title: Antibody mimicry, receptors and clinical applications.
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.
authors.affiliation: Laboratory of Immunogenetics, Department of Medical Sciences, University of Torino, Torino 10126, Italy.|CeRMS, University of Torino, Torino 10126, Italy.
authors.forename: Alberto L
authors.initials: AL
authors.lastname: Horenstein
authors.affiliation: Laboratory of Immunogenetics, Department of Medical Sciences, University of Torino, Torino 10126, Italy.|CeRMS, University of Torino, Torino 10126, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Chillemi
authors.affiliation: Laboratory of Immunogenetics, Department of Medical Sciences, University of Torino, Torino 10126, Italy.|CeRMS, University of Torino, Torino 10126, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Quarona
authors.affiliation: Laboratory of Immunogenetics, Department of Medical Sciences, University of Torino, Torino 10126, Italy.|CeRMS, University of Torino, Torino 10126, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Zito
authors.affiliation: Laboratory of Immunogenetics, Department of Medical Sciences, University of Torino, Torino 10126, Italy.|CeRMS, University of Torino, Torino 10126, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Mariani
authors.affiliation: Laboratory of Immunogenetics, Department of Medical Sciences, University of Torino, Torino 10126, Italy.|CeRMS, University of Torino, Torino 10126, Italy.
authors.forename: Angelo C
authors.initials: AC
authors.lastname: Faini
authors.affiliation: Laboratory of Oncology, Istituto Giannina Gaslini, Genova 16148, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Morandi
authors.affiliation: Department of Infectious, Parasitic, and Immune-Mediated Diseases, Istituto Superiore di Sanità, Roma 00161, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Schiavoni
authors.affiliation: Department of Infectious, Parasitic, and Immune-Mediated Diseases, Istituto Superiore di Sanità, Roma 00161, Italy.
authors.forename: Clara Maria
authors.initials: CM
authors.lastname: Ausiello
authors.affiliation: Laboratory of Immunogenetics, Department of Medical Sciences, University of Torino, Torino 10126, Italy.|CeRMS, University of Torino, Torino 10126, Italy.|Transplantation Immunology, Città della Salute e della Scienza, Torino 10126, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Malavasi
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics / Q000276:immunology; D000494:Allosteric Regulation; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D000918:Antibody Specificity; D036563:Cyclic ADP-Ribose / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D007155:Immunologic Factors / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D008024:Ligands; D018716:Molecular Mimicry / Q000276:immunology*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D011485:Protein Binding; D020239:Receptor Cross-Talk / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D007141:Immunoglobulin Fc Fragments; D007155:Immunologic Factors; D008024:Ligands; D011948:Receptors, Antigen, T-Cell; D036563:Cyclic ADP-Ribose; D051997:ADP-ribosyl Cyclase 1
keywords: Monoclonal antibodies; agonistic; allosteric; antagonistic; anti-CD38 antibodies; biespecific