Biologics: Monoclonal Antibodies for Non-cancer Therapy, Cytokines, Fusion Proteins, Enzymes, and Hormones

Baldo, Brian A.; Pham, Nghia H.

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.