REVIEWS Soluble ligands as drug targets Misty M. Attwood 1, Jörgen Jonsson1, Mathias Rask- Andersen 2 and Helgi B. Schiöth 1,3 ✉ Abstract | Historically, the main classes of drug targets have been receptors, enzymes, ion channels and transporters. However, owing largely to the rise of antibody- based therapies in the past two decades, soluble protein ligands such as inflammatory cytokines have become an increasingly important class of drug targets. In this Review, we analyse drugs targeting ligands that have reached clinical development at some point since 1992. We identify 291 drugs that target 99 unique ligands, and we discuss trends in the characteristics of the ligands, drugs and indications for which they have been tested. In the last 5 years, the number of ligand-targeting drugs approved by the FDA has doubled to 34, while the number of clinically validated ligand targets has doubled to 22. Cytokines and growth factors are the predominant types of targeted ligands (70%), and inflammation and autoimmune disorders, cancer and ophthalmological diseases are the top therapeutic areas for both approved agents and agents in clinical studies, reflecting the central role of cytokine and/or growth factor pathways in such diseases. Drug targets In the twentieth century, drug discovery largely involved far more challenging to achieve with small- molecule Pharmacological targets, such the identification of small molecules that exert their drugs. Protein ligands have been successfully targeted as proteins, that mediate the therapeutic effects by interacting with the binding sites by many drugs since the first FDA approval of the desired therapeutic effect of of endogenous small- molecule ligands such as neuro- ligand- targeting agents etanercept and infliximab in a drug. This Review focuses on endogenous soluble protein transmitters or hormones on target proteins. Reflecting 1998, including cytokines such as tumour necrosis factor ligands, such as cytokines, this, drug targets fell mainly into one of four classes of pro- (TNF) and growth factors such as vascular endothelial as drug targets. teins: receptors, enzymes, ion channels and transporters. growth factor A (VEGFA). However, while small molecules remain the predominant Therapeutic mAbs and their targets have been inves- Cytokines therapeutic modality among approved agents1–5, advances tigated, often with a focus on specific indications — pre- Small proteins involved in cell signalling, including in molecular and cellular biology, genomics and pharma- dominantly cancer or inflammatory diseases — and other interleukins, interferons, cology in the past few decades have enabled the develop- modalities such as gene therapies and their targets have tumour necrosis factors, ment of several other therapeutic modalities, including also been reviewed10–12. However, to our knowledge, a chemokines and lymphokines, full- length monoclonal antibodies (mAbs), decoy recep- comprehensive study of the endogenous soluble ligands but not hormones or growth factors. tors, antibody fragments and mimetics, oligonucleotide targeted by all therapeutic modalities has not been pub- therapies and gene therapies6. Antibody- based therapies lished. Here we present an analysis of soluble ligands in particular have dramatically changed the landscape as a class of drug targets based on approved agents and of drug development; more than 80 mAbs have been agents in clinical trials between 1992 and 2020 (see BOX 1 1Functional Pharmacology, approved since the pioneering mAb muromonab-CD3 for details of the origin of the dataset and analysis), Department of Neuroscience, was approved by the FDA in 1986, and three of the top ten including the types of ligands being targeted and the Uppsala University, Uppsala, best-selling drugs in 2018 and 2019 were ligand-targeting characteristics of the drugs and their indications. Sweden. mAbs7–9. Furthermore, we discuss strategic issues such as the pros 2Medical Genetics and Genomics, Department The expansion in the types of biopharmaceutical and cons of different ligand-targeting therapeutic modal- of Immunology, Genetics agents has broadened the types of targets of approved ities and why targeting ligands versus their receptors and Pathology, Uppsala drugs and drugs in clinical trials because characteristics might be preferable in different disease contexts. University, Uppsala, Sweden. of these agents, such as their target specificity and size, 3Institute for Translational enable the effective modulation of target types that are Overview of ligand- targeting drugs Medicine and Biotechnology, far less tractable for small molecules. In particular, sol- The FDA has approved 34 new molecular entities Sechenov First Moscow cytokines growth factors State Medical University, uble protein ligands such as and (NMEs) that target soluble ligands since the first such Moscow, Russia. can be readily targeted with mAbs, fusion proteins and agents — etanercept and infliximab — were approved ✉e- mail: [email protected] other modalities such as aptamers to achieve a thera- in 1998 (Fig. 1). There is a trend towards an increasing https://doi.org/10.1038/ peutic goal such as blockade of the interaction between number of ligand- targeting drugs being approved, with s41573-020-0078-4 protein ligands and their receptors — a goal that is more than half of the NMEs gaining approval in the last NATURE REVIEWS | DRUG DISCOVERY VOLUME 19 | OCTOBER 2020 | 695 REVIEWS Box 1 | Dataset and analysis The overall dataset, which is provided in Supplementary Approved ligand-targeting drugs Novel investigational agents Table 1, comprises FDA-approved agents as well as Data sources investigational drugs that target soluble ligands. • DrugBank dataset • CenterWatch clinical trials dataset The dataset for FDA-approved ligand-targeting drugs is • Drugs@FDA: FDA-approved drugs • Literature reviews composed of a manually selected subset from the updated 2018 • AdisInsight database dataset2 of the study by Rask-Andersen et al. on drug–target interactions of approved agents that affect targets that are Datasets encoded by the human genome130 (see the left side of the figure). The original study, which extends from 1982, was based FDA-approved ligand-targeting drugs Investigational ligand-targeting agents in clinical trials on the DrugBank database131, with further updates and 1998–2020 1992–2020 verifications from the Drugs@FDA website and monthly Beginning from first ligand-targeting Beginning from study start date of first reports. The ligand-targeting subset spans from 1998, when drug approved by the FDA clinical trial of ligand-targeting drug the first drugs targeting ligands were approved, to 15 June 2020. registered in ClinicalTrials.gov The dataset of investigational ligand-targeting agents in clinical trials is also a manually selected subset from the updated Validation of drug–target interactions 2018 dataset2 based on the study by Rask-Andersen et al. on the • Google Scholar • Google Scholar druggable genome and evaluation of drug targets in clinical • Patent applications • Patent applications trials1 (see the right side of the figure). The original study was • PubMed • PubMed based on the CenterWatch Drugs in Clinical Trials Database • Industry press releases • Industry press releases (DCTD; not currently accessible), which was established in 1994, • Conference abstracts • Conference abstracts and subsequent updates from the CenterWatch Weekly Pipeline. Additionally, literature reviews and the publicly accessible pages Final results from the AdisInsight database were used to identify potential 34 FDA-approved drugs acting on 257 novel investigational agents acting on investigational agents that target ligands. Investigational agents 22 novel ligands, including 77 novel ligands, including verified to have an NCT (National Clinical Trials) number in 3 combinations 22 combinations ClinicalTrials.gov were included in the dataset. In addition, there were 27 agents that had literature describing trials but an NCT number conference abstracts and patent applications. The drug–target mechanism could not be found. ClinicalTrials.gov was launched to the public in 2000 of action was carefully researched to exclude targets that induce owing to the requirements of the FDA Modernization Act of 1997 and is pleiotropic or other unknown effects. As the focus is on innovation of the registry of US clinical trials information. Registration requirements agents and targets, biosimilars were excluded from the dataset. Trial of trials expanded in 2007 after the FDA Amendments Act was passed and information for interventional studies with the primary purpose of hence the database has grown significantly since that time. Our subset of treatment was obtained from ClinicalTrials.gov for each agent. The NCT investigational agents targeting ligands spans from 1992, the first year in number, which signifies one record per unique study protocol, was used to which we identify one of the ligand-targeting agents began a registered distinguish individual clinical trials. The ‘study start date’ field was used clinical trial, to 15 June 2020. As the registration of clinical trials has been to identify when studies of novel agents and targets began as well as when inconsistent, particularly in the decades preceding and immediately trial phases were initiated. To assess whether an agent was still being following the turn of the century, our dataset may underestimate the actively investigated, the status of its clinical trials was first reviewed,