Abstract
Purpose: Despite high initial response rates with cytoreductive surgery, conventional chemotherapy and the incorporation of biologic agents, ovarian cancer patients often relapse and die from their disease. New approaches are needed to improve patient outcomes. This study was designed to evaluate the antitumor activity of NEO-201 monoclonal antibody (mAb) in preclinical models of ovarian cancer where the NEO-201 target is highly expressed.Experimental Design: Functional analysis of NEO-201 against tumor cell lines was performed by antibody-dependent cellular cytotoxicity (ADCC) assays. Binding of NEO-201 to tumor tissues and cell lines were determined by immunohistochemistry (IHC) and flow cytometry, respectively. Further characterization of the antigen recognized by NEO-201 was performed by mass spectrometry. Ovarian cancer models were used to evaluate the anti-tumor activity of NEO-201 in vivo. NEO-201 at a concentration of 250 g/mouse was injected intraperitoneally (IP) on days 1, 4, and 8. Human PBMCs were injected IP simultaneously as effector cells.Results: Both IHC and flow cytometry revealed that NEO-201 binds prominently to the colon, pancreatic, and mucinous ovarian cancer tissues and cell lines. Immunoprecipitation of the antigen recognized by NEO-201 was performed in human ovarian, colon, and pancreatic cancer cell lines. From these screening, carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and CEACAM6 were identified as the most likely targets of NEO-201. Our results confirmed that NEO-201 binds different types of cancers; the binding is highly selective for the tumor cells without cross reactivity with the surrounding healthy tissue. Functional analysis revealed that NEO-201 mediates ADCC killing against human ovarian and colorectal carcinoma cell lines in vitro. In addition, NEO-201 inhibited tumor growth in the presence of activated human PBMCs in orthotopic mouse models of both primary and metastatic ovarian cancer. Importantly, NEO-201 prolonged survival of tumor-bearing mice.Conclusions: These data suggested that NEO-201 has an antitumor activity against tumor cells expressing its antigen. Targeting an antigen expressed in tumors, but not in normal tissues, allows patient selection for optimal treatment. These findings strongly indicate that NEO-201 warrants clinical testing as both a novel therapeutic and diagnostic agent for treatment of ovarian carcinomas. A first in human clinical trial evaluating NEO-201 in adults with chemo-resistant solid tumors is ongoing at the NIH clinical Center.
Highlights
Ovarian cancer is the most lethal gynecologic malignancy in the United States
We further assessed the degree of NEO-201 binding in the tissues from patients with different ovarian cancer subtypes, using a tissue microarray (TMA) containing 627 ovarian cancer samples including 11 ovarian cancer histological subtype (Figure 1A, bottom)
It is possible that a difference in glycosylation pattern explains the specific binding of NEO-201 to specific tumor-associated carcinoembryonic antigen-related cell adhesion molecule (CEACAM)-5 and CEACAM-6 variants but not to those expressed on healthy tissues as shown by the immunohistochemistry analysis
Summary
Ovarian cancer is the most lethal gynecologic malignancy in the United States. It accounts for only 3% of cancers among women, it is the fifth most common cause of cancer-related death [1]. The treatment of primary and recurrent ovarian cancer groups most epithelial ovarian subtypes together, in a common therapeutic approach. Recent efforts in cancer therapeutics have focused on the development of immune checkpoint inhibitors, which are FDA approved for the treatment of certain tumor types. To date, this class of drugs in ovarian cancer has shown limited activity when used as monotherapy [2]. Ongoing trials are evaluating the activity of PD-1/PD-L1 inhibition in combinations with other therapeutic agents that have shown activity in ovarian cancers such as VEGF and PARP inhibitors [3]
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