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

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.

Identification of the O-Glycan Epitope Targeted by the Anti-Human Carcinoma Monoclonal Antibody (mAb) NEO-201

“…In previous studies, we showed that NEO-201 specifically recognizes a tumor-associated variant of CEACAM5 and CEACAM6, which is not expressed in normal tissues, and proved that NEO-201 binds to both mammalian-expressed recombinant human CEACAM5 and CEACAM6 but not to CEACAM1 or CEACAM8 by ELISA [ 2 , 23 ].…”

“…In previous studies, we demonstrated that NEO-201 reacts to colon, ovarian, pancreatic, non-small cell lung, head and neck, cervical, uterine and breast cancers expressing tumor-associated variants of CEACAM5 and CEACAM6 but does not react to normal tissues [ 1 , 2 , 23 ]. NEO-201 can also bind to human regulatory T cells as well as human neutrophils, AML and MM cell lines in vitro [ 1 , 2 , 3 , 4 , 5 , 6 ].…”

“…A first-in-human clinical trial using NEO-201 for the treatment of patients with metastatic colon cancer, pancreatic cancer, breast cancer, non-small cell lung cancer (NSCLC) and mucinous ovarian cancer, who were no longer eligible for standard therapy, has completed accrual and is currently undergoing data analysis [ 23 ].…”

CEACAMS 1, 5, and 6 in disease and cancer: interactions with pathogens

“…In coordination with CEACAM1s ability to downregulate immune cells, CEACAM5 is a binding partner to CEACAM1 that can elicit this signaling, allowing for immune evasion by cancer cells [ 102 ]. Therapies targeting CEACAM5 in cancer are being developed to block this evading immune function [ 103 , 104 ]. CEACAM5 has also been shown to be important in metastasis in colorectal cancer.…”

Effect of N6-methyladenosine (m6A) regulator-related immunogenes on the prognosis and immune microenvironment of breast cancer

“…The tumor immune microenvironment (TIME) consists of protumor and antitumor immune cells, which can be reprogrammed by tumor-derived factors involved in immune escape and tumor progression (8,9). Accumulating evidence has shown that the TIME plays a critical role in the development of tumors and affects the clinical results of immune checkpoint blockade (ICB) therapies, e.g., those for blocking PD-1/L1 or CTLA-4 (10)(11)(12)(13)(14). In recent years, some studies have found a special relationship between the TIME infiltration of immune cells and N6-methyladenosine (m6A) modification (15,16).…”