Antibody mimicry, receptors and clinical applications

Alberto L. Horenstein, Antonella Chillemi, Valeria Quarona, Andrea Zito, Valentina Mariani, Angelo C. Faini, Fabio Morandi, Ilaria Schiavoni, Clara Maria Ausiello, Fabio Malavasi

Research output: Contribution to journalReview articlepeer-review

Abstract

This review focuses on the concept of antibodies acting as receptor agonists and antagonists, and on the potential relevance of this notion in applied medicine. Antibodies are composed of three functional units: Two antigen-binding fragments (Fabs) that confer antigen specificity and one constant fragment (Fc) linking antibodies to immune effector functions. The proofof-concept that large amounts of highly specific and homogeneous antibodies could be produced was provided in 1975 by César Milstein and Georges Köhler. These monoclonal antibody (mAb) reagents started a revolution in medical research, diagnostics, and clinical applications. Alongside diagnostic applications, mAbs were successfully used in vivo: (i) to bind (neutralize/antagonize) antigens expressed on the surface of tumor cells; (ii) to activate immune effector mechanisms; (iii) to crosslink plasma membrane receptors and hence activate therapeutic signaling pathways; and lastly, (iv) the technique was expanded to produce bispecific mAbs, which can bind two different antigens while retaining the ability to activate immune effector functions. The abilities of mAbs to bind, transduce signals, and exert immunostimulatory agonistic capacities are the central issues of this review. The starting point is that some mAbs operate as molecular agonists, substituting for the natural ligand of the receptor. Our analysis is restricted to mAbs that act as receptor agonist/antagonists by either mimicking ligand binding, or through allosteric modulation mediated by binding sites that are topographically distinct from the orthosteric binding site. Functional considerations based on the agonistic stimulation of human CD38 by specific mAbs as surrogate ligands are described as examples of the features of such molecules.

Original languageEnglish
Pages (from-to)75-85
Number of pages11
JournalHuman Antibodies
Volume25
Issue number3-4
DOIs
Publication statusPublished - Apr 24 2017

Keywords

  • Agonistic
  • Allosteric
  • Antagonistic
  • Anti-CD38 antibodies
  • Biespecific
  • Monoclonal antibodies

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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