title: 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.affiliation: Department of Immunobiology, Biogen Idec, Cambridge, MA 02142, USA.
authors.forename: Matvey
authors.initials: M
authors.lastname: Lukashev
authors.forename: Doreen
authors.initials: D
authors.lastname: LePage
authors.forename: Cheryl
authors.initials: C
authors.lastname: Wilson
authors.forename: Véronique
authors.initials: V
authors.lastname: Bailly
authors.forename: Ellen
authors.initials: E
authors.lastname: Garber
authors.forename: Alex
authors.initials: A
authors.lastname: Lukashin
authors.forename: Apinya
authors.initials: A
authors.lastname: Ngam-ek
authors.forename: Weike
authors.initials: W
authors.lastname: Zeng
authors.forename: Norman
authors.initials: N
authors.lastname: Allaire
authors.forename: Steve
authors.initials: S
authors.lastname: Perrin
authors.forename: Xianghong
authors.initials: X
authors.lastname: Xu
authors.forename: Kendall
authors.initials: K
authors.lastname: Szeliga
authors.forename: Kathleen
authors.initials: K
authors.lastname: Wortham
authors.forename: Rebecca
authors.initials: R
authors.lastname: Kelly
authors.forename: Cindy
authors.initials: C
authors.lastname: Bottiglio
authors.forename: Jane
authors.initials: J
authors.lastname: Ding
authors.forename: Linda
authors.initials: L
authors.lastname: Griffith
authors.forename: Glenna
authors.initials: G
authors.lastname: Heaney
authors.forename: Erika
authors.initials: E
authors.lastname: Silverio
authors.forename: William
authors.initials: W
authors.lastname: Yang
authors.forename: Matt
authors.initials: M
authors.lastname: Jarpe
authors.forename: Stephen
authors.initials: S
authors.lastname: Fawell
authors.forename: Mitchell
authors.initials: M
authors.lastname: Reff
authors.forename: Amie
authors.initials: A
authors.lastname: Carmillo
authors.forename: Konrad
authors.initials: K
authors.lastname: Miatkowski
authors.forename: Joseph
authors.initials: J
authors.lastname: Amatucci
authors.forename: Thomas
authors.initials: T
authors.lastname: Crowell
authors.forename: Holly
authors.initials: H
authors.lastname: Prentice
authors.forename: Werner
authors.initials: W
authors.lastname: Meier
authors.forename: Shelia M
authors.initials: SM
authors.lastname: Violette
authors.forename: Fabienne
authors.initials: F
authors.lastname: Mackay
authors.forename: Dajun
authors.initials: D
authors.lastname: Yang
authors.forename: Robert
authors.initials: R
authors.lastname: Hoffman
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Browning
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000627:therapeutic use; D007075:Immunoglobulin M / Q000276:immunology / Q000627:therapeutic use; D000077146:Irinotecan; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D053259:Lymphotoxin beta Receptor / Q000819:agonists* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011897:Random Allocation; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000627:therapeutic use; D016037:Single-Blind Method; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D007075:Immunoglobulin M; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D011993:Recombinant Fusion Proteins; D000077146:Irinotecan; D002166:Camptothecin