title: Prevention of immunotoxin-induced immunogenicity by coadministration with CTLA4Ig enhances antitumor efficacy.
abstract: 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.
authors.affiliation: Molecular Immunology Department, Bristol-Myers Squibb Pharmaceutical Research Institute, Syracuse, NY 13057, USA. Clay_B._Siegall@ccmail.bms.com
authors.forename: C B
authors.initials: CB
authors.lastname: Siegall
authors.forename: H G
authors.initials: HG
authors.lastname: Haggerty
authors.forename: G L
authors.initials: GL
authors.lastname: Warner
authors.forename: D
authors.initials: D
authors.lastname: Chace
authors.forename: B
authors.initials: B
authors.lastname: Mixan
authors.forename: P S
authors.initials: PS
authors.lastname: Linsley
authors.forename: T
authors.initials: T
authors.lastname: Davidson
mesh_terms: D000069594:Abatacept; D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis*; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000008:administration & dosage / Q000276:immunology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology; D060908:CTLA-4 Antigen; D002277:Carcinoma; D003110:Colonic Neoplasms; D004285:Dogs; D005260:Female; D006801:Humans; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage*; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D000922:Immunotoxins / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D011914:Rats, Inbred BN; D011920:Rats, Inbred WF; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000276:Adjuvants, Immunologic; D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000970:Antineoplastic Agents; C089583:BR96 sFv-PE40; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments; D007166:Immunosuppressive Agents; D000922:Immunotoxins; D011993:Recombinant Fusion Proteins; D000069594:Abatacept