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Review
, 7 (6), e00535

The Pharmacology and Therapeutic Applications of Monoclonal Antibodies

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Review

The Pharmacology and Therapeutic Applications of Monoclonal Antibodies

María Sofía Castelli et al. Pharmacol Res Perspect.

Abstract

Monoclonal antibodies (mAbs) have emerged as a major class of therapeutic agents on the market. To date, approximately 80 mAbs have been granted marketing approval. In 2018, 12 new mAbs were approved by the FDA, representing 20% of the total number of approved drugs. The majority of mAb therapeutics are for oncological and immunological/infectious diseases, but these are expanding into other disease areas. Over 100 monoclonal antibodies are in development, and their unique features ensure that these will remain a part of the therapeutic pipeline. Thus, the therapeutic value and the elucidation of their pharmacological properties supporting clinical development of these large molecules are unquestioned. However, their utilization as pharmacological tools in academic laboratories has lagged behind their small molecule counterparts. Early therapeutic mAbs targeted soluble cytokines, but now that mAbs also target membrane-bound receptors and have increased circulating half-life, their pharmacology is more complex. The principles of pharmacology have enabled the development of high affinity, potent and selective small molecule therapeutics with reduced off-target effects and drug-drug interactions. This review will discuss how the same basic principles can be applied to mAbs, with some important differences. Monoclonal antibodies have several benefits, such as fewer off-target adverse effects, fewer drug-drug interactions, higher specificity, and potentially increased efficacy through targeted therapy. Modifications to decrease the immunogenicity and increase the efficacy are described, with examples of optimizing their pharmacokinetic properties and enabling oral bioavailability. Increased awareness of these advances may help to increase their use in exploratory research and further understand and characterize their pharmacological properties.

Keywords: Fc gamma receptors; Fc neonatal receptors; half-life; pharmacodynamics; pharmacokinetics; protein therapeutic.

Conflict of interest statement

Dr Pamela Hornby is a full‐time employee of Janssen R&D. The rest of the authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Working model used to establish the pharmacology of intestinal FcRn. This was used for the selection of a mAb in order to assess oral bioavailability in a 10 week dosing study in cynomolgus monkeys. 1. In human, FcRn expression increasing proximal‐distal gradient in the intestine. 2. Lyophilized mAb stable and loaded in sufficient amounts for dosing into enteric‐coated capsule protected from dissolution at low pH. 3. Enteric coating undergoes rapid dissolution at pH 7.5 in the terminal ileum to release mAbs that resist luminal proteases. 4. mAbs reach the apical surface of enterocytes and are limited by the rate of pinocytosis, unless there is IgG‐FcRn receptor surface binding. 5. Low pH favors mAbs binding at the apical cell surface or within the endosome, where they are trafficked to the basolateral side. 6. mAbs must have a fast off‐rate at pH 7.4 to reach lymphatic lacteals and eventually the systemic circulation. ▼, FcRn; Y, mAb; double lined oval, enteric coated capsule

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