The pharmacology and therapeutic applications of monoclonal antibodies

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.

Pharmacokinetics, Pharmacodynamics and Drug–Drug Interactions of New Anti-Migraine Drugs—Lasmiditan, Gepants, and Calcitonin-Gene-Related Peptide (CGRP) Receptor Monoclonal Antibodies

“…Anti-CGRP monoclonal antibodies are less hepatotoxic than gepants, their metabolism is based on reticuloendothelial uptake. Since monoclonal antibodies are not known to be eliminated via renal pathways or metabolized in the liver, renal and hepatic impairment are not expected to impact their pharmacokinetics [111][112][113][114][115][116][117][118].…”

“…Bioavailability and absorption rate of mAbs depend, among other things, on the route of administration. Due to their protein structure, mAbs are transported in the body by endocytosis, pinocytosis, or passive transport through the pores in intercellular space [111,118]. The lymphatic system plays an active part in mAb absorption and the main route of transport after subcutaneous (s.c.) administration is lymph, unlike small molecule drugs that are transported through blood plasma.…”

“…The lymphatic system plays an active part in mAb absorption and the main route of transport after subcutaneous (s.c.) administration is lymph, unlike small molecule drugs that are transported through blood plasma. Therefore, one of the key factors affecting bioavailability of mAbs and their absorption rate upon s.c. administration is the transit time of mAbs with the lymph [111][112][113][114]118].…”

Innate Inspiration: Antifungal Peptides and Other Immunotherapeutics From the Host Immune Response

“…In 2018 alone, twelve new mAb were approved by the FDA, representing 20% of the total number of approved drugs and sales of mAb were forecast to reach US $125 Bn by 2020. Most therapeutic monoclonal antibodies are used for the treatment of cancer or immunological disorders ( 397 , 398 ). The development of monoclonal antibodies for the prevention and treatment of infectious diseases lags somewhat behind their development for other therapeutic areas, e.g., cancer and autoimmune diseases ( 399 ), and only three monoclonal antibodies have received approval for infectious disease prophylaxis or treatment; palivizumab for prevention of respiratory syncytial virus in high-risk infants ( 400 ); and obiltoxaximab ( 401 ) and raxibacumab ( 402 ) for prophylaxis and treatment of anthrax.…”

IgG4 Autoantibodies Attenuate Systemic Lupus Erythematosus Progression by Suppressing Complement Consumption and Inflammatory Cytokine Production

“…In fact, natural or improved IgG4 frameworks have been used to develop therapeutic antibodies that do not require effector functions. Currently, the marketing of several IgG4-type therapeutic antibodies, including Keytruda R and OPDIVO R for PD-1 targets, has been approved (19).…”