Approved Biologics Used for Therapy and Their Adverse Effects

Abstract

Proteins dominate the growing list of the more than 200 approved biotherapeutic agents used in medicine today. From vaccines; many enzymes; targeted antibodies, fusion proteins, and receptors; “factors” involved in blood clotting, homeostasis, and thrombosis; the extremely potent botulinum neurotoxins; and tiny concentrations of hormones and cytokines, proteins, often in recombinant form, comprise the majority of FDA- and EMA-approved biologics. Of 24 different mAbs with approved indications covering blood, solid tumor, and skin cancers to a similar sized range of others specifically developed for the management of a variety of diseases, mAb development continues to be extended and refined. There is a somewhat smaller list of approved cytokines, a number of which, like enzymes used in enzyme replacement therapies, have been developed as orphan drugs. These are available in highly purified, well-characterized recombinant form. Perceived 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, faster regulatory approval time, and their uniqueness allowing better patent protection for developers and marketers. 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. Even small differences which are often difficult to control can affect a protein’s purity, specificity, potency, and safety. Type I hypersensitivities, anaphylaxis and urticaria, are rarely seen following biotherapy, 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 signs and symptoms of one or more of cytokine release syndrome, an anaphylactic/anaphylactoid reaction, and a direct toxicity are often less easy to define with precision. Biologics, particularly mAbs, may also provoke types II, III, and IV hypersensitivities in the form of autoimmunities, serum sickness, vasculitis, pulmonary events, and cutaneous reactions, some of them severe toxidermias. The list of category A and B adverse reactions to biologics is being progressively enlarged as effects related to cumulative dose, time and dose, drug withdrawal, resistance to drug action, and genetics are better defined, interpreted, and understood. 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 some rare syndromes provoked by biologics, release of a cascade of inflammatory cytokines is a common feature.