Strategy to Prevent Drug-Related Hypersensitivity in Folate-Targeted Hapten Immunotherapy of Cancer
Journal Title: The AAPS Journal - Year 2009, Vol 11, Issue 3
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 under-immunized 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 and Affiliations
Yingjuan Lu, Patrick J. Klein, Elaine Westrick, Le-Cun Xu, Hari Krishna R. Santhapuram, Alicia Bloomfield, Stephen J. Howard, Iontcho R. Vlahov, P. Ron Ellis, Philip S. Low, Christopher P. Leamon
Keywords
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- EP ID EP681493
- DOI 10.1208/s12248-009-9139-7
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