Safety of biologics therapy: Monoclonal antibodies, cytokines, fusion proteins, hormones, enzymes, coagulation proteins, vaccines, botulinum toxins

Safety of Biologics Therapy by Brian A. Baldo and published by Springer International, is a comprehensive treatise of biologic medicines that not only covers the many issues that relate to the safety of these primarily recombinant DNA (rDNA)-derived proteins, but also provides details of the major classes or categories of biologics, namely monoclonal antibodies, cytokines, fusion proteins, hormones, enzymes, vaccines and botulinum toxins. Specific biologics within these categories are described in detail, and explanations of their somewhat complex mechanism(s) of action and potential adverse reactions and events are also included. Chapter 1 begins with the overriding theme of the book, i.e., the safety of biologics and the adverse effects of approved biologic medicines. Definitions of the specific composition of biologic medicines are provided, which is important because the term has evolved since the Biologics Control Act of 1902, where biologics were defined as “any virus, therapeutic serum, toxin, antitoxin or analogous product applicable to the prevention, treatment or cure of diseases of injuries to man.” As the author points out, the advent of rDNA technology and the ability to produce protein therapeutics ex vivo has revolutionized biologic medicine production, and today the industry generally regards biologics medicines as rDNA-derived proteins, as these provide the bulk of the global revenue for biologics. Indeed the author highlights the enormous growth in approved monoclonal antibody therapies reflected by the fact that today 6 of the top 10 selling drugs globally are monoclonal antibodies. Importantly a comparison of the attributes and properties of biologics and small molecules is provided, and an explanation of why growth in the number of approved biologics is outstripping small molecules; i.e., overall a lower occurrence of adverse reactions and a shorter path from discovery to approval for several reasons. As the book is principally associated with safety, indepth coverage of the terminology of adverse reactions and adverse events is provided. Critically, it is pointed out that “while an adverse reaction is a reaction directly related to use of the drug, an adverse event in a patient may not necessarily be directly drug related during the treatment period.” Tables are provided that encapsulate information in interpreting and categorizing adverse events and adverse drug reactions; in particular, the classification of adverse drug reactions highlights the varied and diverse drug reactions that can occur. For example, immune-mediated reactions or hypersensitivities based on the Gell and Coombs classification can subdivided into 4 categories (types I, II, III and IV), each operating through distinct immune mechanisms as described in detail by the author. Various syndromes that may manifest during or post-treatment are also described and include capillary leak syndrome, cytokine release syndrome and hemophagocytic lymphohistiocytosis, macrophage activation syndrome, systemic inflammatory response syndrome, tumor lysis syndrome, posterior reversible encephalopathy syndrome and immune reconstitution inflammatory syndrome, and progressive multifocal leukoencephalopathy. Although infrequent, these syndromes may be life threatening and so vigilance is required. Chapters 2, 3 and 4 are associated with monoclonal antibodies, the largest grouping of biologic medicines. Monoclonal antibodies and their derivatives are experiencing rapid growth, in part due to their exquisite specificity in targeting antigens, the observation that they are well tolerated with lower risk and the identification of new targets, including GD2, CD38 and SLAMF7 to name a few mentioned by the author. Chapter 2 is an introduction to monoclonal antibodies, and includes a recent summary table of approved antibodies and derivatives. The chapter provides a brief history of monoclonal antibody development, from the initial landmark discovery by K€ohler and Milstein in 1975 that fusing B cells with myelomas to produce hybridomas facilitated the efficient production of antibodies ex vivo (i.e., culturing cells in bioreactors), through chimeric and CDR-grafted antibodies, to the current technologies for producing fully human antibodies, including phage display and transgenic mice. The progression from mouse to fully human antibodies has reduced immunogenicity of antibodies; however, the author presses the point that immunogenicity is a problem for even human antibodies (i.e., anti-idiotype, and allotype), and a cause of potential adverse reaction. Antibody-drug conjugates are also mentioned as a method of “supercharging” antibodies by conjugating drug molecules at various positions on the antibody molecule. A case in point is ado-trastuzumab emtansine (Kadcyla ), whereby an average of 3.5 molcules of the anti-