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Open Access Research article

The anti-CD74 humanized monoclonal antibody, milatuzumab, which targets the invariant chain of MHC II complexes, alters B-cell proliferation, migration, and adhesion molecule expression

Daniela Frölich12, Daniela Blaβfeld12, Karin Reiter12, Claudia Giesecke12, Capucine Daridon12, Henrik E Mei12, Gerd R Burmester12, David M Goldenberg3, Abdulagabar Salama4 and Thomas Dörner12*

Author Affiliations

1 CC12 Department of Medicine, Rheumatology and Clinical Immunology, Charité - University Medicine Berlin, Chariteplatz 1, Berlin 10117, Germany

2 Deutsches Rheumaforschungszentrum (DRFZ), Charité - University Medicine Berlin, Chariteplatz 1, Berlin 10117, Germany

3 Immunomedics, Inc., and Center for Molecular Medicine and Immunology, 300 The American Road, Morris Plains, NJ 07950, USA

4 CC14 Institute of Transfusion Medicine, Charité - University Medicine Berlin, Chariteplatz 1, Berlin 10117, Germany

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Arthritis Research & Therapy 2012, 14:R54  doi:10.1186/ar3767

Published: 9 March 2012

Abstract

Introduction

Targeting CD74 as the invariant chain of major histocompatibility complexes (MHC) became possible by the availability of a specific humanized monoclonal antibody, milatuzumab, which is under investigation in patients with hematological neoplasms. CD74 has been reported to regulate chemo-attractant migration of macrophages and dendritic cells, while the role of CD74 on peripheral naïve and memory B cells also expressing CD74 remains unknown. Therefore, the current study addressed the influence of milatuzumab on B-cell proliferation, chemo-attractant migration, and adhesion molecule expression.

Methods

Surface expression of CD74 on CD27- naïve and CD27+ memory B cells as well as other peripheral blood mononuclear cells (PBMCs) obtained from normals, including the co-expression of CD44, CXCR4, and the adhesion molecules CD62L, β7-integrin, β1-integrin and CD9 were studied after binding of milatuzumab using multicolor flow cytometry. The influence of the antibody on B-cell proliferation and migration was analyzed in vitro in detail.

Results

In addition to monocytes, milatuzumab also specifically bound to human peripheral B cells, with a higher intensity on CD27+ memory versus CD27- naïve B cells. The antibody reduced B-cell proliferation significantly but moderately, induced enhanced spontaneous and CXCL12-dependent migration together with changes in the expression of adhesion molecules, CD44, β7-integrin and CD62L, mainly of CD27- naïve B cells. This was independent of macrophage migration-inhibitory factor as a ligand of CD74/CD44 complexes.

Conclusions

Milatuzumab leads to modestly reduced proliferation, alterations in migration, and adhesion molecule expression preferentially of CD27- naïve B cells. It thus may be a candidate antibody for the autoimmune disease therapy by modifying B cell functions.