Abstract
Proteins dominate the extensive and growing list of approved biotherapeutic agents used in medicine today. Proteins, as targeted antibodies, tiny concentrations of hormones and cytokines; many enzymes; fusion proteins and receptors; “factors” involved in blood-clotting, homeostasis, and thrombosis; and vaccines, often in recombinant form, comprise the majority of FDA- and EMA-approved biologics. Of the 51 different mAbs currently approved and many under development for the management of a variety of non-cancer diseases, mAb development continues to be extended and refined. There is a smaller list of approved cytokines, a number of which, like enzymes used in enzyme replacement therapies, have been developed as orphan drugs. These recombinant proteins are available in highly purified, well-characterized form. Some advantages of protein therapeutics over small MW drugs include specificity of action and potent therapeutic efficiency, more predictable behavior after administration, fewer side effects including the expected lower immunogenicity due to their human origin, and faster regulatory approval time. Unlike small drug molecules, protein therapeutics are typically more complex with the possibility of heterogeneity due to changes in amino acid sequence, the presence and extent of glycosylation, folding, and protein-protein interactions. Type I hypersensitivities, anaphylaxis and urticaria, are generally not often seen following conventional small molecule therapy, but both reactions are known to occur with many different biologic agents, particularly mAbs, hormones (e.g., insulin), and enzymes, including recombinant preparations used in enzyme replacement therapies. Many infusion reactions with some signs and symptoms of cytokine release syndrome, anaphylactic/anaphylactoid reactions, and direct toxicity are often less easy to define precisely and confidently. Biologics, particularly mAbs, may also provoke type II, III, and IV hypersensitivities in the form of cytopenias, autoimmunities, serum sickness, vasculitis, pulmonary events, liver injury, and cutaneous reactions, some of them severe toxidermias. A number of systemic potentially life-threatening syndromes may occur with low frequency during or following the administration of a variety of biologic agents. For most, if not all, of the rare syndromes provoked by biologics, release of a cascade of inflammatory cytokines is a common feature.
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Further Reading
Baldo BA. Side effects of cytokines approved for therapy. Drug Saf. 2014;37:921–43.
Baldo BA. Chimeric fusion proteins used for therapy: indications, mechanisms, and safety. Drug Saf. 2015;38:455–79.
Baldo BA. Enzymes approved for human therapy: indications, mechanisms, and adverse effects. BioDrugs. 2015;29:31–55.
Baldo BA. Safety of biologics therapy: monoclonal antibodies, cytokines, fusion proteins, hormones, enzymes, coagulation proteins, vaccines, botulinum toxins. Cham: Springer; 2016. p. 1–56, 141–215, 217–61, 263–307, 314–26, 420–77.
Beck A, Diemer H, Ayoub D, et al. Analytical characterization of biosimilar antibodies and Fc-fusion proteins. Trends Anal Chem. 2013;48:81–95.
Blijlevens N, Sonis S. Palifermin (recombinant keratinocyte growth factor-1): a pleiotropic growth factor with multiple biological activities in preventing chemotherapy- and radiotherapy-induced mucositis. Ann Oncol. 2007;18:817–26.
Chamow SM, Ryll T, Lowman HB, Farson D, editors. Therapeutic Fc-fusion proteins. Weinheim: Wiley-Blackwell; 2014.
Cheifetz A, Smedley M, Martin S, et al. The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenterol. 2003;98:1315–24.
Elloso MM, Gomez-Angelats M, Fourie AM. Targeting the Th17 pathway in psoriasis. J Leukoc Biol. 2012;92:1187–97.
Fattovich G, Giustina G, Favarato S, et al. A survey of adverse events in 11,241 patients with chronic viral hepatitis treated with alfa interferon. J Hepatol. 1996;24:38–47.
Ferenczy MW, Marshall LJ, Nelson CDS, et al. Molecular biology, epidemiology, and pathogenesis of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain. Clin Microbiol Rev. 2012;25:471–506.
Fried MW. Side effects of therapy of hepatitis C and their management. Hepatology. 2002;36(Suppl 1):S237–S44.
Grampp G, Felix T. Pharmacovigilance considerations for biosimilars in the USA. BioDrugs. 2015;29:309–21.
Heinzerling L, Raile K, Rochlitz H, et al. Insulin allergy: clinical manifestations and management strategies. Allergy. 2008;63:148–55.
Hilvering B, Xue L, Pavord ID. Evidence for the efficacy and safety of anti-interleukin-5 treatment in the management of refractory eosinophilic asthma. Ther Adv Respir Dis. 2015;9:135–45.
Irani V, Guy AJ, Andrew D, et al. Molecular properties of human IgG subclasses and their implications for designing therapeutic monoclonal antibodies against infectious diseases. Mol Immunol. 2015;67:171–82.
Jones TD, Carter PJ, Plückthun A, et al. The INNs and outs of antibody nonproprietary names. MAbs. 2016;8:1–9.
Kaplon H, Reichert JM. Antibodies to watch in 2019. MAbs. 2019;11:219–38. https://doi.org/10.1080/19420862.2018.1556465.
Kaplon H, Muralidharan M, Schneider Z, et al. Antibodies to watch in 2020. MAbs. 2020;12:1703531. https://doi.org/10.1080/19420862.2019.1703531.
Keene DL, Legare C, Taylor E, et al. Monoclonal antibodies and progressive multifocal leukoencephalopathy. Can J Neurol Sci. 2011;38:565–71.
Kinch MS. An overview of FDA-approved biologics medicines. Drug Discov Today. 2015;20:393–8.
Leader B, Baca QJ, Golan DE. Protein therapeutics: a summary and pharmacological classification. Nat Rev Drug Discov. 2008;7:21–39.
Liu L. Antibody glycosylation and its impact on the pharmacokinetics and pharmacodynamics of monoclonal antibodies and Fc-fusion proteins. J Pharm Sci. 2015;104:1866–84.
Meyer-Tamaki KB. Preclinical development of monoclonal antibodies. In: Faqi AS, editor. A comprehensive guide to toxicology in preclinical drug development. London: Academic Press; 2013. p. 489–516.
Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, et al., editors. The metabolic and molecular basis of inherited disease. 8th ed. New York: McGraw-Hill; 2001. p. 3421–52.
Parren PWHI, Carter PJ, Plückthun A. Changes to International Nonproprietary Names for antibody therapeutics 2017 and beyond: of mice and men. MAbs. 2017;9:898–906.
Rare diseases: common issues in drug development. Guidance for industry. U.S. Department of Health and Human Services; Food and Drug Administration Center for Drug Evaluation and Research (CDER); Center for Biologics Evaluation and Research (CBER), January 2019. https://www.fda.gov/media/119757/download. Accessed 30 Sept 2019.
Rath T, Baker K, Dumont JA, et al. Fc-fusion proteins and FcRn: structural insights for longer-lasting and more effective therapeutics. Crit Rev. Biotechnol. 2015;35:235–54. https://doi.org/10.3109/07388551.2013.834293.
Roselló S, Blasco I, García Fabregat L, et al. Management of infusion reactions to systemic anticancer therapy: ESMO clinical practice guidelines. Ann Oncol. 2017;28(Suppl 4):iv100–18.
Santos RB, Galvão VR. Monoclonal antibodies hypersensitivity: prevalence and management. Immunol Allergy Clin N Am. 2017;37:695–711.
Schmidt SR, editor. Fusion protein technologies for biopharmaceuticals. Applications and challenges. Hoboken: Wiley; 2013.
Strohl WR, Strohl LM. Therapeutic antibody engineering: current and future advances driving the strongest growth area in the pharmaceutical industry, Woodhead publishing series in biomedicine, vol. 11. Cambridge: Woodhead Publishing Ltd; 2012.
Tanaka T, Narazaki M, Kishimoto T. Therapeutic targeting of the interleukin-6 receptor. Annu Rev. Pharmacol Toxicol. 2012;52:199–219.
Tsuchikama K, An Z. Antibody-drug conjugates: recent advances in conjugation and linker chemistries. Protein Cell. 2018;9:33–46. https://doi.org/10.1007/s13238-016-0323-0.
Turner MD, Nedjai B, Hurst T, et al. Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease. Biochem Biophys Acta. 2014;1843:2563–82.
Vacchelli E, Galluzzi L, Eggermont A, et al. Immunostimulatory cytokines. OncoImmunology. 2012;1:493–506. https://doi.org/10.4161/onci.20459.
van Schouwenburg PA, Rispens T, Wolbink GJ. Immunogenicity of the anti-TNF biologic therapies for rheumatoid arthritis. Nat Rev. Rheumatol. 2013;9:164–72.
Winkler U, Jensen M, Manzke O, et al. Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood. 1999;94:2217–24.
Zeltser R, Valle L, Tanck C, et al. Clinical, histological, and immunophenotypic characteristics of injection site reactions associated with etanercept: a recombinant tumor necrosis factor alpha receptor: Fc fusion protein. Arch Dermatol. 2001;137:893–9.
Zhang P, Woen S, Wang T, et al. Challenges of glycosylation analysis and control: an integrated approach to producing optimal and consistent therapeutic drugs. Drug Discov Today. 2016; https://doi.org/10.1016/j.drudis.2016.01.006.
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Baldo, B.A., Pham, N.H. (2021). Biologics: Monoclonal Antibodies for Non-cancer Therapy, Cytokines, Fusion Proteins, Enzymes, and Hormones. In: Drug Allergy. Springer, Cham. https://doi.org/10.1007/978-3-030-51740-3_13
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DOI: https://doi.org/10.1007/978-3-030-51740-3_13
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