New Horizons in Therapeutic Antibody Discovery: Opportunities and Challenges versus Small-Molecule Therapeutics

Abstract

Antibody drugs have become an increasingly significant component of the therapeutic landscape. Their success has been driven by some of their unique properties, in particular their very high specificity and selectivity, in contrast to the offtarget liabilities of small molecules (SMs). Antibodies can bring additional functionality to the table with their ability to interact with the immune system, and this can be further manipulated with advances in antibody engineering. This review summarizes what antibody therapeutics have achieved to date and what opportunities and challenges lie ahead. The target landscape for large molecules (LMs) versus SMs and some of the challenges for antibody drug development are discussed. Effective penetration of membrane barriers and intracellular targeting is one challenge, particularly across the highly resistant blood-brain barrier. The expanding pipeline of antibody-drug conjugates offers the potential to combine SM and LM modalities in a variety of creative ways, and antibodies also offer exciting potential to build bi-and multispecific molecules. The ability to pursue more challenging targets can also be further exploited but highlights the need for earlier screening in functional cell-based assays. I discuss how this might be addressed given the practical constraints imposed by high-throughput screening sample type and process differences in antibody primary screening.

Structure-based Discovery of Novel Small Molecule Wnt Signaling Inhibitors by Targeting the Cysteine-rich Domain of Frizzled

“…The discovery of novel FZD CRD inhibitors may add important candidates to the Wnt signaling regulator pool and will be valuable for further understanding Wnt signaling and discovering most effective therapeutic combinations by targeting abnormal Wnt signaling based on genetic profiles of individuals. Moreover, besides the cost factor associated with antibody drugs ( 45 , 46 ), another advantage of FZD CRD inhibitors is that they may have a broader spectrum of the targets; perhaps a small molecule inhibitor drug can be developed to target most, if not all, of the 10 human FZDs.…”

Web-based display of protein surface and pH-dependent properties for assessing the developability of biotherapeutics

“…Protein biopharmaceuticals (biologics), and in particular monoclonal antibodies, are crucial for many new generation therapeutic interventions 1,2 . Compared to traditional small chemical drugs, antibodies have a higher specificity, as well as target selectivity, leading to fewer off-target effects 3 . However, due to the liquid formulation requirements, and the general instability of proteins compared to small molecules 4,5 , the development of monoclonal antibody biopharmaceuticals can be difficult.…”

Cheminformatic comparison of approved drugs from natural product versus synthetic origins

“…Most notably, small molecules are still more effective at addressing intracellular targets than most biologics. 8,9 However, small-molecule drugs address a rather limited range of targets. A 2006 study estimated that approved small-molecule drugs target only 207 proteins encoded by the human genome.…”