha and IL-12 secretion by DCs, reduce neutrophil transmigration, increase neutrophil reactive oxygen species generation, and to promote resolutive-type macrophage conversion.

However, despite chronic inflammation in humans having increasingly been associated with an SPM deficit, current treatments based on proresolutive drug delivery are limited, due to the limited bioavailability and rapid SPM clearance.

"Several SPMs, including RvE1 analogues, have been developed and some are still in clinical development for inflammatory diseases," noted Poirier.

"However, these SPMs are difficult to manufacture and have a very rapid elimination within minutes of administration, whereas our MAb drugs [are effective for] several days to weeks of exposure after administration in monkeys," he said.

Whether OSE-230 might promote efficient resolution of chronic inflammation was investigated in the new Science Advances study, in which transcriptional analyses in up to 300 IBD patients identified potential therapeutic targets mediating chronic inflammation.

The researchers found that ChemR23, the GPCR targeted by RvE1, was overexpressed in inflamed colons of severe IBD patients, who were unresponsive to anti-TNF-alpha or anti-alpha4beta7 therapies and whose disease was associated with significant mucosal neutrophil accumulation.

"ChemR23 was significantly overexpressed in inflamed human tissues, including in colon or ileal biopsies from IBD patients as compared to non-IBD controls," noted Poirier.

"In particular, we found that in IBD patients, those that would not respond to anti-TNF or anti-integrin illustrated significant overexpression before and after therapy as compare to responders," he told BioWorld Science.

"In these nonresponding patients, we observed increased neutrophil transcriptomic signature expression, as well as the accumulation of neutrophils in inflamed lesions as seen using histological staining."

The research team also identified the anti-ChemR23 agonist MAb, OSE-230, which they showed to induce receptor signaling, promote macrophage efferocytosis, and to reduce neutrophil apoptosis at the inflammation site.

"The agonist MAb has been characterized to trigger receptor signaling similarly to RvE1 on both macrophages and neutrophils which expressed ChemR23 and overexpressed the target in inflammatory settings," explained Poirier.

"The direct consequence of this signaling is repolarization of macrophages towards a pro-resolutive type secreting, for example, IL-10 and on other cell subsets, acceleration of neutrophils apoptosis, and inhibition of their migration across endothelial barriers."

Regarding safety, "to date, no significant immunogenicity has been observed in nonhuman primates and there has been no impact on the pharmacokinetic (PK) profile," said Poirier. Intravenous administration was very well tolerated in both rodents and nonhuman primates, without any signs of local or systemic hematological or immunological toxicity.

Collectively, these findings suggest that the failure of current IBD therapies may be associated with neutrophil infiltration and that ChemR23 represents a promising therapeutic target for chronic inflammation, which is currently under active investigation.

"At the research level, we are continuing to explore other chronic inflammatory indications as well as noninflammatory indications of interest, since the product's mechanism of action is broad and ChemR23 is overexpressed in a wide numbers of diseases in man," said Poirier.

Regarding the product's future development, he said, "we have initiated manufacturing development in order to prepare the toxicological studies for the end of the year and for entry into clinical trials in 2022." (Trilleaud, C. et al. Sci Adv 2021, 7(14): eabd1453).