Biologics are drugs that are derived from living organisms. In the broadest sense, this category encompasses any agent made by biological processes, including recombinant therapeutic proteins, as well as blood, blood products, proteins or other molecules purified from living material, such as IVIG (see Chapter 15 ), cells and gene therapies ( Chapter 16 ), allergens ( Chapter 23 ) and vaccines. We discuss in this chapter therapeutic proteins that are monoclonal antibodies or soluble receptor constructs. They have all been developed by genetic engineering, and they are produced in vitro in large cultures of prokaryotic or eukaryotic cells. Therapeutic cytokines manufactured by recombinant technology comprise another increasingly important subset of biologics. They are listed in Table 17-1 but will not be further described here.

The fundamental therapeutic rationale underlying the biologics discussed in this chapter relates to the exquisite specificity of the humoral immune system’s antibodies or of certain physiologic receptor-ligand interactions, coupled with the identification of molecules or cells that are critical to the pathologic processes of disease. This permits the development of agents that will target selected steps in a disease pathway with very high affinity yet have little propensity to have ‘off-target’ interactions that could lead to serious side-effects. In addition to their specificity, many of the biologics closely resemble physiologic molecules, and as such, they may be administered in large quantities to achieve the substantial levels (hundreds of micrograms per mL) that can potentially block all of their targets in vivo. This pharmacodynamic efficiency of the biologics certainly accounts for their impressive efficacy in many uses. It also implies that the failure of a particular biologic to provide therapeutic benefit in a given situation makes it unlikely that the targeted molecule plays a non-redundant role in the disease process.

The complex nature of biologics in part accounts for their high cost, which limits their general use, particularly in developing countries. It also presents several other potential problems particular to this group of drugs. Their molecular complexity makes them relatively difficult to develop and often entails a degree of structural heterogeneity that may have unintended consequences. Any change in the manufacturing process must be assumed to change the final product to some extent. This makes the generation of generic forms of biologics essentially impossible. So-called ‘biosimilars’ can have the same amino acid sequence as the first-approved biologic, but the post-translational modifications will not be identical. This variability demands that the regulatory requirements for approval must go beyond any demonstration of chemical identity and should include some biological measures of equivalence in pharmacokinetics, pharmacodynamics, clinical efficacy and safety. Such requirements would need to be less stringent than those applied to a new compound, or the potential financial benefit of the biosimilar (i.e. lower patient cost) would be abrogated. Biosimilar mimics of the compounds discussed in detail in this chapter have not yet appeared in the US market, and the path to approval will have to be developed individually in each case. Compounds that have the same targets but are independently developed (e.g. adalimumab and infliximab), are of course not biosimilars, and each has to undergo its own extensive developmental process. Nevertheless, the success and failures of a given compound will help guide the clinical development of others with the same target. In addition, the safety concerns that the US Food and Drug Administration (FDA) requires in the package inserts may reflect analogies with other compounds with the same target, even in the absence of adverse event data that are directly relevant.

Another general concern about biologics is immunogenicity. As large protein molecules, these drugs are potentially good immunogens. Most of the receptor constructs, such as rilonacept, are different from any autologous protein in the overall structure (anakinra is the exception), although they are made up of faithful portions of individual physiologic molecules. The monoclonal antibodies are more physiologic, but they also can provoke immune responses. Muromonab-CD3, the first monoclonal antibody approved in the USA in 1986, was derived from a mouse immunized with human T cells. It recognizes the CD3ε subunit of the T cell receptor-CD3 complex, and it is effective in treating allograft rejection. However, it frequently induces anti-mouse IgG antibodies (termed HAMA, or human anti-mouse antibodies), which is part of the reason it was withdrawn from the market in 2010. Some murine monoclonal antibodies are still used clinically (e.g. ibritumomab in adults) for short courses of therapy, but in general, further genetic modifications are undertaken to render the monoclonal more human and thus, less immunogenic.

A monoclonal antibody is usually selected from a mouse immunized with the appropriate human cells or protein. The variable regions of both the light and heavy chains are then joined, respectively, to the constant region domains of human κ or λ, and IgG (IgG1, IgG2 or IgG4) to a make a chimeric molecule that is about two thirds of human origin. Infliximab is an example. Such proteins can still not infrequently induce antibody responses, termed HACA, or human anti-chimera antibodies. Further humanization can be obtained by substituting the framework regions in the variable domains with human framework sequences. This leaves only the complementarity determining regions (hypervariable regions) from the original mouse monoclonal. These are the sequences that determine the antigen-binding site, so the specificity of the engineered monoclonal remains the same, but it now has only about 10% mouse sequences. An example of such a humanized monoclonal is eculizumab.

A fully human monoclonal antibody can be produced in two ways. In one approach, a mouse is used in which the immunoglobulin genes have been replaced with human genes. This mouse then makes antibody responses that use human antibody sequences. Canakinumab was produced in this way. A second approach uses a bacteriophage display library of human variable region sequences and selects for antigen binding in vitro. The selected genes are then combined with human constant region genes to reconstitute a complete IgG antibody. Adalimumab was derived in this manner. Notwithstanding, these human monoclonals can provoke immune responses (termed HAHA, or human anti-human antibody), probably largely akin to anti-idiotype responses that are themselves specific for the reagents’ complementarity determining regions. Table 17-2 describes how the mouse/human composition of the monoclonal antibody produced is reflected in the spelling of the penultimate and antepenultimate syllables of its common name.

The immune responses to biologic agents that are often seen in a significant minority of patients may hasten the clearance of the drug, decrease its effectiveness or result in adverse reactions such as hypersensitivity. In many cases, however, they do not seem to have apparent clinical significance, and their presence is not assayed in routine clinical care. In the early studies with infliximab, it was found that higher doses of drug, or giving it along with methotrexate, decreased the incidence of HACA formation. It is not known how well this paradigm may extend to other compounds.

Another class of adverse reactions to the biologics comes from their therapeutic potency. Although they are unlikely to have ‘off-target’ side-effects, they are often so thorough in inhibiting their target that the normal physiologic functions of that target are blocked. Thus, the anti-TNF agents can reactivate latent mycobacterial infections in a characteristic way, or eculizumab (anti-C5) can put patients at risk for serious infections with Gram-negative cocci by blocking the terminal complement cascade.

The compounds discussed below are biologic monoclonal antibodies or receptor constructs that have an FDA-indicated use in the pediatric population as of mid-2014 (see Table 17-3 ). Other biologics approved only for adults have found common use in children. Some of them are listed in Table 17-4 , but they will not be further discussed here.