Antibody mimicry, receptors and clinical applications

Issue title: This issue is dedicated to George Klein, 1925-2016, a giant creative and stimulating scientist of infinite knowledge, friend and mentor

Guest editors: Michael Steinitz

Article type: Research Article

Authors: Horenstein, Alberto L.^{a; b; *} | Chillemi, Antonella^{a; b} | Quarona, Valeria^{a; b} | Zito, Andrea^{a; b} | Mariani, Valentina^{a; b} | Faini, Angelo C.^{a; b} | Morandi, Fabio^c | Schiavoni, Ilaria^d | Ausiello, Clara Maria^d | Malavasi, Fabio^{a; b; e}

Affiliations: [a] Laboratory of Immunogenetics, Department of Medical Sciences, University of Torino, Torino 10126, Italy | [b] CeRMS, University of Torino, Torino 10126, Italy | [c] Laboratory of Oncology, Istituto Giannina Gaslini, Genova 16148, Italy | [d] Department of Infectious, Parasitic, and Immune-Mediated Diseases, Istituto Superiore di Sanità, Roma 00161, Italy | [e] Transplantation Immunology, Città della Salute e della Scienza, Torino 10126, Italy

Correspondence: [*] Corresponding author: Alberto L. Horenstein, Laboratory of Immunogenetics, Department of Medical Sciences, University of Torino, Torino 10126, Italy. E-mail:[email protected]

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 proof-of-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.

Keywords: Monoclonal antibodies, agonistic, antagonistic, allosteric, biespecific, anti-CD38 antibodies

DOI: 10.3233/HAB-160305

Journal: Human Antibodies, vol. 25, no. 3-4, pp. 75-85, 2017