OSE publishes data supporting new mechanism of action for BI 765063

The publication identifies a new T cell exclusion mechanism attributed to CD47-SIRPα signaling

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OSE publishes data supporting new mechanism of action for BI 765063

NANTES, France—OSE Immunotherapeutics has announced a publication of translational and preclinical study data in rodent in vivo and human ex vivo models which characterizes the efficacy and mechanism of action of BI 765063, which was formerly known as OSE-172. BI 765063 is the first selective antibody antagonist of SIRPα-mediated “Don’t Eat Me” signals.

The OSE R&D team has reported the identification of a complementary SIRPα-mediated “Don’t Find Me” mechanism that tumors use to evade immune detection by preventing T lymphocytes from entering the tumor core.

The article, which was published in the Journal of Clinical Investigation, is entitled “Selective SIRPα blockade reverses tumor T cell exclusion and overcomes cancer immunotherapy resistance.” It reports on the discovery that the anti-SIRPα strategy reverses a major mechanism of resistance and escape to immunotherapy called T-cell exclusion. This means that the activated T lymphocytes aren’t able to penetrate the tumor core and remain blocked at its periphery.

“To evaluate the clinical potential of anti-SIRPα mAbs and understand how SIRPα signals modify the TME [tumor microenvironment], we tested non-cytotoxic antagonist anti-SIRPα mAbs on SIRPα-negative tumor syngeneic and orthotopic mouse models. We found that blocking SIRPα signaling was sufficient for modifying the TME,” the article notes. “Moreover, anti-SIRPα monotherapy was effective in inhibiting tumor growth and preventing tumor metastasis in triple-negative breast cancer and mesothelioma orthotopic models that are highly enriched in myeloid cells.”

“In models where anti-SIRPα monotherapy showed weak efficacy (e.g., orthotopic HCC [hepatocellular carcinoma] or subcutaneous CRC [colorectal carcinoma] models), a strong synergistic association was found with immunotherapies promoting T cell responses, such as PD1/PD-L1 antagonists or a 4-1BB costimulatory agonist,” continues the article. “Most of the mice (60%–80%) treated with SIRPα/PD-L1 or SIRPα/4?1BB combination therapy eradicated the primary tumor and developed robust and durable adaptive immune memory.”

In in vivo models of resistance to anti-PD-1, PD-L1 or 4-1BB co-stimulation activators, studies have demonstrated that T lymphocytes initially blocked at the tumor’s margin could efficiently penetrate into the tumor when blocking SIRPα in parallel. Crossing this barrier is associated with positive modulation of macrophage expression and secretion of chemokines, allowing the penetration of T lymphocytes into the heart of the tumor.

“Our studies show that macrophages are inhibited when in contact with tumors expressing CD47 via the SIRPα pathway and thus they no longer secrete chemokines — small protein mediators which attract immune cells. By overexpressing CD47, tumors not only induce a ‘Don’t Eat Me’ signal to macrophages but, as we discovered, they also induce a ‘Don’t Find Me’ signal and consequently T lymphocytes are no longer attracted to the tumor core by the secretion of chemokines from the macrophages,” explained Nicolas Poirier, chief scientific officer of OSE Immunotherapeutics. “Our new anti-SIRPα strategy reverses this major mechanism of resistance named ’T-cell exclusion’ by releasing the break on T lymphocyte chemotaxis and migration into the heart of the tumors.”

“This study shows that selectively blocking SIRPα on myeloid cells even without tumor cell opsonization promotes antitumor responses and positively modifies the TME. Notably, the SIRPα/CD47 axis inhibits not only macrophage phagocytosis, but also chemokine secretion of human myeloid cells, thereby inducing T cell exclusion from the tumor nest and contributing to resistance to anti-PD1/PD-L1 immunotherapies,” the article explains. “Finally, we uncover a role for the human-specific SIRPγ/CD47 axis in promoting human antitumor T cell responses. Thus, selective blockade of SIRPα signaling may open novel treatment avenues to reinstate efficient adaptive immune responses against tumor antigens while offering different therapeutic indices than current anti-CD47–based approaches.”

BI 765063 is being evaluated in a Phase 1 clinical trial conducted in patients with advanced solid tumors. It is a dose finding study of the myeloid checkpoint inhibitor BI 765063, both as a single agent and in combination with Boehringer Ingelheim’s monoclonal antibody PD-1 antagonist BI 754091, which is a T lymphocyte checkpoint inhibitor.

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