Hot Topics: Soluble ligands as drug targets

Historically, the main classes of drug targets have been receptors, enzymes, ion channels and transporters which are primarily targeted by small molecules. However, advances in molecular biology, genomics, and pharmacology have facilitated the development of different therapeutic modalities which in turn have broadened the types of drug targets. In particular, soluble ligands have growing interest as targets and now constitute 10% of novel targets in clinical trials and are currently the third-largest target class of therapeutic agents targeting human protein products, after enzymes and receptors [1].

A new analysis of ligand-targeting [2], illustrates the different classes of ligand-targeting drugs and targets as well as analysing the success of the different technology platforms. This emerging class of drug targets is very dynamic with 291 agents that target 99 unique ligands reaching clinical development from 1992 to 2020. In the last five years, the number of ligand-targeting agents which are FDA-approved has doubled to 34, while the number of clinically validated ligand targets has doubled to 22. Therapeutic antibodies are the most common class of both approved and investigative ligand-targeting agents, followed by decoy receptors. Several technology platforms are successfully being developed, enhancing the opportunities of drug development using antibody fragments, single-domain antibodies, aptamers, spiegelmers, engineered protein scaffolds, gene therapy, therapeutic vaccines and oligonucleotides. There is an increase in the number of agents that target more than one ligand, as well as the number of unique combinations of ligands. Advances in engineering technology and the ability to effectively and safely target more than one ligand has combined with increased knowledge of disease pathways to effectively utilize bispecific antibodies and decoy receptors, amongst others, to selectively disrupt multiple biological pathways by blocking two (or more) related or unrelated ligands. Cytokines and growth factors are the predominant types of targeted ligands (70%), which is consistent with the three major disease groups being treated by both approved and investigational agents: inflammation and autoimmune diseases, cancer, and ophthalmological diseases.

Several factors contribute to the increasing importance of soluble ligands as drug targets, including the growing understanding of the role of the immune system in many diseases in conjunction with the tractability of cytokines as therapeutic agents, and the relative accessibility of ligands in comparison to their receptors to therapeutic agents. Given the increasing body of evidence that inflammation is involved in many diseases beyond typical inflammation disorders and the position of ligand-targeting drugs at the forefront of anti-inflammatory therapies, there will be continued interest in this class of agents. Furthermore, there is vast territory to explore in the ligand target landscape, as there are almost 600 endogenous human peptides according to IUPHAR/BPS Guide to PHARMACOLOGY (https://www.guidetopharmacology.org) with approximately 150 of these identified as having specifically curated immunopharmacological data associated with them (IUPHAR Guide to IMMUNOPHARMACOLOGY: https://www.guidetoimmunopharmacology.org/immuno/).

In conclusion, ligands as a type of drug target now merit consideration as a distinct and expanding group of targets for a range of therapeutic modalities that can exert their effects through single targets or selected combinations.

Comments by Misty Attwood and Helgi Schiöth, University of Uppsala, Uppsala, Sweden. Helgi Schiöth is Chair for NC-IUPHAR Subcommitees for Melanocortin receptors and Prolactin-releasing peptide receptor. Twitter: @FunctPharm

1. Attwood, M. M., Rask- Andersen, M. & Schiöth, H. B. Orphan drugs and their impact on pharmaceutical development. Trends Pharmacol. Sci. 39, 525–535 (2018). [PMID: 29779531]
2. Attwood, M.M., Jonsson, J., Rask-Andersen, M & Schiöth, H. B. Soluble ligands as drug targets. Nature Reviews Drug Discovery. Online ahead of print (2020 Sep 2.). [PMID: 32873970]