Abstract
Infusion reactions (IRs) are common immune-mediated side effects in patients treated with a variety of drug products, including, but not limited to, nanotechnology formulations. The mechanism of IRs is not fully understood. One of the best studied mechanisms of IRs to nanomedicines is the complement activation. However, it is largely unknown why some patients develop reactions to nanomedicines while others do not, and why some nanoparticles are more reactogenic than others. One of the theories is that the pre-existing anti-polyethylene glycol (PEG) antibodies initiate the complement activation and IRs in patients. In this study, we investigated this hypothesis in the case of PEGylated liposomal doxorubicin (Doxil), which, when used in a clinical setting, is known to induce IRs; referred to as complement activation-related pseudoallergy (CARPA) in sensitive individuals. We conducted the study in vitro using plasma derived from C57BL/6 mice and twenty human donor volunteers. We used mouse plasma to test a library of well-characterized mouse monoclonal antibodies with different specificity and affinity to PEG as it relates to the complement activation by Doxil. We determined the levels of pre-existing polyclonal antibodies that bind to PEG, methoxy-PEG, and PEGylated liposomes in human plasma, and we also assessed complement activation by Doxil and concentrations of complement inhibitory factors H and I in these human plasma specimens. The affinity, specificity, and other characteristics of the human polyclonal antibodies are not known at this time. Our data demonstrate that under in vitro conditions, some anti-PEG antibodies contribute to the complement activation by Doxil. Such contribution, however, needs to be considered in the context of other factors, including, but not limited to, antibody class, type, clonality, epitope specificity, affinity, and titer. In addition, our data contribute to the knowledge base used to understand and improve nanomedicine safety.
Highlights
Infusion reactions (IRs) are immune-mediated toxicities that occur within the first minutes to hours of the systemic administration of various drug products used at their relevant therapeutic doses to treat or diagnose a disease [1,2,3,4,5,6,7,8,9,10,11]
We note that the results of our study may be different from those of other studies detecting the presence of the polyethylene glycol (PEG)-reactive antibodies using a different assay format, because there is currently no universal agreement on the assay format for the detection of such antibodies
When we compared the levels of the pre-existing anti-PEG antibodies and the magnitude of the complement activation by doxorubicin formulation (Doxil) in the plasma from the same donors, we did not find a direct correlation
Summary
Infusion reactions (IRs) are immune-mediated toxicities that occur within the first minutes to hours of the systemic administration of various drug products used at their relevant therapeutic doses to treat or diagnose a disease [1,2,3,4,5,6,7,8,9,10,11]. We used PEGylated liposomal doxorubicin formulation (Doxil) to investigate the influence of anti-PEG antibodies on the complement activation. Current clinical experience with this drug demonstrates that Doxil causes CARPA in sensitive patients [8,14,18,19,20] This toxicity can be modeled in vitro using a blood plasma assay for the assessment of complement split products, as well as in vivo using an animal model (e.g., pig) for the evaluation of the hemodynamic changes [15,26,27,34,35]. The results of our study demonstrate that anti-PEG antibodies may contribute to the complement activation by Doxil, but other factors influence the reaction and, cannot be discounted. CFH—complement factor H; PEG—polyethylene glycol; CRL—Charles River Laboratories
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