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

  • Cancer Res. 2006 Oct 1;66(19):9617-24. doi: 10.1158/0008-5472.CAN-06-0217.
Matvey Lukashev  1 ,  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
Affiliations
  • 1. Department of Immunobiology, Biogen Idec, Cambridge, MA 02142, USA.
PMID: 17018619 DOI: 10.1158/0008-5472.CAN-06-0217
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.

Products