title: Monocytes mediate shaving of B-cell-bound anti-CD20 antibodies.
abstract: Anti-CD20 monoclonal antibodies are promising for the treatment of B-cell malignancies such as chronic lymphocytic leukaemia and autoimmune diseases where auto-antibodies play an important role. Anti-CD20 such as rituximab (RTX) mediates B-cell depletion through mechanisms such as complement-mediated cytotoxicity and antibody-dependent cellular cytotoxicity. However, in haematological malignancies, such effector mechanisms can be saturated and result in release of malignant B cells with reduced levels of CD20. It has been hypothesized that this is the result of monocyte-mediated shaving of the CD20/RTX complex from the B-cell surface. Here, we confirm, that in vitro co-culture of human monocytes and RTX-labelled syngeneic B cells results in reduced expression of CD20/RTX complex on the B cell surface. This shaving mechanism was the result of active protease activity because EDTA and PMSF were able to mediate partial inhibition. Also, a series of alternative anti-CD20 antibodies representing both type I and type II antibodies were tested for their ability to induce the shaving reaction. These results demonstrate that a monocyte-mediated shaving reaction can lead to complete loss of most anti-CD20 antibodies from the surface of B cells even from healthy donors and this is an important obstacle for antibody-mediated immune therapy. The findings demonstrate the necessity of developing novel antibodies that maintain high effector functions without enabling activation of the shaving reaction.
authors.affiliation: Department of International Health, Immunology and Microbiology, The Panum Institute, University of Copenhagen, Denmark.
authors.forename: Anders E
authors.initials: AE
authors.lastname: Pedersen
authors.forename: Mette B
authors.initials: MB
authors.lastname: Jungersen
authors.forename: Charlotte D
authors.initials: CD
authors.lastname: Pedersen
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity; D018951:Antigens, CD20 / Q000276:immunology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001402:B-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D005434:Flow Cytometry; D019337:Hematologic Neoplasms / Q000276:immunology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D010447:Peptide Hydrolases / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D000069283:Rituximab
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D000069283:Rituximab; D010447:Peptide Hydrolases