In “Targeting chemokines and chemokine receptors with antibodies”, Alex Klarenbeek et al.  present recent progress in the generation and clinical study of mAbs that intervene in the chemokine system. Drug targets within this system are attractive because they are relevant in numerous human illnesses, including cancer, autoimmune disorders and infectious diseases. The authors provide an overview of the commercial development of mAbs targeting either chemokines or their endogenous receptors. In addition, they detail promising approaches (e.g. active immunization with whole receptor, DNA immunization) to circumventing the challenges associated with generating mAbs to chemokine receptors, which are G-protein coupled receptors with seven-transmembrane regions.  

The review “Monoclonal antibodies for chronic refractory asthma and pipeline developments” by Riccardo Polosa and Thomas Casale recounts the numerous cellular and molecular mechanisms involved in chronic asthma, for example,  IgE, tumor necrosis factor, interleukin (IL)-5, IL-4, IL-13, IL-9, and presents clinical evidence from studies of mAbs against these targets. The authors note that only one mAb, omalizumab, has been approved for treatment of severe asthma, and they provide balanced accounts of both negative and positive outcomes for 12 mAbs investigated in clinical studies of asthma patients. Polosa and Casale conclude that the complexity of the disease may preclude responses to canonical mAbs because they block only one pathway, and recommend improvement in the identification of patients who might be more likely to benefit from treatment with specific mAbs.        

My colleague Eugen Dhimolea and I ponder the future of antibodies as cancer drugs in a review that provides an overview of the commercial pipeline of antibodies for cancer. We document the growing number of non-canonical mAbs, for example, bispecific mAbs, glycoengineered mAbs, antibody fragments, in clinical studies, and suggest that the increased functionality of these mAbs may make them more efficacious compared to unmodified, full-length immunoglobin molecules but pivotal clinical study results are needed to make this determination. The most frequent targets (epidermal growth factor receptor, human epidermal growth factor receptor-2, CD20, vascular growth factor receptors) are discussed, and we profile mAbs targeting these antigens. We also note a trend toward targeting less well-validated antigens and exploration of innovative approaches, such as use of indirect mechanisms of action or recruitment of T cells.

Within the context of the characterization of epitopes recognized by mAbs, Nicola Clementi, Nicasio Mancini, Mattea Castelli, Massimo Clementi and Roberto Burioni discuss experimental approaches that incorporate freely accessible bioinformatic tools. They note that detailed knowledge of mAb/antigen interactions is fundamental for vaccine development, and that, although co-crystal structures would supply the most information, these are not often available. Three surrogate approaches (peptide mapping, alanine scanning, amide hydrogen/deuterium exchange mass spectrometry) that apply bioinformatics to experimental data and one approach (docking predictions) based only on computational analysis are reviewed. The authors acknowledge the valuable contribution of bioinformatics approaches, but emphasize that computational analysis is not sufficient and must be supplemented with experimental data from the mAb/antigen pair of interest.

The informative reviews provided with this newsletter offer insights into some of the many uses of antibodies, and I am sure these will benefit Drug Discovery Today readers.

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