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, in-depth 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 Köhler 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-mitotic maytansinoid drug DM1 is conjugated to Herceptin®. The safety implication of antibody-drug conjugates is highlighted, not the least of which is the stability of the conjugation, which has obvious systemic toxicity implications.
Chapters 3 is of particular significance because it covers the use of monoclonal antibodies as anti-cancer drugs, and the author points out that of the 50 or so antibodies approved, half are indicated for cancer treatment. Antibodies are typically used in combination with various traditional chemotherapeutic drugs, resulting in more optimal clinical outcomes than systemic chemotherapy alone. The author makes a point that antibodies impart anti-tumor activity via several different immune mechanisms, and it is difficult to apportion the extent of cytotoxic activity to these specific mechanisms, making it challenging, if not impossible, to predict a priori therapeutic efficacy or, for that matter, the manifestation and extent of adverse reaction(s), also taking into account genetic variations within the population. The chapter contains sections on approved antibodies, with details of mechanism of action, and potential adverse reactions and events, including types I-IV hypersensitivities and cytopenias, infusion reactions, cytokine release syndrome, pulmonary and cardiac events. An example of a non-immune adverse reaction to cetuximab and panitumumab, which are antibodies that target the epidermal growth factor receptor (EGFR), is provided, i.e., mucocutaneous reaction, causing papulopustular skin eruptions. Interestingly, there are anti-EGFR antibodies in development that exhibit similar efficacy but reduced mucocutaneous reaction. The author makes special mention of immune checkpoints and relatively new approved antibodies that bind checkpoint targets, where remarkable response rates are now being achieved for treatment of metastatic melanoma. Checkpoint inhibition immunotherapy seeks to activate exhausted T cells that can reside within tumors, thus switching on the immune system to seek and destroy micrometastases. There are many immune checkpoints which the author suggests play a role in balancing immune reactions against self-antigens while maintaining the ability to protect against foreign antigens, and research in developing inhibitory antibodies to other checkpoints is ongoing. Approved checkpoint inhibitors include monoclonal antibodies that bind PD-1 (pembrolizumab, Keytruda®; nivolumab, Opdivo®), CTLA4, (ipilumumab, Yervoy®), and PD-L1 (atezolizumab, Tecentriq®). Combination trials with these antibodies are also showing promise for treatment of other solid tumors such as colorectal cancer.
Chapter 4 discusses antibodies approved for other disease indications besides cancer, and focuses on antibodies to tumor necrosis factor (TNF), a major mediator of inflammatory disease processes. There are 4 approved anti-TNF antibodies (adalimumab, Humira®; infliximab, Remicade®; certolizumab pegol, Cimzia® and golimumab, Simponi®) that have been approved to treat inflammatory diseases such as rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, and various types of psoriasis. With sales in excess of $US 16 B, Humira® was the top selling drug globally in 2016, and Remicade® was among the top 5 best-selling drugs that year. Together with etanercept (Enbrel®, p75 TNF receptor-antibody Fc fusion), these anti-TNF biologic medicines have been spectacularly successful for treating inflammatory disease indications. The author readily points out, however, that this success is not without drawbacks, and adverse reaction is common with these therapies and can be severe. The author also explains that, although these antibodies all bind TNF, there are significant differences in their pharmacology (pharmacokinetics and pharmacodynamics), which differentiates these antibodies. Immunogenicity is the most notable of the drawbacks with these therapies; for example it has been reported that in excess of 15% of patients have an immune response to Humira®. The author dedicates several sections to detailing the structures of these antibodies, their mechanism(s) of action, together with the myriad of adverse reactions that may occur upon their administration. The severity of these adverse reactions is the core reason why there are several approved biologic TNF antagonists, allowing rheumatologists to cycle patients through the various anti-TNF biologics with the advent of adverse reaction(s). The remaining sections of the chapter deal with other antibodies used to treat a wide variety of disease indications, again articulating the intricate details of mechanisms of action and adverse reactions. These sections highlight the spectacular success of monoclonal antibodies and their versatility, made possible through the capacity to isolate human antibodies to potentially any given target with modern antibody engineering technologies.
chapter 5 covers the topic of cytokines. Prior to the upsurge in monoclonal antibody approvals, cytokines were collectively the biggest selling class of biologic medicines. This was principally due to 2 products; erythropoietin (EPO, epoetin alfa) and granulocyte colony-stimulating factor (G-CSF, filgrastim). The author mentions the difficulties in classifying cytokines, as they impart a diverse array of biologic functions including growth factor activity, differentiation, activation, inflammation and chemotaxis. Historically the classification of cytokines has been challenging, and several criteria have been used based on structure or function. As they are powerful modulators of the immune system, among other functions, cytokines can impart profound physiologic responses, and demonstrate paracrine, autocrine and endocrine activity. Their physiologic concentration is in the picomolar range and reflects their very strong affinity of interaction for their respective receptors. A table lists the approved cytokines, including 23 that were approved by the Food and Drug Administration (FDA) at the time of publication. The author presents a separate section on “adverse effects of individual approved recombinant cytokine analogs,” and discusses the reasons why cytokines may cause a wide range of adverse reactions upon administration; these include the pleiotropic nature of cytokines (potential for several activities) and the downstream release of other cytokines, which, taken together with patient genetic diversity, can lead to unpredictable adverse reactions. The author reveals that 16 of the 23 FDA-approved cytokine preparations carry warnings, 10 being black box warnings. It is interesting to note that 5 epoetin alfa and 9 filgrastim biosimilars have been approved in the European Union, introducing competition into the market.
Chapter 6 describes the 11 approved fusion proteins, and demonstrates the power of rDNA technology to mix and match desired protein domains from unrelated sources to produce a molecular entity with dual or multiple functionalities. The most common fusion partner is the Fc portion of the immunoglobulin molecule, where the Fc may be derived from IgG1, IgG2, IgG3 or IgG4; the author notes that 9 of the 11 Fc fusion proteins utilize the IgG1 Fc region. The author explains that there are several reasons for choosing the Fc region of human antibodies. The principle rationale is to produce a stable molecule, large enough to demonstrate a similar pharmacokinetic profile compared with those of antibodies, and to take advantage of the properties imparted by the Fc region; this includes the salvage neonatal FcRn receptor pathway involving FcRn-mediated recycling of the fusion protein to the cell surface post endocytosis, avoiding lysosomal degradation and resulting in release back into the bloodstream, thus contributing to an extended serum half-life. Another obvious advantage is the Fc's binding to Protein A, which simplifies downstream processing during production. Enbrel® was the first Fc fusion protein to be approved; others include immunomodulators abatacept (Orencia®) and belatacept (Nulojix®); these biologics are composed of protein domains that bind CTLA4 and a modified CTLA4, respectively, fused to an Fc region. Besides the Fc portion of antibodies, other fusion partners include human serum albumin; there are 2 licensed albumin fusion products, albiglutide (Tanzeum®, a glucagon-like peptide-1 receptor agonist) and the Factor IX fusion protein rIX-FP (Idelvion®). The author has included sections on the immunogenicity and diagnosis of hypersensitivities to fusion proteins, and provides documented details of the broad range of adverse reactions to individual fusion proteins.
Chapters 7 and 8 cover peptide hormones and glycoprotein hormones, respectively. In Chapter 7, the author has provided in-depth coverage of insulin, including details of its structure, production, release, receptor binding and signaling, and diabetes mellitus. There are numerous types of insulin (i.e., rapid-, short-, long-, intermediate-acting and combinations thereof), and the author summarizes the properties of various insulin preparations in a table. Routes of administration and delivery systems are also discussed, as well as a relatively new preparation (Afreeza®), delivered via inhalation, to be administered in conjunction with long-acting insulin. The author has documented the “warnings, precautions and adverse events” associated with insulin, of which there are many. Hypoglycemia, hyperglycemia and coma can manifest if an incorrect dosage is applied, or through inadequate food intake or vigorous exercise. Various hypersensitivity reactions can occur, and adverse reactions, including rashes, pruritus, weight gain, edema and injection site irritation, are mentioned. The remaining sections of the chapter deal with other peptide hormones, including glucagon, growth hormone and insulin-like growth factor 1. Chapter 8 details the glycoprotein hormones, including gonadotropins follicle-stimulating hormone, luteinizing hormone, human chorionic gonadotrophin and non-gonadotropin thyroid stimulating hormone. These glycoprotein hormones are peptides with 2 N-linked complex glycans on each of the α and β subunits. The degree of sialic capping of the glycans has profound effects on the pharmacology of the hormones, with the acidic charge isoforms having a longer half-life and consequently greater in vivo potency. The α subunit is common to these hormones while the β subunit conveys receptor specificity. The author describes the indications for usage, mechanisms of action and provides sections on warnings, precautions and adverse events.
In Chapter 9, the author describes enzyme defects and the diseases that result. The author focuses on enzyme replacement therapy for lysosomal storage diseases. A table listing the approved therapeutic enzymes and the corresponding disease indications is provided, and demonstrates the success of enzymes as biologic medicines for treating these rare diseases. Blood coagulation factors are described in Chapter 10, which includes a table of all approved blood coagulation factors, with indications, warnings and precautions, and adverse events. The author describes the coagulation cascade that links the network of coagulation factors involved in blood clotting. The author also details the various preparations of coagulation factors, some of which are stand-alone clotting factors while others are fused to carries such as albumin (e.g., Idelvion®, the previously mentioned Factor IX albumin fusion protein) for increased serum half-life.
Vaccines are discussed in Chapter 11, and the author succeeds in describing the various types of vaccines in this broad class of biologics. An extensive list of vaccines is provided, including live, attenuated, subunit, acellular, conjugate and DNA vaccines. Not surprisingly adverse events are numerous and diverse, and reflect the complex and broad nature of vaccines. The author has included a section on “allergic reactions to egg proteins in vaccines,” as vaccines such as influenza are produced in eggs and contain small amounts of the antigen ovalbumin, and pose a potential threat to individuals with egg allergy. However, 2 relatively new preparations of trivalent influenza virus vaccine types A and B (Flublok® and Flucelvax®) are recombinant proteins produced in cells, thus eliminating the need for production in eggs.
Botulinum neurotoxins is the topic of Chapter 12. As the author points out, botulinum toxin from the Gram-positive bacteria Clostridium botulinum is a very potent neurotoxin, a feature that can be harnessed to produce a biologic drug. The well-known preparation Botox® is used for cosmetic applications, to reduce skin wrinkles. Other indications where botulinum toxin is used include cervical dystonia, upper limb spasticity and blepharospasm. More recently Botox® has been used to treat children with cerebral palsy and to reduce spasticity. Unsurprisingly due to the toxicity of botulinum toxin, the author presents several sections on the adverse effects, warnings and precautions and immunogenicity.
In the last chapter (13), the author raises the topic of biosimilars, and includes some historical information associated with the evolution of biosimilars and speculation about their future. The author also addresses the choice facing companies that wish to develop follow-on biologics, i.e., to develop a biosimilar, which requires extensive physicochemical characterization but allows an abbreviated clinical program to demonstrate biosimilarity of the product, or to develop a biobetter product (i.e., a molecule with different composition and better properties, such as enhanced pharmacokinetics) that must undergo a full clinical program. Interestingly, the author presents data showing that as of the end of 2014, although the path to approval for biosimilars has an abbreviated clinical program compared with that of biobetters, there are nevertheless many biobetters under preclinical and clinical development.
In summary, Safety of Biologics Therapy is a comprehensive, concise and up-to-date guide to approved biologic medicines predominantly produced by rDNA technology. As the title suggests, there is a plethora of information that documents the many aspects and issues associated with the safety of these medicines. The chapters follow a logical sequence and are well structured; the illustrations are of high quality, and the numerous tables convey accurate and pertinent information. The book is an excellent reference text for experts in the field and biologics industry stakeholders, and as a general educational reference book for students looking to expand their knowledge in the increasingly important area of biopharmaceutical products.