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.
Highlights
It has been said, somewhat facetiously, that pharmacology may be considered a branch of organic chemistry.[1]
Targeting neonatal Fc receptor (FcRn) ex‐ pressed by enterocytes in adult primates to enable oral delivery of monoclonal antibody (mAb) has been successfully demonstrated, but the efficiency of the process needs additional improvement before it can be considered for therapeutic application
The mAb market is expected to con‐ tinue to grow in the following years, given the large number of mAbs currently in development and the continued interest shown by phar‐ maceutical companies
Summary
Somewhat facetiously, that pharmacology may be considered a branch of organic chemistry.[1]. Bevacizumab (Avastin) blocks the binding of vascular endothelial growth factors, which are overexpressed in various cancers, to the receptor in the vas‐ cular endothelium, inhibiting angiogenesis.[15] Another approach for anticancer mAb‐based therapies is the targeting of immune cells. The manufacturing process for mAbs involves cell production of batches with quality control to ensure the product is within pre‐ defined parameters One consequence of this is that in contrast to generic versions of small molecule therapeutics, biosimilar mAbs can only be highly similar to an existing FDA‐approved reference product, with no clinically meaningful differences. An example of an ADC is trastuzumab‐emtamsine (Kadcyla ®), a breakthrough formulation that targets the HER2 receptor and de‐ livers emtasine to cancer cells in HER2‐positive metastatic breast cancer.[45] Given their large size, polarity, limited membrane permeability and poor gastrointestinal stability, mAbs do not have good oral bioavail‐ ability (
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