Complement (C) activation-related hypersensitivity reactions (HSRs) represent an unsolved adverse immune effect of many i.v. administered “nanomedicines”, such as liposomal doxorubicin (Doxil/Caelyx). Because these ...Complement (C) activation-related hypersensitivity reactions (HSRs) represent an unsolved adverse immune effect of many i.v. administered “nanomedicines”, such as liposomal doxorubicin (Doxil/Caelyx). Because these pseudoallergic reactions can be severe or even lethal, it is an important clinical objective to find biomarkers for proneness for C activation by reactogenic nanoparticles that will allow the prediction of in vivo reactions by in vitro assays. With this goal in mind we identified a normal human blood donor who consistently showed high sensitivity to Caelyx-induced C activation in vitro, whose plasma (Caelyx sensitive plasma, CSP) was subjected to proteome profiling with a library of human plasma proteome specific mAbs. The chip (PlasmaScan-380TM) contained 380 non redundant (with respect to epitopes) mAbs. The analysis revealed 8 proteins that were differentially represented in CSP in comparison with Caelyx-insensitive control plasma. These proteins were identified by mass spectrometry and Western blot analyses to represent factor H (decreased in CSP), factor H related protein, serum amyloid P component, fibronectin, complement component C4, Apo B100, prothrombin and alpha-2-HS glycoprotein (all increased in CSP). Some of these protein changes are consistent with proneness for increased C activation, suggesting the potential use of this method in the search for biomarkers for liposome-induced or other types of nanomedicine-induced HSRs.展开更多
Complement activation-related pseudoallergy (CARPA) is a frequent side effect of intravenous therapies with nanoparticle-containing drugs and biologicals that are recognized by the immune system as foreign. It is an a...Complement activation-related pseudoallergy (CARPA) is a frequent side effect of intravenous therapies with nanoparticle-containing drugs and biologicals that are recognized by the immune system as foreign. It is an acute infusion reaction dominated by cutaneous and hemodynamic changes, most significantly a cardiopulmonary distress involving major pulmonary hypertension, systemic hypotension and arrhythmias. Because CARPA is unpredictable by conventional allergy tests and it may be life threatening, it can represent a major barrier to the safe therapeutic application of many modern medicines, including liposomal drugs and monoclonal antibodies. This review summarizes and updates the facts and opens questions regarding this phenomenon, with particular focus on its porcine model.展开更多
文摘Complement (C) activation-related hypersensitivity reactions (HSRs) represent an unsolved adverse immune effect of many i.v. administered “nanomedicines”, such as liposomal doxorubicin (Doxil/Caelyx). Because these pseudoallergic reactions can be severe or even lethal, it is an important clinical objective to find biomarkers for proneness for C activation by reactogenic nanoparticles that will allow the prediction of in vivo reactions by in vitro assays. With this goal in mind we identified a normal human blood donor who consistently showed high sensitivity to Caelyx-induced C activation in vitro, whose plasma (Caelyx sensitive plasma, CSP) was subjected to proteome profiling with a library of human plasma proteome specific mAbs. The chip (PlasmaScan-380TM) contained 380 non redundant (with respect to epitopes) mAbs. The analysis revealed 8 proteins that were differentially represented in CSP in comparison with Caelyx-insensitive control plasma. These proteins were identified by mass spectrometry and Western blot analyses to represent factor H (decreased in CSP), factor H related protein, serum amyloid P component, fibronectin, complement component C4, Apo B100, prothrombin and alpha-2-HS glycoprotein (all increased in CSP). Some of these protein changes are consistent with proneness for increased C activation, suggesting the potential use of this method in the search for biomarkers for liposome-induced or other types of nanomedicine-induced HSRs.
文摘Complement activation-related pseudoallergy (CARPA) is a frequent side effect of intravenous therapies with nanoparticle-containing drugs and biologicals that are recognized by the immune system as foreign. It is an acute infusion reaction dominated by cutaneous and hemodynamic changes, most significantly a cardiopulmonary distress involving major pulmonary hypertension, systemic hypotension and arrhythmias. Because CARPA is unpredictable by conventional allergy tests and it may be life threatening, it can represent a major barrier to the safe therapeutic application of many modern medicines, including liposomal drugs and monoclonal antibodies. This review summarizes and updates the facts and opens questions regarding this phenomenon, with particular focus on its porcine model.
