Hemocompatibility testing for nanomedicines and biologicals: Predictive assays for complement mediated infusion reactions

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52 Citations (Scopus)

Abstract

Infusion, or hypersensitivity reactions (HSRs) are frequent side effects of i.v. administered nanomedicines and biologicals. These, mostly mild and well tolerated, but occasionally severe or fatal allergic reactions represent a hemo-incompatibility due to activation of the complement (C) system. This review details the HSRs caused by marketed nanomedicines (liposomal drugs, micellar systems, polymer-conjugates of proteins, imaging agents, drug carrier nanosystems) and antibody therapeutics (mAbs), pointing out the remarkable similarity of clinical symptoms and difference from true (IgE-mediated) allergy. Beside the essentials, such as terminology, prevalence, risk factors and molecular and cellular mechanism of C activation-related pseudoallergy (CARPA) caused by the above agents, the paper highlights the biological rationale of these reactions, i.e., misinterpretation of nanoparticulate drugs by the immune system as pathogenic viruses, and C activation being an inherent function of mAbs. The public, as well as regulatory agencies are increasingly aware of the safety risks of possibly severe adverse immune reaction of drugs in the above categories, expressing need for new and appropriate immune toxicity tests in the preclinical stage. Here we outline and comment on the available methods for C activation and CARPA testing in vitro and in vivo, namely, the ELISA of C cleavage products (C3a, C5a, C4d, Bb, SC5b-9), the hemolytic (CH50) C assay, FACS measurement of basophil leukocyte activation, a - potentially - multiplex bead assay for C activation byproducts, the porcine assay of nanoparticle-induced cardiopulmonary distress and other CARPA tests in animals. The proven parallelisms between C activation and HSRs in vivo provide rationale for using these tests as predictors of infusion hypersensitivity, and the review suggests a decision tree for their use.

Original languageEnglish
Pages (from-to)33-53
Number of pages21
JournalEuropean Journal of Nanomedicine
Volume4
Issue number1
DOIs
Publication statusPublished - ápr. 2012

Fingerprint

Nanomedicine
Medical nanotechnology
Materials Testing
Biological Assay
complement
Assays
Hypersensitivity
Chemical activation
activation
Testing
drugs
Complement Hemolytic Activity Assay
Virus Activation
Toxicity Tests
Decision Trees
Drug Carriers
Basophils
Complement Activation
Drug-Related Side Effects and Adverse Reactions
Antigen-antibody reactions

ASJC Scopus subject areas

  • Bioengineering
  • Medicine (miscellaneous)
  • Physical and Theoretical Chemistry
  • Biomedical Engineering

Cite this

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title = "Hemocompatibility testing for nanomedicines and biologicals: Predictive assays for complement mediated infusion reactions",
abstract = "Infusion, or hypersensitivity reactions (HSRs) are frequent side effects of i.v. administered nanomedicines and biologicals. These, mostly mild and well tolerated, but occasionally severe or fatal allergic reactions represent a hemo-incompatibility due to activation of the complement (C) system. This review details the HSRs caused by marketed nanomedicines (liposomal drugs, micellar systems, polymer-conjugates of proteins, imaging agents, drug carrier nanosystems) and antibody therapeutics (mAbs), pointing out the remarkable similarity of clinical symptoms and difference from true (IgE-mediated) allergy. Beside the essentials, such as terminology, prevalence, risk factors and molecular and cellular mechanism of C activation-related pseudoallergy (CARPA) caused by the above agents, the paper highlights the biological rationale of these reactions, i.e., misinterpretation of nanoparticulate drugs by the immune system as pathogenic viruses, and C activation being an inherent function of mAbs. The public, as well as regulatory agencies are increasingly aware of the safety risks of possibly severe adverse immune reaction of drugs in the above categories, expressing need for new and appropriate immune toxicity tests in the preclinical stage. Here we outline and comment on the available methods for C activation and CARPA testing in vitro and in vivo, namely, the ELISA of C cleavage products (C3a, C5a, C4d, Bb, SC5b-9), the hemolytic (CH50) C assay, FACS measurement of basophil leukocyte activation, a - potentially - multiplex bead assay for C activation byproducts, the porcine assay of nanoparticle-induced cardiopulmonary distress and other CARPA tests in animals. The proven parallelisms between C activation and HSRs in vivo provide rationale for using these tests as predictors of infusion hypersensitivity, and the review suggests a decision tree for their use.",
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