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Evaluation of the Anti-Tumor Activity of the Humanized Monoclonal Antibody NEO-201 in Preclinical Models of Ovarian Cancer.
Zeligs, Kristen P; Morelli, Maria Pia; David, Justin M; Neuman, Monica; Hernandez, Lidia; Hewitt, Stephen; Ozaki, Michelle; Osei-Tutu, Akosua; Anderson, David; Andresson, Thorkell; Das, Sudipto; Lack, Justin; Abdelmaksoud, Abdalla; Fantini, Massimo; Arlen, Philip M; Tsang, Kwong Y; Annunziata, Christina M.
Afiliação
  • Zeligs KP; Women's Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
  • Morelli MP; Women's Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
  • David JM; Precision Biologics, Inc., Bethesda, MD, United States.
  • Neuman M; Women's Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
  • Hernandez L; Women's Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
  • Hewitt S; Women's Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
  • Ozaki M; Women's Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
  • Osei-Tutu A; Women's Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
  • Anderson D; Women's Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
  • Andresson T; Protein Characterization Laboratory of the Cancer Research Program (CRTP)/Mass Spectrometry Center, National Institutes of Health, Fredrick, MD, United States.
  • Das S; Protein Characterization Laboratory of the Cancer Research Program (CRTP)/Mass Spectrometry Center, National Institutes of Health, Fredrick, MD, United States.
  • Lack J; NIAID Collaborative Bioinformatics Resource (NCBR), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.
  • Abdelmaksoud A; Frederick National Laboratory for Cancer Research, Advanced Biomedical Computational Science, Fredrick, MD, United States.
  • Fantini M; Frederick National Laboratory for Cancer Research, Advanced Biomedical Computational Science, Fredrick, MD, United States.
  • Arlen PM; Frederick National Laboratory for Cancer Research, CCR Collaborative Bioinformatics Resource, Fredrick, MD, United States.
  • Tsang KY; Precision Biologics, Inc., Bethesda, MD, United States.
  • Annunziata CM; Precision Biologics, Inc., Bethesda, MD, United States.
Front Oncol ; 10: 805, 2020.
Article em En | MEDLINE | ID: mdl-32637350
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.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2020 Tipo de documento: Article