Non-IgE adverse reactions to biologics

Biologics encompass a class of new therapeutic agents that consists mAbs, fusion proteins, and nanobodies. Adverse reactions to biologics limit their use have broad clinical impact because they affect all medical specialties.1Isabwe G.A.C. Garcia Neuer M. de las Vecillas Sanchez L. Lynch D.M. Marquis K. Castells Hypersensitivity monoclonal antibodies: phenotypes endotypes.J Allergy Clin Immunol. 2018; 142: 159-170.e2Abstract Full Text PDF PubMed Scopus (88) Google Scholar are generally well tolerated, but immunogenic structure, can be recognized as non–self-epitopes inducing cellular humoral immune responses.2Vultaggio A. Petroni G. Pratesi S. Nencini F. Cammelli D. Milla et al.Circulating T cells infliximab detectable mainly in treated patients developing anti-drug antibodies hypersensitivity reactions.Clin Exp 2016; 186: 364-372Crossref (20) (HSRs) been reported with variable frequency depending on the agents.1Isabwe The structural differences IgG molecules result generation compounds elicit antidrug (ADAs), immunocomplex production, interactions cells. ADAs relates loss drug efficacy HSRs.3Matucci Virgili al.Allergological vitro vivo evaluation infliximab.Clin Allergy. 2013; 43: 659-664PubMed mAbs chimeric, humanized, or fully human Fab portion. Their immunogenicity is lower when sequences increased, carbohydrate side chains, it not eliminated.1Isabwe Scholar,3Matucci induce lysis targeted subsequence release proinflammatory mediators, which involved development non–ADA-mediated HSRs.4Yildizhan E. Kaynar Cytokine syndrome.J Oncol Sci. 4: 134-141Crossref Current classification HSRs based expression symptoms (phenotypes) underlying molecular mechanisms (endotypes).1Isabwe Biomarkers help characterize elucidate endotypes, skin testing, specific IgE, tryptase has used for diagnosis type I/IgE-mediated reactions.1Isabwe Non–IgE-mediated present immediate during shortly after administration mediated by non-IgE driven cytokines (cytokine [CR]). Sometimes, both IgE coexist, constellation express mixed fever, chills, urticaria, shortness breath, desaturation, hypotension, among other symptoms, elevated IL-6.1Isabwe Scholar,4Yildizhan Scholar,5Vultaggio Matucci Parronchi P. Rossi O. al.Anti-infliximab induction infusion-related severe anaphylactic reactions.Allergy. 2010; 65: 657-661Crossref (183) Delayed onset include serum sickness–like reactions, maculopapular rash, cutaneous adverse Scholar,6Picard Galvao V.R. knowledge management antibodies.J Immunol Pract. 2017; 5: 600-609Abstract (63) ADA-mediated characterized such flushing, pruritus, urticaria/angioedema, wheezing, vomiting, diarrhea, desaturation lead life-threatening anaphylaxis similar IgE-mediated different ADA isotypes beyond IgE.3Matucci titers higher who suffer compared those efficacy.2Vultaggio A prevalence 56.6% specific-ADA detected HSRs5Vultaggio only 20% were ADAs.3Matucci These findings suggest existence IgG-mediated biologics. In models shown FcɣRIIA contributes through mast cell activations passive active anaphylaxis, basophils, neutrophils, monocytes, macrophages systemic anaphylaxis.7Jönsson Mancardi D.A. Kita Y. Karasuyama H. Iannascoli B. Rooijen N Van al.Mouse neutrophils anaphylaxis.J Investig. 2011; 121: 1484-1496Crossref (207) these platelet-activating factor, histamine, MIP-α7Jönsson (Fig 1). also generate drug-IgG-ADA immunocomplexes, activate complement anaphylatoxins C3a C5a. bind receptors activation further mediators.1Isabwe could explain negative testing results 44% biologics.1Isabwe Interestingly, rituximab do develop first year treatment at risk subsequent exposures.8Nencini Vultaggio Fiori al.The kinetics antibodies, levels, outcomes infliximab-exposed immune-mediated disorders.J 6: 2065-2072.e2Abstract (12) Serum levels may explored biomarkers predict HSRs.8Nencini Sensitization trastuzumab, infliximab, period interruption reexposure associated HSRs.1Isabwe Two HSR described linked CR induced biologics: infusion syndrome (CRS).1Isabwe Infusion self-limited less repeated exposures, typically managed anti-inflammatory premedications decreasing rate.1Isabwe CRS desensitization. Characteristic headache, back pain, dizziness, oxygen into hypotension cardiovascular collapse.1Isabwe seen up 70% dose, decrease 40% cycles premedications.4Yildizhan mechanism due targeted-cell FcɣR, macrophages, cytotoxic cells.4Yildizhan Detection increased TNF-α, INF-a, IL-6 observed leukemia rituximab4Yildizhan elevation desensitization brentuximab obinutuzumab.1Isabwe Endothelium markers Ang-2 von Willebrand factor possible role reactions.4Yildizhan Negative test current biomarkers, tumor must differential diagnosis.4Yildizhan Mixed presenting CRS-induced occur elevations, most positive result.1Isabwe deposition (soluble antigens aggregate IgG/IgM) target tissues injection- site subcutaneous adalimumab,1Isabwe (1%-20% prevalence), omalizumab9Succaria Sahni Wolpowitz Rituximab-induced reaction: histopathologic viewpoint.Am J Dermatopathol. 38: 321-322Crossref (7) Symptoms appear around 7 14 days exposure usually self-limited.9Succaria rashes involving cells, good prognosis.1Isabwe Severe (SCARs) rarely very few cases symmetrical intertriginous flexural exanthema Stevens-Johnson rituximab, toxic epidermal necrolysis cetuximab6Picard Because potential effects desensitization, need reintroduce same biological needs weighed against changing an alternative treatment. However, switching first-line treatments quality life patient survival.1Isabwe reintroduction should phenotype endotype severity Rapid modulate responses cetuximab, obinutuzumab, others.10Vultaggio Bormioli Dies Vivarelli Maggi al.Desensitization modulates response reaction.J 2020; 8: 1764-1767.e1Abstract (6) Desensitization protocols adapted address initial reaction including intravenous fluids, dilute drugs mediators time case series 104 ADA-mediated, CRS, delayed rash successfully desensitized, breakthrough Further studies needed better understand treating preventing reactions. After SCAR nonimmediate biologic, discontinuation indicated sharing common epitopes avoided.9Succaria Mild addressed rapid slow protocols1Isabwe production drug-specific cell-targeted cytokines. involved. More research provide personalized diagnosis. Desensitizations useful tools