SIRP-alpha expressed on immune cells binds to CD47 on tumor cells, down-regulating myeloid lineage cells such as dendritic cells, tumor-associated macrophages and myeloid-derived suppressor cells (MDSCs).
"While a handful of companies are targeting CD47, which is expressed on all cells, OSE is different in that they decided to aim at SIRP-alpha," Scott DeWire, head of business development and licensing in cancer immunology at Boehringer, told BioWorld.
By blocking SIRP-alpha, OSE-172 promotes the activation of T cells by turning MDSCs into effector cells, enhancing antigen presentation by dendritic cells and promoting phagocytic and inflammatory properties of macrophages in the tumor microenvironment. Importantly OSE-172 doesn't bind to SIRP-gamma, which has an opposite effect of SIRP-alpha in that it directly promotes T-cell responses.
"We allow the T cells to work again because it's not a suppressive atmosphere," Dominique Costantini, CEO of OSE, told BioWorld.
OSE has preclinical data in a variety of tumor types showing the drug appears to be working as its mechanism of action would suggest.
At the 15th Annual Discovery on Target conference last year, OSE showed that OSE-172 decreased tumor growth and inhibited the spread of metastasis in a triple-negative breast cancer model. As expected, treatment with OSE-172 increases the number of activated memory T cells in the tumor and lymph nodes.
In an ex vivo model using ovarian cancer ascites, OSE-172 reduced myeloid cells' immunosuppressive functions. And in a hepatocellular carcinoma model, OSE-172 had a synergistic effect on survival when combined with drugs that block PD-1, another immunology checkpoint.
The potential for OSE-172 to be used in combination with other drugs was one of the things that attracted Boehringer to OSE-172, according to DeWire. "This partnership complements our overarching goal of developing first-in-class combination therapies."
Boehringer has an anti-PD-1 antibody, BI-754091, in development and clearly sees the benefit of targeting multiple pathways, having announced last year plans to test BI-754091 in combination with BI-891065, a SMAC mimetic, and with BI-754111, an anti-LAG 3 antibody.
In looking for a partner to maximize the value of OSE-172, Boehringer rose to the top because of its strong presence in immuno-oncology, according to Costantini. "We were convinced by this agreement to sign now before the clinical [development began] because we [now] have the capabilities to develop a very active program."
As part of the deal, Nantes, France-based OSE gets €15 million (US$18.5 million) up front, with the potential for another €15 million relatively quickly for initiation of a phase I study. There is also the potential for more than €1.1 billion (US$1.35 billion) in undisclosed pre-specified development, commercialization and sales milestones, plus royalties on worldwide net sales.
Prior to the deal, OSE was planning on starting a phase I trial later this year, so it'll continue with that program, which will now be funded by Boehringer and could be pushed into early 2019. OSE plans to start with patients with solid tumors with poor prognosis since those patients typically have high levels of myeloid cells and macrophages present in their tumors. After the phase I trial, Boehringer will take over development of OSE-172.