| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics, Molecular Targets, and Chemical Biology |
1 Seattle Genetics, Inc., Bothell, Washington and 2 Department of Immunology, Genentech, Inc., South San Francisco, California
Requests for reprints: Che-Leung Law, Seattle Genetics, Inc., 21823 30th Drive Southeast, Bothell, WA 98021. Phone: 425-527-4612; Fax: 425-527-4609; E-mail: claw{at}seagen.com.
SGN-40 is a humanized IgG1 antihuman CD40 that is currently in a phase I clinical trial for the treatment of multiple myeloma. As surface CD40 expression on B-lineage cells is maintained from pro-B cells to plasma cells, SGN-40 may be applicable to treatment of other B-cell neoplasias, including non-Hodgkin's lymphoma. In this study, we examined potential in vitro and in vivo anti–B-lineage lymphoma activity of SGN-40. Recombinant SGN-40 was expressed and purified from Chinese hamster ovary cells and characterized based on binding affinity, specificity, and normal B-cell stimulation. The ability of SGN-40 to target neoplastic B cells was examined in vitro by proliferation inhibition, cytotoxicity, and antibody-dependent cell cytotoxicity assays and in vivo by human lymphoma xenograft models. Recombinant SGN-40 showed high affinity, Kd of 
1 nmol/L, and specific binding to CD40. Whereas SGN-40 was a weak agonist in stimulating normal B-cell proliferation in the absence of IL-4 and CD40L, it delivered potent proliferation inhibitory and apoptotic signals to, and mediated antibody-dependent cytotoxicity against, a panel of high-grade B-lymphoma lines. These in vitro antilymphoma effects were extended to disseminated and s.c. xenograft CD40 tumor models. In these xenograft models, the antitumor activity of SGN-40 was comparable with that of rituximab. The preclinical in vitro and in vivo antilymphoma activity of SGN-40 observed in this study provides a rationale for the clinical testing of SGN-40 in the treatment of CD40+ B-lineage lymphomas.
This article has been cited by other articles:
|
|
 |
|
  B. Varghese, A. Widman, J. Do, B. Taidi, D. K. Czerwinski, J. Timmerman, S. Levy, and R. Levy Generation of CD8+ T cell-mediated immunity against idiotype-negative lymphoma escapees Blood, November 12, 2009; 114(20): 4477 - 4485. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Advani, A. Forero-Torres, R. R. Furman, J. D. Rosenblatt, A. Younes, H. Ren, K. Harrop, N. Whiting, and J. G. Drachman Phase I Study of the Humanized Anti-CD40 Monoclonal Antibody Dacetuzumab in Refractory or Recurrent Non-Hodgkin's Lymphoma J. Clin. Oncol., September 10, 2009; 27(26): 4371 - 4377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q.-L. Wu, I. N. Buhtoiarov, P. M. Sondel, A. L. Rakhmilevich, and E. A. Ranheim Tumoricidal Effects of Activated Macrophages in a Mouse Model of Chronic Lymphocytic Leukemia J. Immunol., June 1, 2009; 182(11): 6771 - 6778. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-T. Tai, M. Dillon, W. Song, M. Leiba, X.-F. Li, P. Burger, A. I. Lee, K. Podar, T. Hideshima, A. G. Rice, et al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu Blood, August 15, 2008; 112(4): 1329 - 1337. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Puliaev, I. Puliaeva, L. A. Welniak, A. E. Ryan, M. Haas, W. J. Murphy, and C. S. Via CTL-Promoting Effects of CD40 Stimulation Outweigh B Cell-Stimulatory Effects Resulting in B Cell Elimination and Disease Improvement in a Murine Model of Lupus J. Immunol., July 1, 2008; 181(1): 47 - 61. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Martin, R. R. Furman, M. Coleman, and J. P. Leonard Phase I to III Trials of Anti B Cell Therapy in Non Hodgkin's Lymphoma Clin. Cancer Res., September 15, 2007; 13(18): 5636s - 5642s. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. H. Vonderheide Prospect of Targeting the CD40 Pathway for Cancer Therapy Clin. Cancer Res., February 15, 2007; 13(4): 1083 - 1088. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Hollmann, T. Owens, J. Nalbantoglu, T. J. Hudson, and R. Sladek Constitutive Activation of Extracellular Signal-Regulated Kinase Predisposes Diffuse Large B-Cell Lymphoma Cell Lines to CD40-Mediated Cell Death. Cancer Res., April 1, 2006; 66(7): 3550 - 3557. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Antilymphoma Activity of an Anti-CD40 Antibody Cancer Res., February 15, 2006; 66(4): 2495 - 2495. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
