CD32B, the human inhibitory Fc-gamma receptor IIB, as a target for monoclonal antibody therapy of B-cell lymphoma.

Human CD32B (FcgammaRIIB), the low-affinity inhibitory receptor for IgG, is the predominant Fc receptor (FcR) present on B cells. Immunohistochemical and expression studies have identified CD32B expression in a variety of B-cell malignancies, suggesting that CD32B is a potential immunotherapeutic target for B-cell malignancies. A high-affinity monoclonal antibody (mAb 2B6), from a novel panel of anti-human CD32B-specific mAbs, was chimerized (ch2B6) and humanized (hu2B6-3.5). Both ch2B6 and hu2B6-3.5 were capable of directing cytotoxicity by peripheral blood mononuclear cells and monocyte-derived macrophages against B-lymphoma lines in vitro. In a human B-cell lymphoma mouse xenograft model, administration of ch2B6 or hu2B6-3.5 reduced tumor growth rate and improved tumor-free survival. Both the in vitro and in vivo activities of 2B6 required an intact Fc, suggesting an FcR-mediated mechanism of action. These data support the hypothesis that CD32B is a viable target for mAb treatment of B-cell lymphoproliferative disorders.

[1]  J. Ravetch,et al.  Activating and inhibitory IgG Fc receptors on human DCs mediate opposing functions. , 2005, The Journal of clinical investigation.

[2]  Chris Doane,et al.  Development of a humanized monoclonal antibody with therapeutic potential against West Nile virus , 2005, Nature Medicine.

[3]  R. Steinman,et al.  Selective blockade of inhibitory Fcgamma receptor enables human dendritic cell maturation with IL-12p70 production and immunity to antibody-coated tumor cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[4]  A. Jemal,et al.  Cancer Statistics, 2005 , 2005, CA: a cancer journal for clinicians.

[5]  G. Fey,et al.  Chimeric CD19 antibody mediates cytotoxic activity against leukemic blasts with effector cells from pediatric patients who received T-cell-depleted allografts. , 2004, Blood.

[6]  M. Cragg,et al.  Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents. , 2004, Blood.

[7]  T. Molina,et al.  FcγRIIB is differentially expressed during B cell maturation and in B‐cell lymphomas , 2004 .

[8]  T. Molina,et al.  FcgammaRIIB is differentially expressed during B cell maturation and in B-cell lymphomas. , 2004, British journal of haematology.

[9]  M. Reiser,et al.  Rituximab monotherapy is effective in patients with poor risk refractory aggressive non-Hodgkin's lymphoma. , 2004, Haematologica.

[10]  V. Diehl,et al.  The human anti-CD30 antibody 5F11 shows in vitro and in vivo activity against malignant lymphoma. , 2003, Blood.

[11]  Mitchell R. Smith.  Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance , 2003, Oncogene.

[12]  C. Sautès-Fridman,et al.  Modulation of tumor growth by inhibitory Fcγ receptor expressed by human melanoma cells , 2002 .

[13]  T. Takai.  Roles of Fc receptors in autoimmunity , 2002, Nature Reviews Immunology.

[14]  C. Sautès-Fridman,et al.  Modulation of tumor growth by inhibitory Fc(gamma) receptor expressed by human melanoma cells. , 2002, The Journal of clinical investigation.

[15]  J. Baars,et al.  Complement activation plays a key role in the side‐effects of rituximab treatment , 2001, British journal of haematology.

[16]  A. Zelenetz,et al.  Deregulation of FCGR2B expression by 1q21 rearrangements in follicular lymphomas , 2001, Oncogene.

[17]  J. V. Ravetch,et al.  IgG Fc receptors. , 2001, Annual review of immunology.

[18]  H Zola,et al.  CD32 (Fc gammaRII). , 2000, Journal of biological regulators and homeostatic agents.

[19]  L. Presta,et al.  Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets , 2000, Nature Medicine.

[20]  M. Dyer,et al.  The IgG Fc receptor, FcgammaRIIB, is a target for deregulation by chromosomal translocation in malignant lymphoma. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[21]  V. Diehl,et al.  Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. , 1998, Blood.

[22]  D. Weisenburger,et al.  New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  R. Levy,et al.  Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  A. Houghton,et al.  Fc receptors are required in passive and active immunity to melanoma. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[25]  W. Fridman,et al.  The murine Fc‐gamma (Fcγ) receptor type II B1 is a tumorigenicity‐enhancing factor in polyoma‐virus‐transformed 3T3 cells , 1996, International journal of cancer.

[26]  M. Nussenzweig,et al.  A 13-amino-acid motif in the cytoplasmic domain of FcγRIIB modulates B-cell receptor signalling , 1994, Nature.

[27]  M. Nussenzweig,et al.  A 13-amino-acid motif in the cytoplasmic domain of FcγRIIB modulates B-cell receptor signalling , 1994, Nature.

[28]  L. Picker,et al.  Anti-CD19 inhibits the growth of human B-cell tumor lines in vitro and of Daudi cells in SCID mice by inducing cell cycle arrest. , 1994, Blood.

[29]  M. Hulett,et al.  Mapping epitopes of human Fc gamma RII (CDw32) with monoclonal antibodies and recombinant receptors. , 1993, Journal of immunology.

[30]  W. Fridman,et al.  Cytoplasmic domain heterogeneity and functions of IgG Fc receptors in B lymphocytes. , 1992, Science.

[31]  E. Kabat,et al.  Sequences of proteins of immunological interest , 1991 .

[32]  R. Connor,et al.  Evaluation of the antibody-dependent cytotoxic capabilities of individual human monocytes. Role of Fc gamma RI and Fc gamma RII and the effects of cytokines at the single cell level. , 1990, Journal of immunology.

[33]  S L Morrison,et al.  Studies of aglycosylated chimeric mouse-human IgG. Role of carbohydrate in the structure and effector functions mediated by the human IgG constant region. , 1989, Journal of immunology.

[34]  J. Ravetch,et al.  Structure and expression of human IgG FcRII(CD32). Functional heterogeneity is encoded by the alternatively spliced products of multiple genes , 1989, The Journal of experimental medicine.

[35]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[36]  C. Anderson,et al.  Human monocytes and U937 cells bear two distinct Fc receptors for IgG. , 1986, Journal of immunology.

[37]  S L Morrison,et al.  Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[38]  P. Frost,et al.  An isotope release cytotoxicity assay applicable to human tumors: the use of 111indium. , 1977, Oncology.

[39]  N. Mantel.  Evaluation of survival data and two new rank order statistics arising in its consideration. , 1966, Cancer chemotherapy reports.

[40]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .