Monocytes mediate shaving of B-cell-bound anti-CD20 antibodies

TY - JOUR

T1 - Monocytes mediate shaving of B-cell-bound anti-CD20 antibodies

AU - Pedersen, Anders Elm

AU - Jungersen, Mette B

AU - Pedersen, Charlotte D

N1 - © 2011 The Authors. Immunology © 2011 Blackwell Publishing Ltd.

PY - 2011/6

Y1 - 2011/6

N2 - 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.

AB - 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.

KW - Antibodies, Monoclonal

KW - Antibodies, Monoclonal, Murine-Derived

KW - Antibody-Dependent Cell Cytotoxicity

KW - Antigens, CD20

KW - Antineoplastic Agents

KW - B-Lymphocytes

KW - Cells, Cultured

KW - Flow Cytometry

KW - Hematologic Neoplasms

KW - Humans

KW - Leukocytes, Mononuclear

KW - Peptide Hydrolases

KW - Protein Binding

U2 - 10.1111/j.1365-2567.2011.03434.x

DO - 10.1111/j.1365-2567.2011.03434.x

M3 - Journal article

C2 - 21426340

SN - 0019-2805

VL - 133

SP - 239

EP - 245

JO - Immunology

JF - Immunology

IS - 2

ER -