Hypersensitivity Reactions to Monoclonal Antibodies: Classification and Treatment Approach (Review)

EXPERIMENTAL AND THERAPEUTIC MEDICINE 22: 949, 2021 Hypersensitivity reactions to monoclonal antibodies: Classification and treatment approach (Review) IRENA PINTEA1,2*, CARINA PETRICAU1,2, DINU DUMITRASCU3, ADRIANA MUNTEAN1,2, DANIEL CONSTANTIN BRANISTEANU4*, DACIANA ELENA BRANISTEANU5* and DIANA DELEANU1,2,6 1Allergy Department, ‘Professor Doctor Octavian Fodor’ Regional Institute of Gastroenterology and Hepatology; 2Allergology and Immunology Discipline, 3Anatomy Discipline, ‘Iuliu Hatieganu’ University of Medicine and Pharmacy, 400000 Cluj‑Napoca; Departments of 4Ophthalmology and 5Dermatology, ‘Grigore T. Popa’ University of Medicine and Pharmacy, 700115 Iasi; 6Internal Medicine Department, ‘Professor Doctor Octavian Fodor’ Regional Institute of Gastroenterology and Hepatology, 400000 Cluj‑Napoca, Romania Received February 16, 2021; Accepted March 18, 2021 DOI: 10.3892/etm.2021.10381 Abstract. The present paper aims to review the topic of adverse Contents reactions to biological agents, in terms of the incriminating mechanisms and therapeutic approach. As a result of immuno‑ 1. Introduction modulatory therapy, the last decade has achieved spectacular 2. Adverse reactions to monoclonal antibodies: Classification results in the targeted treatment of inflammatory, autoimmune, 3. Therapeutic approach: Rapid drug desensitization and neoplastic diseases, to name a few. The widespread use of 4. Conclusions biological agents is, however, associated with an increase in the number of observed adverse drug reactions ranging from local erythema to systemic reactions, including life‑threatening 1. Introduction immunologically mediated events, which justifies the need for a deeper understanding of this subject. Rapid desensitiza‑ Drug allergy is the unpredictable adverse reaction that occurs tion to biological agents emerges as a treatment strategy for as a result of the administration of a drug at a given dose, anaphylactic (immediate or delayed) hypersensitivity reactions tolerated by normal subjects and based on an immunological as well as for severe infusion reactions. Drug desensitization mechanism, either immunoglobulin E (IgE)‑mediated or is the administration of progressively increasing doses of non‑IgE‑mediated (through IgG or lymphocytes) (1). One or the specific preparation until reaching the therapeutic dose more immune mechanisms can compete in the development of in order to induce immunological tolerance and is indicated allergic drug reactions (1‑3). when the drugs are indispensable to the therapeutic regimen of In 1977, Rawlins and Thompson proposed the classifica‑ individuals with hypersensitivity reactions to the preparation, tion of adverse drug reactions into type A (‘augmented’): with no reasonable alternatives. Predictable, dose‑related and based on the pharmacological action of the drug and type B (‘bizarre’): Unpredictable, non‑dose reactions or drug action (Table I) (4). Thirty‑seven years later, the World Allergy Organization (WAO) refined the classification of adverse drug reactions in Correspondence to: Dr Adriana Muntean, Allergology and Immunology Discipline, ‘Iuliu Hatieganu’ University of Medicine and relation to the onset of clinical manifestations, which broadly Pharmacy, 19‑21 Croitorilor Street, 400000 Cluj‑Napoca, Romania allows for the differentiation of IgE‑mediated type I‑type E‑mail: [email protected] hypersensitivity reactions that typically start in the first hour after exposure, with some exceptions (slow absorp‑ Professor Daciana Elena Branisteanu, Department of Dermatology, tion due to oral drug administration or concomitantly with ‘Grigore T. Popa’ University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania food), and late onset reactions mediated by type II, III or IV E‑mail: [email protected] hypersensitivity, in which manifestations occur usually after six hours of exposure and, typically, days after the initiation *Contributed equally of treatment. WAO also suggests the use of the following terms: Immune‑mediated hypersensitivity reactions and Key words: desensitization, hypersensitivity reactions, adverse non‑immune‑mediated hypersensitivity reactions. The first reactions, monoclonal antibodies, biological agents, drug allergy, category of ‘drug hypersensitivity reactions’ includes clinical immunomodulators signs and symptoms initiated by exposure to a tolerated dose by individuals under physiological conditions. According to 2 PINTEA et al: HYPERSENSITIVITY REACTIONS TO MONOCLONAL ANTIBODIES WAO, drug allergy defines immunologically mediated hyper‑ associated with the clinical phenotype of type III hypersen‑ sensitivity reactions and includes immediate, IgE‑mediated sitivity or with immediate reactions that mimic the clinical and delayed non‑IgE‑mediated reactions. In the second manifestations of type I hypersensitivity (11). Hypersensitivity category, ‘non‑allergic hypersensitivity reactions’ include reactions to biologics may be directed against excipients non‑immune‑mediated immune drug responses. WAO also and not the actual biological agent. This category includes proposes the differentiation of adverse drug reactions (ADRs) polysorbate and polyethylene glycol (12,13). Polysorbate is a from adverse drug events (ADEs). This latter category includes non‑ionic surfactant, contained in many MoAbs, and has the medical errors, drug side effects, and food‑drug interactions (5). role of preventing aggregate formation. A series of cases of Due to immunomodulatory therapy, the last decade has late phase hypersensitivity reactions to omalizumab have brought spectacular results in the targeted treatment of inflam‑ been attributed to polysorbate (14). Polyethylene glycol is an matory, autoimmune, and neoplastic diseases, to name a few. excipient found in pharmaceutical preparations, having the The widespread use of biological agents is, however, associated role of slowing down their plasma clearance. Similarly, more with the increase in the number of adverse drug reactions and immediate hypersensitivity reactions to drugs are attributed implicitly those which are immunologically mediated, which to polyethylene glycol (15). Hypersensitivity to polyethylene justifies the need for a deeper understanding of this subject. glycol should be suspected in individuals with a history of allergic reactions to processed foods, cosmetics, various 2. Adverse reactions to monoclonal antibodies: Classification classes of drugs and other substances containing or manufac‑ tured with polyethylene glycol (16). Beta‑type reactions thus The adverse reactions associated with biological agents encompass immune‑mediated reactions through IgE, IgG and vary widely and include local site reactions, infusion‑related T‑lymphocytes. These correspond, in fact, to the Gell and reactions, hypersensitivity reactions, blood dyscrasia, serum Coombs hypersensitivity reactions classification as follows: sickness, vasculitis, demyelinating disease, reactivation of Type I hypersensitivity reactions, which are IgE‑mediated, latent infections (tuberculosis, fungal and viral infections), with immediate onset (within 1‑2 h after administration), clini‑ neoplasms or autoimmune diseases. Adverse effects associ‑ cally ranging from urticaria and angioedema to the dramatic ated with immunomodulatory therapy are thus potentially expression of anaphylaxis. There have also been reported cases severe and sometimes life‑threatening (6). of IgE‑mediated manifestations to biological agents a few days Since adverse reactions from biological agents differ from after exposure (17‑21). adverse reactions from other drugs, Pichler proposed a new Type II and III hypersensitivity reactions are based on classification of adverse reactions produced by biological the synthesis of anti‑MoAb isotype G antibodies, which lead agents in 2006, which includes five types of reactions (7). to the formation of immune complexes and the activation of Fc receptors for IgG and consequently complement cascade Alpha‑type reactions. Alpha‑type reactions are caused by activation, clinically resulting in vasculitis, serum sickness, cytokine overload either as a result of high cytokine doses for nephritis and cytopenia. Type II and III hypersensitivity reac‑ therapeutic purposes or systemic cytokine release syndrome. tions generally have a delayed onset. IgG antibodies to the Examples of alpha‑type reactions include: Flu‑like manifes‑ drug can also intervene by inhibiting therapeutic response tations, myalgias, arthralgia, febrile syndrome, that occur and by inactivating MoAb. In such cases, administration of frequently in the context of interferon (IFN)α administration; MoAbs will not induce side effects but will be ineffective, multiple organ dysfunction and necrotizing vasculitis with documenting a significant reduction in the MoAb serum digital gangrene to TGN1412 agent, directed against T cell concentration. The formation of anti‑drug antibodies [murine surface CD28, caused by polyclonal activation of T lympho‑ anti‑proteins, also called human anti‑chimeric antibodies cytes and secondary cytokine storm; aseptic meningitis, (HACA), human anti‑human antibodies (HAHA)], sometimes capillary permeability syndrome and secondary pulmonary documented during MoAb therapy, is associated with the risk edema, encephalopathy, fever, in the context of muromonab of hypersensitivity reactions, insufficient response/failure of (OK3) administration, a monoclonal antibody to CD3 therapy or increased therapeutic dose requirements (22‑30). expressed

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