Developing Therapies to Fight Cancer and Autoimmune Diseases

We recently spoke to Alexis Peyroles, CEO at OSE Immunotherapeutics to hear more about the findings of their recent study, published in Nature Communications, describing, for the first time ever, the in vivo mechanism of action of interleukin 7 receptor alpha (IL-7Rα) monoclonal antibodies, suggesting therapeutic efficacy in controlling chronic inflammation.

Alexis discusses the role of interleukin-7 (IL-7) in chronic autoimmune and inflammatory diseases, the company’s research & development activities in both immuno-oncology and autoimmune disease areas, and the therapeutic development of OSE-127, an anti-IL-7 receptor monoclonal antibody.

Laura Lansdowne (LL): Could you tell us more about OSE Immunotherapeutics, the company history, mission and goals?

Alexis Peyroles (AP): OSE Immunotherapeutics was founded in 2012 by Dr Dominique Costantini, who acquired rights to the Tedopi technology from Takeda for its development as an immuno-oncology therapy. Three years later, OSE went public with an IPO on EuroNext that raised over €20 million. Over the past three years we have been busy building out our developmental pipeline of clinical assets, which includes developing and initiating a number of academic and industry partnerships to bring field and drug development expertise, expand our research capabilities and also help cover R&D costs associated with clinical development.

Our mission has always been to leverage world-class clinical immunology expertise and a validated R&D platform to deliver first-in-class targets addressing unmet needs in immuno-oncology and autoimmune diseases. We have a strong connection to top academic research centers around the world and have leveraged our unique experience in clinical immunology and transplant surgery to develop first-in-class therapeutic targets. Our developmental pipeline has repeatedly been validated through premier international, academic and industrial partnerships that cover R&D and increase shareholder value.

LL: Could you touch on the company’s research & development activities in both immuno-oncology and autoimmune disease areas?

AP: We currently have several clinical-stage developmental programs in the fields of immuno-oncology (IO) and autoimmune diseases (AD). In IO, our lead product, Tedopi®, is a proprietary combination of neo-epitopes aimed at stimulating T-lymphocytes intended to restore immune surveillance of cancer. Tedopi is currently in a Phase 3 clinical trial in advanced non-small-cell lung carcinoma (NSCLC) post checkpoint inhibitor (CKI) failure, with data expected in 2019. We also recently announced a Phase 2 trial of Tedopi paired with a checkpoint inhibitor in pancreatic cancer. This trial will be executed with our research partners at GERCOR, a cooperative group of digestive oncology experts with international recognition based on France.

In addition, we are developing OSE-172, a first-in-class myeloid checkpoint inhibitor transforming suppressive cells into effector cells within the tumor microenvironment. OSE-172 targets CD47 through blocking SIRpa, a completely differentiated approach with potential benefits as compared to all other therapies in the CD47 space. We are developing OSE-172 with our partner Boehringer Ingelheim and are planning to enter clinical Phase 1 testing before year's end.

We are also developing OSE-703, a cytotoxic targeted mAb against the interleukin-7 receptor (IL-7R). OSE-703 is currently being developed in partnership with the Memorial Sloan Kettering Cancer Center (MSKCC) by a research team lead by Dr Prasad S. Adusumilli, M.D., a thoracic surgeon with expertise in tumor immunology and CAR-T-cell immunotherapy. We hope to enter the clinic in the near future to study the efficacy of OSE-703 in various solid tumors.

In AD we are developing OSE-127 a selective antagonist of the IL-7R with a recently published mechanism of action that suggests it has significant potential for therapeutic efficacy in controlling chronic inflammation. We are currently developing OSE-127 in partnership with Servier with a Phase 1 clinical trial expected to start this year.

We are also developing FR-104, a CD28 antagonist intended to target a key receptor on effector T lymphocytes while potentiating regulatory T cells. The clinical applications based on strong preclinical data could be in a multiple inflammatory and autoimmune diseases including rheumatoid arthritis. Following promising positive Phase 1 results with good safety and first signal of efficacy, we are evaluating the best options for continuing the development of FR-104 and to explore worldwide partnering opportunities.

OSE Immunotherapeutics recently announced publication in Nature Communications of its monoclonal antibody (OSE-127) which targets the IL-7 Receptor (IL-7R):

LL: Could you tell us about the role of interleukin-7 (IL-7) in chronic autoimmune and inflammatory diseases?

AP: Interleukin-7 is a limiting and non-redundant cytokine that is mainly produced by epithelial and stromal cells and regulates T cell homeostasis, proliferation, and survival. Conventional mature T lymphocytes express high levels of the IL-7R, with the exception of naturally-occurring regulatory T-cells (Tregs) that express low IL-7R. IL-7 represents the fuel of auto immunes diseases and a major challenge in the treatment of inflammatory diseases with the presence of pathogenic memory T cells in the tissues, which are likely resistant to conventional immune modulator therapy and tolerance strategies. Several genome-wide association studies have identified IL-7R alpha chain (IL-7Rα) polymorphism as one of the first non–major histocompatibility complex–linked risk loci for susceptibility in several autoimmune diseases. We think this constitutes a unique opportunity to selectively target pathogenic effectors while preserving natural T regulators.

LL: What were the key findings of the study and how do these findings impact the approach to treating chronic autoimmune and inflammatory diseases?

AP: The first important key finding from the study is the first-ever description of the in vivo mechanism of action of IL-7R antagonists. Because of its particular binding to an epitope on IL7-Rα, which prevents antibody-mediated receptor internalization, the anti-IL-7R monoclonal antibody OSE-127 demonstrates full antagonist activity whereas other tested anti-IL-7R antibodies had paradoxical agonist/antagonist properties, limiting their efficacy.  A better control of IL-7-dependent pathologic antigen-specific T cell responses is observed only for anti-IL-7R antibody presenting full antagonist properties like OSE-127. Additionally, in a non-human primate model of chronic skin inflammation, OSE-127 demonstrated a long-term control (up to 1 year) of antigen-specific memory T cell responses with minimal impact on naïve and quiescent T cells, while sparing Treg cells. In addition, transcriptome analyses of human peripheral blood mononuclear cells exposed to OSE-127 show significant translational modifications compatible with control of T cell activation and inflammatory responses.

Taken together, these findings suggest that targeting the IL-7R could be an exciting new therapeutic target for long-term control of autoimmune diseases. By blunting memory T cell responses, which are responsible for long-term storage of antigen recognition information, IL-7R antagonists can regulate an important mediator of autoimmune responses.

LL: Could you provide an update on the therapeutic development of OSE-127?

AP: We are developing OSE-127 in partnership with Servier and have plans to initiate Phase 1 clinical trial before year's end. We think that there is significant potential for OSE-127 in conditions such as ulcerative colitis, where IL-7 is involved in the maintenance of colon inflammation and Sjögren's syndrome, an autoimmune condition where the body attacks its own saliva and tear producing cells.

Alexis Peyroles was speaking to Laura Elizabeth Lansdowne, Science Writer for Technology Networks.