Monoclonal antibody therapy has revolutionized the management of oncologic and immunologic diseases. However, they also are associated with adverse effects.
In a comprehensive review of adverse effects of 110 agents that have been approved by FDA and/or by the European Medicines Agency, the authors identified both immune- and nonimmune-mediated adverse reactions associated with these drugs.
Immune-mediated adverse events include type I through type IV hypersensitivity reactions. Type I hypersensitivity reactions are mediated by immunoglobulin (Ig) E and manifest as anaphylaxis, urticaria and angioedema. Type II hypersensitivity reactions are cytotoxic reactions mediated by IgG or IgM antibodies. Type III hypersensitivity reactions involve the formation of immune complexes producing serum sickness-like reactions, cutaneous vasculitis, and hypersensitivity pneumonitis.
These three hypersensitivity reactions occur within the first 24 hours of exposure and are considered "immediate" reactions. Type IV hypersensitivity reactions—which are delayed hypersensitivity reactions—can occur up to 72 hours post exposure and result from a cellular response mediated by T cells that produces an inflammatory reaction. Type IV hypersensitivity reactions can manifest as epidermal necrolysis (TENS), Stevens Johnson Syndrome (SJS), erythema multiforme (EM), paraneoplastic pemphigus, lichenoid dermatitis, and vesiculobullous dermatitis.
Chimeric monoclonal antibiotics with mouse and/or rat sequences have the highest risk of type I reactions. These include abciximab, basiliximab, blinatumomab, brentuximab vedotin, catumaxomab (not available in the U.S.), cetuximab, dinutoximab, infliximab, obiltoxaximab, rituximab, and siltuximab. About 18% of monoclonal antibodies are associated with warnings or reports of anaphylaxis. This type of event is more common with monoclonal antibodies used for noncancer indications.
Severe infusion reactions to monoclonal antibodies can mimic anaphylaxis and can present with hypotension, urticaria, or in severe cases, cardiac arrest. These reactions involve cytokine release. Among the monoclonal antibodies with the highest incidence of infusion reactions are rituximab, infliximab, alemtuzumab, ocrelizumab, and trastuzumab. Approximately 40% of patients receiving trastuzumab for the first time will experience an infusion reaction. This incidence is about 77% for patients receiving rituximab.
Cytopenias may be a result of type II hypersensitivity reactions, although causation is unclear. They occur with greater than 30% of monoclonal antibodies, especially those used in oncology. Sacituzumab govetican-hziy, ibritumomab tiuxetan, and alemtuzumab are among the agents with boxed warnings regarding either severe neutropenia, prolonged and severe cytopenias, or bone marrow suppression.
Type III hypersensitivity reactions include serum sickness-like reactions, cutaneous vasculitis, and hypersensitivity pneumonitis. Among the agents associated with hypersensitivity vasculitis are infliximab, rituximab, adalimumab, and alirocumab. Hypersensitivity pneumonitis has been reported with the checkpoint inhibitors, ipilimumab, nivolumab, pembrolizumab, cemiplimab-rwk, atezolizumab, durvalumab, and avelumab, and may involve a combination of type III and IV hypersensitivity reactions. These agents are also involved with adverse immune effects involving the colon, thyroid, liver, and kidney. Serum sickness-like reactions can occur following the administration of rituximab and omalizumab, a humanized monoclonal antibody. In general, chimeric antibodies such as rituximab and infliximab are most commonly associated with type III hypersensitivity reactions.
Ibritumomab tiuxetin has been associated with type IV hypersensitivity reactions. It has a boxed warning for severe cutaneous reactions. Rituximab is also associated with type IV reactions that may manifest as TENS, SJS, EM, exfoliative dermatitis, and bullous dermatitis. Adalimumab, brentuximab vedotin, infliximab, and rituximab have been associated with the development of SJS. Rituximab is also associated with the development of paraneoplastic pemphigus, lichenoid dermatitis, and vesiculobullous dermatitis. Cases of EM have been reported with adalimumab, ibritumomab tiuxetan, infliximab and naxitamab-gqgk. Adalimumab has also been associated with the psoriasis. However, rash and pruritus associated with monoclonal antibodies may not be true hypersensitivity reactions.
Nonimmune mediated adverse events associated with monoclonal antibodies include infusion reactions (which are very common, affecting about 37% of agents), cytopenias (which, as mentioned above, may/not reflect a type of hypersensitivity reaction), pulmonary adverse events, less severe cutaneous reactions, and rare syndromes (e.g., cytokine release syndrome, hemophagocytic lymphohistiocytosis, immune reconstitution inflammatory syndrome, macrophage activation syndrome, progressive multifocal leukoencephalopathy, reversible posterior encephalopathy syndrome, reversible posterior encephalopathy syndrome, systemic capillary leak syndrome, systemic inflammatory response syndrome, and tumor lysis syndrome).
This article contains numerous tables that detail the target and approved indications of monoclonal antibodies; warnings, precautions, and safety risk concerns; specific organ and tissue toxicities; and those associated with cytopenias, cardiac events, hepatic adverse effects, and rare syndromes.
Pharmacists need to be knowledgeable about the immunological and nonimmunological adverse events associated with this class of medications to be able to monitor and counsel for these untoward effects.
The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.
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Published July 13, 2022