Tumor Microenvironment Modulators

Overcome the Acquired Resistance to Checkpoint Inhibitors

The Tumor Microenvironment (TME) is the highly immunosuppressive ecosystem surrounding a tumor that provides nutrients and promotes tumor growth. Myeloid derived suppressor cells (MDSCs) represent a major component of the cells making up the tumor microenvironment. MDSCs produce many soluble factors responsible for creating the immunosuppressive environment in the TME, allowing the tumor to avoid an attack by a patient’s immune system.

Leveraging Novel Antibody Drug Conjugates to Reprogram the Tumor Microenvironment

Our tumor microenvironment modulators are a new class of antibody drug conjugates (ADCs) that target MDSCs, the primary driver of an immunosuppressive tumor microenvironment. MDSCs suppress T- and NK cell function and disrupt IL-2 signaling through the production of multiple immune suppressing factors, such as Arg-1, iNOS, COX2, IDO, IL-10 and TGF. Tumor-associated MDSCs are a major obstacle to immunotherapy; they are responsible for acquired resistance to checkpoint inhibitors and also contribute to T-cell or NK cell exhaustion, preventing cellular therapies from being more effective. Circulating levels of MDSCs predict resistance to checkpoint inhibitors as well as cancer recurrence and progression. Reprogramming MDSC function to bypass tumor microenvironment immunosuppression is a promising strategy to overcome resistance to immunotherapies, such as checkpoint inhibitors.

We have identified a unique delta receptor that is differentially overexpressed on tumor-associated MDSCs and macrophages, and plays a central role in controlling MDSC migration and their production of immune suppressing factors. By targeting this unique delta receptor, we expect to be able to deliver our ADCs directly to MDSCs and destroy them.

We believe our proprietary ADCs represent a paradigm shift in the next generation of these important immunotherapeutics. Current marketed, conventional ADCs utilize an antibody to target a tumor cell surface receptor, conjugated to a cellular toxin as the payload. In contrast, our ADCs employ a small molecule drug that targets the delta receptor on MDSCs, conjugated to an immune effector, such as a checkpoint inhibitor as the payload. This allows our ADCs to have two unique functions: inhibiting the MDSC tumor microenvironment immunosuppressive effect and localizing a checkpoint inhibitor within the TME, amplifying the ability of activated cytotoxic T-cells to overcome resistance, while preventing T-cell exhaustion and be more effective in eradicating the tumor. We believe these novel ADCs will improve the therapeutic index of checkpoint inhibitors, increasing their effectiveness while decreasing indiscriminate check point released activated T-cell toxicity to normal tissues.