title: Strategy to prevent drug-related hypersensitivity in folate-targeted hapten immunotherapy of cancer.
abstract: Cancer vaccine/immunotherapy rarely involves systemic administration of an immunogenic compound to an actively immunized host. We have developed such a strategy that utilizes folate to deliver antigenic haptens [e.g., fluorescein (FITC) and dinitrophenyl] to folate receptor-positive tumors in a hapten-pre-vaccinated host. Here, we investigated the safety of this novel approach and developed strategies to prevent drug-related hypersensitivity. Using FITC as the model hapten, we identified a potential source of allergic species in folate-FITC preparations by LC-MS/MS. In mice and guinea pigs, we tested the significance of this impurity by passive cutaneous anaphylaxis and active systemic anaphylaxis assays. We studied the effect of immunogen (e.g., KLH-FITC) dose and derived a desensitization regimen that was further evaluated in a murine tumor model. Administration of folate-FITC with low multi-haptenated contaminants (e.g. bis-FITC) resulted in hypersensitivity in underimmunized animals. However, this drug-related hypersensitivity may be independently prevented by (1) increasing the immunogen dose and/or (2) desensitizing animals with folate-FITC during vaccination. In addition, such manipulation in vivo did not appear to negatively alter the effectiveness of immunotherapy. This study provided confidence on the safety of folate-hapten-targeted cancer immunotherapy in an actively immunized host.
authors.affiliation: Endocyte Inc, West Lafayette, IN 47906, USA.
authors.forename: Yingjuan
authors.initials: Y
authors.lastname: Lu
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Klein
authors.forename: Elaine
authors.initials: E
authors.lastname: Westrick
authors.forename: Le-Cun
authors.initials: LC
authors.lastname: Xu
authors.forename: Hari Krishna R
authors.initials: HK
authors.lastname: Santhapuram
authors.forename: Alicia
authors.initials: A
authors.lastname: Bloomfield
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Howard
authors.forename: Iontcho R
authors.initials: IR
authors.lastname: Vlahov
authors.forename: P Ron
authors.initials: PR
authors.lastname: Ellis
authors.forename: Philip S
authors.initials: PS
authors.lastname: Low
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Leamon
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004342:Drug Hypersensitivity / Q000517:prevention & control*; D005260:Female; D005493:Folic Acid Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D006168:Guinea Pigs; D006241:Haptens / Q000009:adverse effects / Q000627:therapeutic use*; D007167:Immunotherapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy / Q000628:therapy*
chemical_list: D005493:Folic Acid Antagonists; D006241:Haptens