Monocytes mediate shaving of B-cell-bound anti-CD20 antibodies
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Monocytes mediate shaving of B-cell-bound anti-CD20 antibodies. / Pedersen, Anders Elm; Jungersen, Mette B; Pedersen, Charlotte D.
I: Immunology, Bind 133, Nr. 2, 2011, s. 239-45.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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
Y1 - 2011
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
VL - 133
SP - 239
EP - 245
JO - Immunology
JF - Immunology
SN - 0019-2805
IS - 2
ER -
ID: 34074017