PROJECT SUMMARY Cancer will kill over 600,000 people in the US in 2023, causing $200B+ healthcare expenditure. This is happening despite recent advancements in therapy and the emergence of an ever-expanding array of new therapeutics for the over 1.9M new cancer patients every year. Indeed, because of the multitude and redundancy of mechanisms contributing to cancer growth, therapies are often ineffective. Several components should be targeted at the same time to maximize therapy outcome. However, this is particularly hard to attain because of 1) the striking variability among cancers and the limited number of cancer specific targets 2) the ability of cancer cells to orchestrate a microenvironment of healthy tissue and cells around them, that promote cancer growth and therapy resistance. Boston Immune Technologies and Therapeutics (BITT) is developing BITR2101, able to target both cancer cells and their microenvironment. BITR2101 is an antagonist antibody against TNFR2 – a receptor highly expressed in cancer tissue and immune suppressive cells in the microenvironment, where it mediates pro- survival signaling. Thanks to BITT’s proprietary antibody design platform, BITR-2101 is the first and only antibody able to dominantly shut down TNFR2 signaling. Due to selective expression and key role of TNFR2 for a variety of cancers and tumor microenvironment cells, BITR2101 is expected to find application in the therapy of several cancers either as a monotherapy or in combination with other treatments. BITT has already completed extensive pre-clinical validation for BITR-2101, demonstrating potent activity in several malignancies in state-of-the-art animal models. As part of (R44CA265510) awarded by the NCI, BITT has completed GLP toxicology assessment in NHPs and has confirmed the possibility to obtain cGMP grade quality for BITR2101. This has allowed to obtain IND approval for use in NHL/CTCL. In the proposed PhaseIIb project, BITT aims at accelerating the clinical use of BITR2101 by pursuing clinical validation in NHL/CTCL as a keystone to demonstrate BITR2101 value in cancer therapy. This will boost the capability of BITT to attract private funds from already contacted investors to a) complete early clinical testing (up to Phase II); b) turn the already attracted interest of pharmaceutical companies towards our therapeutic into formal partnerships to complete later stage clinical testing (Phase III) and launch BITR2101 into international markets; c) explore early clinical application (Phase I-II) for additional malignancies, multiplying the impact that our therapeutic can bring to a wide variety of cancer patients.

PROJECT NARRATIVE TNFR2 is an extremely promising target for therapy in multiple cancers. However, current strategies aimed at TNFR2 targeting fail to shut down its pro-survival signaling. BITT is advancing a first-in-class dominant antagonist to TNFR2 with potent anti-tumor effect to clinical testing.