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Pharmacologic targeting of oncogenic pathways
Bryan C. Barnhart, Oncology Drug Discovery, Bristol-Myers Squibb, Co., Princeton, NJ, USA,
Marco M. Gottardis, Oncology Drug Discovery, Bristol-Myers Squibb, Co., Princeton, NJ, USA,
Matthew V. Lorenzi, Oncology Drug Discovery, Bristol-Myers Squibb, Co., Princeton, NJ, USA
Targeted biologic therapeutics have become an important class of oncology drugs, and could be the predominant class of approved anti-tumor treatments in the coming years. Within the class of biologic therapies, multiple monoclonal antibodies have achieved approval for a variety of cancer indications (Table 78.1). This chapter will provide an overview of biologics therapy from an oncology drug-discovery perspective, including a review of monoclonal antibodies, oncology targets for antibody therapy, the challenges for antibodies as drug-discovery targets, and the future of protein therapeutics in oncology drug discovery.
Overview of antibodies as cancer therapeutics
An overview of antibody structure and function is essential to understanding their role as drugs (1). Antibodies are produced by B cells, having evolved as a defense mechanism mediated by their specific, high-affinity binding and subsequent neutralization of target pathogens or particles. Antibodies are comprised of two heavy chains and two light chains (Figure 78.1a). The heavy and light chains are tethered by disulfide bonds, and the heavy chains are themselves bound by additional disulfide bonds creating a four protein-chain molecule. The heavy and light chains each contain variable and constant regions, the variable regions differ between antibodies and are responsible for binding to the target; the constant regions’ amino-acid sequences remain fixed amongst antibodies. Each heavy and light chain contributes to the antibody binding domain, forming the complementarity determining region (CDR) which interacts with the target antigen. The binding characteristics of CDRs are defined by their specific amino-acid sequence. B cells initially produce low-affinity, high-avidity (decavalent) IgM molecules (Figure 78.1b). Antigen binding is enhanced through T-cell-directed affinity maturation. Isotype switching results in an exchange of the non-binding portion of the antibody to a bivalent IgG, establishing distinct effector functions, while retaining the CDR and thus target specificity. All marketed cancer therapeutics are one of the IgG class of antibodies. The Fc domain, which is made up of the region of the antibody distal to the CDRs and is comprised of the two associated heavy chains, is also important for antibody therapeutics in mediating effector functions, including the activation of immune-dependent activities that require the constant region of the antibody. Such activities are complement fixation, activation of immune cell cytotoxicity, and triggering of phagocytic activity of certain cells. These effector functions are responsible for many of the therapeutic outcomes of antibody treatment.
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