INB03is a protein biologic that could have many beneficial effects in patients with cancer. INmune Bio is focused in on using INB03 to change the tumor microenvironment (TME) to improve the response to targeted therapies for cancer. INB03 has three major effects:
- Reverses resistance to trastuzumab based immunotherapy: Trastuzumab (traz) binds HER2 on cancer cells to promote cancer cell death. HER2 is expressed on breast, gastric, colo-rectal and other carcinomas. Historically, traz therapy has been used to treat patient with high HER2 expression (3+) in combination with chemotherapy. While effective, primary and secondary resistance to traz is common. MUC4, a surface glycoprotein secreted by many epithelial cancers causes resistance to traz. MUC4 resistance mechanism is simple steric hinderance. MUC4 prevents binding of traz to the HER2 binding epitope. MUC4 expression is driven by soluble TNF (sTNF). INB03 neutralizes sTNF to reverse MUC4 expression. Without MUC4 on the cell surface, traz function is normal. MUC4 induced traz resistance occurs to “naked” traz and to traz based ADC (eg: T-DM1).
- Promotes a less immunosuppressive TME: The TME of many cancers is not conducive to tumor killing due to a large number of immunosuppressive MDSC, TAM, Treg cells and lack of tumor killing NK and cytotoxic T cells (a “cold” TME). Treating animals with INB03 converts the “cold” immunosuppressive TME into a “hot” TME where the patient’s immune system targets and kills tumor cells. Phagocytosis of tumor cells by tumor macrophages, recruitment of cytotoxic T cells and decrease in MDSC and Treg populations all promote a TME that is conducive to tumor eradication.
- Reverses resistance to tyrosine kinase inhibitors: Tyrosine kinase inhibitors (TKI) are an important class of cancer therapies. TKI work in some tumors but resistance can occur early. In pre-clinical models, INB03 reverses resistance to TKI in models of breast cancer.
The role of sTNF in promoting resistance to targeted cancer therapy is under appreciated. Many existing therapies are not effective because of resistance mechanisms that are driven by sTNF produced in the tumor. INB03, by neutralizing sTNF, appears to reverse these resistance mechanisms to allow these established therapies to work.