Targeting the lymphotoxin-beta receptor with agonist antibodies as a potential cancer therapy.
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.
Lukashev
Matvey
M
Department of Immunobiology, Biogen Idec, Cambridge, MA 02142, USA.
LePage
Doreen
D
Wilson
Cheryl
C
Bailly
Véronique
V
Garber
Ellen
E
Lukashin
Alex
A
Ngam-ek
Apinya
A
Zeng
Weike
W
Allaire
Norman
N
Perrin
Steve
S
Xu
Xianghong
X
Szeliga
Kendall
K
Wortham
Kathleen
K
Kelly
Rebecca
R
Bottiglio
Cindy
C
Ding
Jane
J
Griffith
Linda
L
Heaney
Glenna
G
Silverio
Erika
E
Yang
William
W
Jarpe
Matt
M
Fawell
Stephen
S
Reff
Mitchell
M
Carmillo
Amie
A
Miatkowski
Konrad
K
Amatucci
Joseph
J
Crowell
Thomas
T
Prentice
Holly
H
Meier
Werner
W
Violette
Shelia M
SM
Mackay
Fabienne
F
Yang
Dajun
D
Hoffman
Robert
R
Browning
Jeffrey L
JL
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
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