title: Cloning of the first human anti-JCPyV/VP1 neutralizing monoclonal antibody: epitope definition and implications in risk stratification of patients under natalizumab therapy.
abstract: JC virus (JCPyV) has gained novel clinical importance as cause of progressive multifocal leukoencephalopathy (PML), a rare demyelinating disease recently associated to immunomodulatory drugs, such as natalizumab used in multiple sclerosis (MS) cases. Little is known about the mechanisms leading to PML, and this makes the need of PML risk stratification among natalizumab-treated patients very compelling. Clinical and laboratory-based risk-stratification markers have been proposed, one of these is represented by the JCPyV-seropositive status, which includes about 54% of MS patients. We recently proposed to investigate the possible protective role of neutralizing humoral immune response in preventing JCPyV reactivation. In this proof-of-concept study, by cloning the first human monoclonal antibody (GRE1) directed against a neutralizing epitope on JCPyV/VP1, we optimized a robust anti-JCPyV neutralization assay. This allowed us to evaluate the neutralizing activity in JCPyV-positive sera from MS patients, demonstrating the lack of correlation between the level of anti-JCPyV antibody and anti-JCPyV neutralizing activity. Relevant consequences may derive from future clinical studies induced by these findings; indeed the study of the serum anti-JCPyV neutralizing activity could allow not only a better risk stratification of the patients during natalizumab treatment, but also a better understanding of the pathophysiological mechanisms leading to PML, highlighting the contribution of peripheral versus central nervous system JCPyV reactivation. Noteworthy, the availability of GRE1 could allow the design of novel immunoprophylactic strategies during the immunomodulatory treatment.
authors.affiliation: Laboratorio di Microbiologia e Virologia, Università "Vita-Salute" San Raffaele, Milan, Italy.
authors.forename: Roberta Antonia
authors.initials: RA
authors.lastname: Diotti
authors.affiliation: Laboratorio di Microbiologia e Virologia, Università "Vita-Salute" San Raffaele, Milan, Italy. Electronic address: mancini.nicasio@hsr.it.
authors.forename: Nicasio
authors.initials: N
authors.lastname: Mancini
authors.affiliation: Laboratorio di Microbiologia e Virologia, Università "Vita-Salute" San Raffaele, Milan, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Clementi
authors.affiliation: Laboratorio di Microbiologia e Virologia, Università "Vita-Salute" San Raffaele, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sautto
authors.affiliation: Laboratorio di Microbiologia e Virologia, Università "Vita-Salute" San Raffaele, Milan, Italy.
authors.forename: Guisella Janett
authors.initials: GJ
authors.lastname: Moreno
authors.affiliation: Laboratorio di Microbiologia e Virologia, Università "Vita-Salute" San Raffaele, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Criscuolo
authors.affiliation: Laboratorio di Microbiologia e Virologia, Università "Vita-Salute" San Raffaele, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cappelletti
authors.affiliation: Institute of Microbiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic; Department of Biochemistry, Faculty of Sciences, Charles University, Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Man
authors.affiliation: Institut de Biologie Structurale, CEA, CNRS, UJF, Grenoble, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Forest
authors.affiliation: Institut de Biologie Structurale, CEA, CNRS, UJF, Grenoble, France.
authors.forename: Louise
authors.initials: L
authors.lastname: Remy
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Giannecchini
authors.affiliation: Laboratorio di Microbiologia e Virologia, Università "Vita-Salute" San Raffaele, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Clementi
authors.affiliation: Laboratorio di Microbiologia e Virologia, Università "Vita-Salute" San Raffaele, Milan, Italy. Electronic address: burioni.roberto@hsr.it.
authors.forename: Roberto
authors.initials: R
authors.lastname: Burioni
mesh_terms: D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D057134:Antibodies, Neutralizing / Q000235:genetics / Q000276:immunology*; D000914:Antibodies, Viral / Q000235:genetics / Q000276:immunology*; D036022:Capsid Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D003001:Cloning, Molecular; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D006801:Humans; D007968:Leukoencephalopathy, Progressive Multifocal / Q000276:immunology / Q000517:prevention & control*; D009103:Multiple Sclerosis / Q000628:therapy; D000069442:Natalizumab; D009500:Neutralization Tests / Q000379:methods; D011120:Polyomavirus / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D036022:Capsid Proteins; D000939:Epitopes; D000069442:Natalizumab; C062481:VP1 protein, polyomavirus
keywords: JCPyV; Monoclonal antibody; Multiple sclerosis; Natalizumab; Neutralizing activity; Progressive multifocal leukoencephalopathy (PML)