Targeting the lymphotoxin-beta receptor with agonist antibodies as a potential cancer therapy.

Abstract

The lymphotoxin-beta receptor (LT beta R) is a tumor necrosis factor receptor family member critical for the development and maintenance of various lymphoid microenvironments. Herein, we show that agonistic anti-LT beta R monoclonal antibody (mAb) CBE11 inhibited tumor growth in xenograft models and potentiated tumor responses to chemotherapeutic agents. In a syngeneic colon carcinoma tumor model, treatment of the tumor-bearing mice with an agonistic antibody against murine LT beta R caused increased lymphocyte infiltration and necrosis of the tumor. A pattern of differential gene expression predictive of cellular and xenograft response to LT beta R activation was identified in a panel of colon carcinoma cell lines and when applied to a panel of clinical colorectal tumor samples indicated 35% likelihood a tumor response to CBE11. Consistent with this estimate, CBE11 decreased tumor size and/or improved long-term animal survival with two of six independent orthotopic xenografts prepared from surgical colorectal carcinoma samples. Targeting of LT beta R with agonistic mAbs offers a novel approach to the treatment of colorectal and potentially other types of cancers.

• Authors: Matvey Lukashev, Doreen LePage, Cheryl Wilson, Véronique Bailly, Ellen Garber, Alex Lukashin, Apinya Ngam-ek, Weike Zeng, Norman Allaire, Steve Perrin, Xianghong Xu, Kendall Szeliga, Kathleen Wortham, Rebecca Kelly, Cindy Bottiglio, Jane Ding, Linda Griffith, Glenna Heaney, Erika Silverio, William Yang, Matt Jarpe, Stephen Fawell, Mitchell Reff, Amie Carmillo, Konrad Miatkowski, Joseph Amatucci, Thomas Crowell, Holly Prentice, Werner Meier, Shelia M Violette, Fabienne Mackay, Dajun Yang, Robert Hoffman, Jeffrey L Browning
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 19 Pg. 9617-24 (Oct 01 2006) ISSN: 1538-7445 [Electronic] United States
• PMID: 17018619 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Immunoglobulin G
• Immunoglobulin M
• Ltbr protein, mouse
• Lymphotoxin beta Receptor
• Recombinant Fusion Proteins
• Irinotecan
• Camptothecin

Topics

• Adenocarcinoma (drug therapy, pathology, therapy)
• Animals
• Antibodies, Monoclonal (immunology, pharmacology, therapeutic use)
• Camptothecin (analogs & derivatives, therapeutic use)
• Cell Line, Tumor
• Colonic Neoplasms (drug therapy, pathology, therapy)
• Combined Modality Therapy
• Drug Synergism
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Immunoglobulin G (immunology, therapeutic use)
• Immunoglobulin M (immunology, therapeutic use)
• Irinotecan
• Lymphocytes, Tumor-Infiltrating (immunology)
• Lymphotoxin beta Receptor (agonists, immunology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Random Allocation
• Recombinant Fusion Proteins (immunology, therapeutic use)
• Single-Blind Method
• Uterine Cervical Neoplasms (drug therapy, pathology, therapy)
• Xenograft Model Antitumor Assays