The JI
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     
 

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Siegall, C. B.
Right arrow Articles by Davidson, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Siegall, C. B.
Right arrow Articles by Davidson, T.

The Journal of Immunology, Vol 159, Issue 10 5168-5173, Copyright © 1997 by American Association of Immunologists

ARTICLES

Prevention of immunotoxin-induced immunogenicity by coadministration with CTLA4Ig enhances antitumor efficacy

CB Siegall, HG Haggerty, GL Warner, D Chace, B Mixan, PS Linsley and T Davidson
Molecular Immunology Department, Bristol-Myers Squibb Pharmaceutical Research Institute, Syracuse, NY 13057, USA. Clay_B._Siegall@ccmail.bms.com

Immunotoxins have shown promise as antitumor agents in clinical trials. However, they have not become part of standard cancer therapy because of factors that include their inherent immunogenicity, which limits the duration of therapy. To address this issue, we evaluated in preclinical models the concomitant use of the immunosuppressive agent CTLA4Ig and BR96 sFv-PE40, a single-chain immunotoxin that binds to carcinoma cells expressing Le(y). Cotreatment with CTLA4Ig, an inhibitor of the CD28/CTLA4-CD80/CD86 costimulation pathway, blocked the production of Abs against BR96 sFv-PE40 in immunocompetent rodents and dogs. It also blocked hypersensitivity reactions in rats carrying colon carcinoma allografts during a second course of BR96 sFv-PE40 therapy, and the cotreatment with CTLA4Ig resulted in enhanced antitumor activity. Cotreatment with CTLA4Ig also prevented hypersensitivity reactions induced by repeat dosing of BR96 sFv-PE40 (q3dx5) in dogs. The production of anti-BR96-sFv-PE40 Abs was decreased in CTLA4Ig-cotreated rodents and dogs resulting in increased plasma levels of BR96 sFv-PE40 relative to non-CTLA4Ig-cotreated animals. These data show that cotreatment of immunotoxins with CTLA4Ig, by inhibiting the production of anti-immunotoxin Abs, can extend the duration of BR96 sFv-PE40 therapy to give greater exposure, reduced toxicities, and increased efficacy.


This article has been cited by other articles:


Home page
 Clin. Cancer Res.Home page
C. J. Henry, M. S. Buss, I. Hellstrom, K. E. Hellstrom, W. G. Brewer, J. N. Bryan, and C. B. Siegall
Clinical Evaluation of BR96 sFv-PE40 Immunotoxin Therapy in Canine Models of Spontaneously Occurring Invasive Carcinoma
Clin. Cancer Res., January 15, 2005; 11(2): 751 - 755.
[Abstract] [Full Text] [PDF]

Home page
 J Oncol Pharm PractHome page
M W J d. Brok, G C de Gast, J H M Schellens, and J H Beijnen
Targeted toxins
Journal of Oncology Pharmacy Practice, December 1, 1999; 5(4): 149 - 165.
[Abstract] [PDF]

Home page
 Toxicol PatholHome page
H.G. Haggerty, W.A. Warner, C.R. Comereski, W.M. Peden, L.E. Mezza, B.D. Damle, C.B. Siegall, and T.J. Davidson
BR96 sFv-PE40 Immunotoxin: Nonclinical Safety Assessment
Toxicol Pathol, January 1, 1999; 27(1): 87 - 94.
[Abstract] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Website Copyright © 1997 by The American Association of Immunologists, Inc. All rights reserved.
All Contents Copyright © 1997 by The American Association of Immunologists, Inc. All rights reserved.