Anaphylaxis caused by repetitive doses of a GITR agonist monoclonal antibody in mice Journal Article

Authors: Murphy, J. T.; Burey, A.; Beebe, A. M.; Gu, D.; Presta, L. G.; Merghoub, T.; Wolchok, J. D.
Article Title: Anaphylaxis caused by repetitive doses of a GITR agonist monoclonal antibody in mice
Abstract: Immunotherapy for cancer using antibodies to enhance T-cell function has been successful in recent clinical trials. Many molecules that improve activation and effector function of T cells have been investigated as potentialnewtargets forimmunomodulatory antibodies, including the tumor necrosis factor receptor superfamily members GITR and OX40. Antibodies engaging GITR or OX40 result in significant tumor protection in preclinical models. In this study, we observed that the GITR agonist antibody DTA-1 causes anaphylaxis in mice upon repeated intraperitoneal dosing. DTA-1-induced anaphylaxis requires GITR, CD4+ T cells, B cells, and interleukin-4. Transfer of serum antibodies from DTA-1-treated mice, which contain high levels of DTA-1-specific immunoglobulin G1 (IgG1), can induce anaphylaxis in naive mice upon administration of an additional dose of DTA-1, suggesting that anaphylaxis results from anti-DTA-1 antibodies. Depletion of basophils and blockade of platelet-activating factor, the key components of the IgG1 pathway of anaphylaxis, rescues themice fromDTA-1-induced anaphylaxis. These results demonstrate a previously undescribed lethal side effect of repetitive doses of an agonist immunomodulatory antibody as well as insight into the mechanism of toxicity, which may offer a means of preventing adverse effects in future clinical trials using anti-GITR or other agonist antibodies as immunotherapies. © 2014 by The American Society of Hematology.
Keywords: genetics; dose response; drug potentiation; mouse; animal; animals; mice; drug administration schedule; interleukin 4; tumor cell culture; dose-response relationship, drug; tumor cells, cultured; mice, inbred c57bl; physiology; b lymphocyte; transgenic mouse; c57bl mouse; b-lymphocytes; mice, transgenic; monoclonal antibody; immunology; antibodies, monoclonal; cd4+ t lymphocyte; cd4-positive t-lymphocytes; drug administration; glucocorticoid induced tumor necrosis factor receptor; anaphylaxis; antigens, differentiation; differentiation antigen; interleukin-4; tnfrsf18 protein, mouse; intraperitoneal drug administration; injections, intraperitoneal; glucocorticoid-induced tnfr-related protein; article; ox40ig
Journal Title: Blood
Volume: 123
Issue: 14
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2014-04-03
Start Page: 2172
End Page: 2180
Language: English
DOI: 10.1182/blood-2013-12-544742
PROVIDER: scopus
PMCID: PMC3975257
PUBMED: 24558202
Notes: Blood -- Export Date: 8 July 2014 -- CODEN: BLOOA -- Source: Scopus
Altmetric Score
MSK Authors
  1. Jedd D Wolchok
    607 Wolchok
  2. Taha Merghoub
    169 Merghoub
  3. Judith Therese Murphy
    6 Murphy
  4. Andre   Burey
    1 Burey