Targets for MAbs: innovative approaches for their discovery & validation, LabEx MAbImprove 6^thantibody industrial symposium, June 25-26, 2018, Montpellier, France

Abstract

Monoclonal antibodies (mAbs) have revolutionized the treatment landscape in many disciplines of human medicine. To continue this exciting trend, sustained identification of new, validated and preferably functional targets are needed. However, this is the precise bottleneck in today’s development of the next generation of therapeutic mAbs. Failures in translating a target into a successful therapeutic mAb are much more frequent than successes. Labex MAbImprove is a French-led consortium of academic laboratories jointly working on several aspects of the development of next-generation mAbs. The network organizes annual international meetings gathering academia and industry to discuss the different challenges faced in the therapeutic mAbs field. The 2018 symposium (also called AIS2018 and co-organized with MabDesign, the immunotherapy French industrial sector) focused on the discovery and validation of new targets for therapeutic mAbs. Key players from industry and academia outlined a number of exciting contributions, notably dealing with new innovations in the target discovery area, but also lessons learned from failures in the past. This report summarizes the talks presented at the AIS2018. We aim at broad dissemination of the most relevant, unpublished findings presented during the meeting, and hope to inspire all the contributors in this field to take new directions and bring about improvements.

The Dawn of a New Era: Targeting the “Undruggables” with Antibody-Based Therapeutics

“…Unlike small-molecule drugs which are in general highly cell-permeable, antibody drugs are cell-impermeant due to their macromolecular structures. Therefore, the vast majority of accessible targets by current antibody drugs are secreted and cell-surface proteins. , As of the end of 2022, there were a total of 76 targets from all currently approved therapeutic antibodies, and 14 of them were targeted by more than two antibody drugs (Figure c). , Among them, the top 8 targets are CD20, CD3, HER2 (human epidermal growth factor receptor 2), PD-1 (programmed cell death protein-1), EGFR (epidermal growth factor receptor), TNF (tumor necrosis factor), CD19 and SARS-CoV-2. These targets generally fall into three major disease areas: cancer (e.g., CD20, HER2, PD-1, EGFR), immune disorders (e.g., CD3, TNF, CD19), and infectious diseases (e.g., SARS-CoV-2).…”

“…Therefore, the vast majority of accessible targets by current antibody drugs are secreted and cell-surface proteins. 43,57 As of the end of 2022, there were a total of 76 targets from all currently approved therapeutic antibodies, and 14 of them were targeted by more than two antibody drugs (Figure 2c). 52,53 Among them, the top 8 targets are CD20, CD3, HER2 (human epidermal growth factor receptor 2), PD-1 (programmed cell death protein-1), EGFR (epidermal growth factor receptor), TNF (tumor necrosis factor), CD19 and SARS-CoV-2.…”

Viro-antibody therapy: engineering oncolytic viruses for genetic delivery of diverse antibody-based biotherapeutics

“…An increasing number of new targets is being evaluated for cancer therapy. 142 This pipeline is fueled by novel tools of antibody discovery, e.g., moving from target-led strategies to phenotypic screening approaches, 26 , 143 including targets associated with the various stages of the metastatic process and the tumor microenvironment. 144 Thereby, the “high-hanging fruits” regarding target biology, target exposure and antibody modes of action are being pursued.…”

Application of quantitative protein mass spectrometric data in the early predictive analysis of membrane-bound target engagement by monoclonal antibodies

“…Approximately 65% of mAb targets are membrane proteins, such as CD20, HER2, EGFR, CD4, PD-1, and PD-L1. 4 Upon antibody binding, these mAb-target complexes undergo cellular internalization and degradation that manifests as target-mediated drug disposition (TMDD) where the pharmacokinetic (PK) behavior of the drug depends on its dose, concentration, and time. 5 Whilst TMDD can complicate the dose-response analysis and prediction, it also lends support to the three pillars of therapeutic drug discovery 6 since the process characterizes the tissue penetration and target engagement properties of the drug at the site of action and elsewhere.…”