Antibody-Recruiting Molecules: An Emerging Paradigm for Engaging Immune Function in Treating Human Disease

Abstract

Synthetic Immunology, the development of synthetic systems capable of modulating and/or manipulating immunological functions, represents an emerging field of research with manifold possibilities. One focus of this area has been to create low molecular-weight synthetic species, called antibody-recruiting molecules (ARMs), which are capable of enhancing antibody binding to disease-relevant cells or viruses, thus leading to their immune-mediated clearance. This article provides a thorough discussion of contributions in this area, beginning with the history of small-molecule-based technologies for modulating antibody recognition, followed by a systematic review of the various applications of ARM-based strategies. Thus, we describe ARMs capable of targeting cancer, bacteria, and viral pathogens, along with some of the scientific discoveries that have resulted from their development. Research in this area underscores the many exciting possibilities at the interface of organic chemistry and immunobiology, and is positioned to advance both basic and clinical science in the years to come.

Controlling the Origins of Inflammation with a Photoactive Lipopeptide Immunopotentiator

“…[5] These methods have been used to discover logic gates and signaling networks that control immune responses [6] resulting in the development of increasingly sophisticated immunotherapies. [7,8] However, removal of critical signaling molecules during post-priming washing steps and disruption of cell-cell contacts often hinder analysis and obscure signals reliant on precise temporal or cell-specific inputs. For instance, cell priming times range from 3-18 h, [9,10] however, early proinflammatory cytokine transcription begins in as little as 15 min, [11,12] implying that the initial portion of Correspondence to: Aaron P. Esser-Kahn, aesserka@uci.edu.…”

A call to ARMs: the promise of immunomodulatory small molecules

“…For example antibody-recruiting molecules are bifunctional (i.e., 'two-headed') agents designed such that one terminus interacts with disease-relevant biomolecular targets, while the other interacts with the Fab domain of antibody proteins. ARMs have been designed for delivery as preformed complexes with antibodies, or to hijack antibodies found innately in the human bloodstream [14]. Both such ARM subclasses represent exciting biomedical advances with significant therapeutic potential.…”

“…Another obstacle is that the extent of variability in the levels, isotype distributions and recognition properties of endogenous antibodies is not comprehensively understood. Although available data are encouraging, and indicate that antihapten antibodies (e.g., antidinitrophenyl, anti-Gal and others) are highly prevalent among humans, future studies will be necessary to illuminate this issue [14,20]. Such data, considered in light of similarities in vaccination patterns, and/or dietary and environmental antigen exposures, are likely to provide useful insights and starting points for the development of broadly applicable antibody-binding motifs.…”

Diversification post-traductionnelle de la spécificité des immunoglobulines

“…La liaison de cofacteurs aux Ig est un phénomène qui avait été décrit par le passé. Il était en effet connu depuis longtemps que le répertoire des immunoglobulines d'un individu sain contient des anticorps ayant la capacité de se lier, avec une forte affinité, à de nombreuses molécules hétérocycliques et aromatiques de bas poids moléculaire, ainsi qu'à des ions métalliques [6,7]. Ainsi avait-t-il été montré qu'une proportion considérable d'anticorps circulants chez les individus sains est capable de lier différents cofacteurs biologiques, tels que la riboflavine et ses dérivés, mais aussi certaines molé-cules xénobiotiques comme le 2,4-dinitrophénol.…”