Advancing BITT-101 a novel dominant CD40 antagonist for use in treatment of Sjogren Syndrome.

PROJECT SUMMARY Sjögren’s syndrome (SjS) is a highly disabling systemic autoimmune disease. Symptoms include mucosal dryness (as a result of the destruction of the epithelium of exocrine glands, mainly the salivary and lacrimal glands), pain, and fatigue. Moreover, 30-50% of patients risk systemic and potentially lethal complications. Candidate therapeutics for the disease over the past 20 years all failed to provide benefit: there is no approved immunomodulatory treatment for SjS patients. Recently, targeting the CD40/CD40L interaction, a key and well- known pathway in T-cell-mediated B-cell activation emerged as a promising therapeutic strategy for SjS in mouse models of the disease. However, prospective clinical use of anti-CD40L antibodies is highly likely to display life- threatening adverse events: these candidates are known to trigger thromboembolic events. Also, testing of current CD40 antagonists in several autoimmune diseases displayed poor results, confirming that CD40 is an extremely elusive target. Boston Immune Technologies and Therapeutics (BITT) is developing BITT-101, a uniquely efficient dominant antagonist to CD40. CD40L can easily displace antagonists raised against trimeric (active) forms of CD40; our BITT-101 binds and stabilizes the inactive dimeric form of CD40, dominantly blocking CD40-CD40L interaction, even in the presence of ligand. BITT has already completed extensive BITT-101 validation, demonstrating its dominant antagonist activity in vitro in CD40L-induced B-cell proliferation assays, and in in vivo models of GvHD. Results in this model also confirmed that BITT-101 outcompetes current CD40 antagonists, by selectively depleting active B cells, prospectively allowing for lower dosage and higher efficacy and safety. In the proposed Fast-Track project, BITT will complete pre-clinical assessment of BITT-101 to obtain relevant data for an Investigational New Drug (IND) application. BITT will confirm BITT-101 activity in primary cells from SjS patients during Phase I, which will provide proof of concept for BITT-101 use in this clinically unmet disease. Positive Phase I results will also allow advancement to IND-enabling toxicology and pharmacokinetic studies, to be conducted in Phase II. During the Phase II, BITT will also test BITT-101 production process suitability for GLP standard compliance. At the end of the SBIR project, BITT will be ready to advance BITT-101 to GMP production and clinical testing for which a combination of third-party investor funds and SBIR Phase IIb are expected to be leveraged. Successful completion of this project and initial clinical testing evidence will help to secure the already expressed interest of pharmaceutical companies with whom BITT will engage to complete late-stage clinical testing in SjS and launch BITT-101 into international markets, first for SjS and then for other auto-immune diseases.