Development and Characterization of an Anti-Cancer Monoclonal Antibody for Treatment of Human Carcinomas

SIMPLE SUMMARY: Cancers can grow and spread to different parts of the body. The aim of immunotherapy is to stimulate the immune system to eliminate cancer cells in a selective manner. Tumor-targeting monoclonal antibodies (mAb) can be used as immunotherapy to stimulate innate antitumor immunity. In this review, we have described the development and characterization of an anti-cancers mAb NEO-201. NEO-201 is an IgG1 humanized mAb that binds specifically to tumor-associated variants of CEACAM-5 and CEACAM-6 expressed by colon, ovarian, pancreatic, non-small cell lung, head and neck, cervical, uterine and breast cancers, but is not reactive against most normal tissues. The peculiarity of NEO-201 is its ability to counteract tumor growth through different mechanisms. NEO-201 engages components of immune system to kill tumor cells expressing its target via antibody-dependent cell-mediated cytotoxicity and complement dependent cytotoxicity. NEO-201 can also indirectly enhance anti-cancer activity through the blockade of the interaction between CEACAM-5 expressed on tumor cells and CEACAM-1 expressed on natural killer cells to reverse CEACAM-1-dependent inhibition of NK cytotoxicity or through its binding to human regulatory T cells. The specificity of NEO-201 in recognizing suppressive regulatory T cells provides the basis for combination cancer immunotherapy with checkpoint inhibitors targeting the PD-1/PD-L1 pathway. ABSTRACT: NEO-201 is an IgG1 humanized monoclonal antibody (mAb) that binds to tumor-associated variants of carcinoembryonic antigen-related cell adhesion molecule (CEACAM)-5 and CEACAM-6. NEO-201 reacts to colon, ovarian, pancreatic, non-small cell lung, head and neck, cervical, uterine and breast cancers, but is not reactive against most normal tissues. NEO-201 can kill tumor cells via antibody-dependent cell-mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) to directly kill tumor cells expressing its target. We explored indirect mechanisms of its action that may enhance immune tumor killing. NEO-201 can block the interaction between CEACAM-5 expressed on tumor cells and CEACAM-1 expressed on natural killer (NK) cells to reverse CEACAM-1-dependent inhibition of NK cytotoxicity. Previous studies have demonstrated safety/tolerability in non-human primates, and in a first in human phase 1 clinical trial at the National Cancer Institute (NCI). In addition, preclinical studies have demonstrated that NEO-201 can bind to human regulatory T (Treg) cells. The specificity of NEO-201 in recognizing suppressive Treg cells provides the basis for combination cancer immunotherapy with checkpoint inhibitors targeting the PD-1/PD-L1 pathway.