| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Department of Biochemistry and Molecular Genetics and
Division of Hematology/Oncology and Hematologic Malignancy Program, University of Virginia School of Medicine, Charlottesville, VA 22908
Clinical investigations have revealed that infusion of immunotherapeutic mAbs directed to normal or tumor cells can lead to loss of targeted epitopes, a phenomenon called antigenic modulation. Recently, we reported that rituximab treatment of chronic lymphocytic leukemia patients induced substantial loss of CD20 on B cells found in the circulation after rituximab infusion, when rituximab plasma concentrations were high. Such antigenic modulation can severely compromise therapeutic efficacy, and we postulated that B cells had been stripped (shaved) of the rituximab/CD20 complex by monocytes or macrophages in a reaction mediated by Fc
R. We developed an in vitro model to replicate this in vivo shaving process, based on reacting rituximab-opsonized CD20+ cells with acceptor THP-1 monocytes. After 45 min at 37°C, rituximab and CD20 are removed from opsonized cells, and both are demonstrable on acceptor THP-1 cells. The reaction occurs equally well in the presence and absence of normal human serum, and monocytes isolated from peripheral blood also promote shaving of CD20 from rituximab-opsonized cells. Tests with inhibitors and use of F(ab')2 of rituximab indicate transfer of rituximab/CD20 complexes to THP-1 cells is mediated by FcR. Antigenic modulation described in previous reports may have been mediated by such shaving, and our findings may have profound implications for the use of mAbs in the immunotherapy of cancer.
This article has been cited by other articles:
|
|
 |
|
  A. W. Pawluczkowycz, F. J. Beurskens, P. V. Beum, M. A. Lindorfer, J. G. J. van de Winkel, P. W. H. I. Parren, and R. P. Taylor Binding of Submaximal C1q Promotes Complement-Dependent Cytotoxicity (CDC) of B Cells Opsonized with Anti-CD20 mAbs Ofatumumab (OFA) or Rituximab (RTX): Considerably Higher Levels of CDC Are Induced by OFA than by RTX J. Immunol., July 1, 2009; 183(1): 749 - 758. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. V. Beum, D. A. Mack, A. W. Pawluczkowycz, M. A. Lindorfer, and R. P. Taylor Binding of Rituximab, Trastuzumab, Cetuximab, or mAb T101 to Cancer Cells Promotes Trogocytosis Mediated by THP-1 Cells and Monocytes J. Immunol., December 1, 2008; 181(11): 8120 - 8132. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Mankai, A. Bordron, Y. Renaudineau, C. Martins-Carvalho, S. Takahashi, I. Ghedira, C. Berthou, and P. Youinou Purine-Rich Box-1-Mediated Reduced Expression of CD20 Alters Rituximab-Induced Lysis of Chronic Lymphocytic Leukemia B Cells Cancer Res., September 15, 2008; 68(18): 7512 - 7519. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Zhou, W. Hu, and X. Qin The Role of Complement in the Mechanism of Action of Rituximab for B-Cell Lymphoma: Implications for Therapy Oncologist, September 1, 2008; 13(9): 954 - 966. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. V. Beum, M. A. Lindorfer, and R. P. Taylor Within Peripheral Blood Mononuclear Cells, Antibody-Dependent Cellular Cytotoxicity of Rituximab-Opsonized Daudi cells Is Promoted by NK Cells and Inhibited by Monocytes due to Shaving J. Immunol., August 15, 2008; 181(4): 2916 - 2924. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. V. Beum, M. A. Lindorfer, F. Beurskens, P. T. Stukenberg, H. M. Lokhorst, A. W. Pawluczkowycz, P. W. H. I. Parren, J. G. J. van de Winkel, and R. P. Taylor Complement Activation on B Lymphocytes Opsonized with Rituximab or Ofatumumab Produces Substantial Changes in Membrane Structure Preceding Cell Lysis J. Immunol., July 1, 2008; 181(1): 822 - 832. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Aucher, E. Magdeleine, E. Joly, and D. Hudrisier Capture of plasma membrane fragments from target cells by trogocytosis requires signaling in T cells but not in B cells Blood, June 15, 2008; 111(12): 5621 - 5628. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Li, M. E. Williams, J. B. Cousar, A. W. Pawluczkowycz, M. A. Lindorfer, and R. P. Taylor Rituximab-CD20 Complexes Are Shaved from Z138 Mantle Cell Lymphoma Cells in Intravenous and Subcutaneous SCID Mouse Models J. Immunol., September 15, 2007; 179(6): 4263 - 4271. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Zimring, C. M. Cadwell, T. E. Chadwick, S. L. Spitalnik, D. A. Schirmer, T. Wu, C. A. Parkos, and C. D. Hillyer Nonhemolytic antigen loss from red blood cells requires cooperative binding of multiple antibodies recognizing different epitopes Blood, September 15, 2007; 110(6): 2201 - 2208. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Withers, C. Fiorini, R. T. Fischer, R. Ettinger, P. E. Lipsky, and A. C. Grammer T cell dependent survival of CD20+ and CD20 plasma cells in human secondary lymphoid tissue Blood, June 1, 2007; 109(11): 4856 - 4864. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. D. Khan, C. Emmanouilides, D. M. Benson Jr., D. Hurst, P. Garcia, G. Michelson, S. Milan, A. K. Ferketich, L. Piro, J. P. Leonard, et al. A Phase 2 Study of Rituximab in Combination with Recombinant Interleukin-2 for Rituximab-Refractory Indolent Non-Hodgkin's Lymphoma Clin. Cancer Res., December 1, 2006; 12(23): 7046 - 7053. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Williams, J. J. Densmore, A. W. Pawluczkowycz, P. V. Beum, A. D. Kennedy, M. A. Lindorfer, S. H. Hamil, J. C. Eggleton, and R. P. Taylor Thrice-Weekly Low-Dose Rituximab Decreases CD20 Loss via Shaving and Promotes Enhanced Targeting in Chronic Lymphocytic Leukemia J. Immunol., November 15, 2006; 177(10): 7435 - 7443. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Teeling, W. J. M. Mackus, L. J. J. M. Wiegman, J. H. N. van den Brakel, S. A. Beers, R. R. French, T. van Meerten, S. Ebeling, T. Vink, J. W. Slootstra, et al. The Biological Activity of Human CD20 Monoclonal Antibodies Is Linked to Unique Epitopes on CD20 J. Immunol., July 1, 2006; 177(1): 362 - 371. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
