![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Vol. 286, Issue 1, 548-554, July 1998
Department of Medicine, UCLA School of Medicine, Los Angeles,
California
For monoclonal antibody therapeutics to access target antigen in
extravascular compartments, an antibody drug delivery technology is
required that has the dual properties of 1)
trans-endothelial migration of the antibody and 2)
endocytosis of the antibody into the target cell. These two objectives
may be achieved with antibody cationization, and the present studies
examine the feasibility of cationizing the humanized 4D5 monoclonal
antibody directed against the p185HER2 oncogenic protein.
The cationized antibody binds to the p185HER2 extracellular
domain with an ED50 of 35 µg/ml and inhibits SK-BR3 cell
proliferation similar to the native antibody. Confocal microscopy showed that although there was binding of the native 4D5 antibody to
the plasma membrane of SK-BR3 cells, this antibody was confined to the
periplasma membrane space with minimal endocytosis into the cell. In
contrast, robust internalization of the cationized 4D5 antibody by the
SK-BR3 cells was demonstrated by confocal microscopy. The systemic
volume of distribution of the cationized 4D5 antibody was 11-fold
greater than that of the native antibody. In summary, these studies
show that a humanized monoclonal antibody may be cationized with
retention of antibody affinity for the target antigen and biological
activity, yet with a marked alteration in the cellular distribution and
pharmacokinetics in vivo.
This article has been cited by other articles:
|
|
 |
|
  D. L. Costantini, C. Chan, Z. Cai, K. A. Vallis, and R. M. Reilly 111In-Labeled Trastuzumab (Herceptin) Modified with Nuclear Localization Sequences (NLS): An Auger Electron-Emitting Radiotherapeutic Agent for HER2/neu-Amplified Breast Cancer J. Nucl. Med., August 1, 2007; 48(8): 1357 - 1368. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Mandler, H. Kobayashi, E. R. Hinson, M. W. Brechbiel, and T. A. Waldmann Herceptin-Geldanamycin Immunoconjugates: Pharmacokinetics, Biodistribution, and Enhanced Antitumor Activity Cancer Res., February 15, 2004; 64(4): 1460 - 1467. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Mandler, C. Wu, E. A. Sausville, A. J. Roettinger, D. J. Newman, D. K. Ho, C. R. King, D. Yang, M. E. Lippman, N. F. Landolfi, et al. Immunoconjugates of Geldanamycin and Anti-HER2 Monoclonal Antibodies: Antiproliferative Activity on Human Breast Carcinoma Cell Lines J Natl Cancer Inst, October 4, 2000; 92(19): 1573 - 1581. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. X. Deng, E. Hanson, and I. Sanz In vivo cell penetration and intracellular transport of anti-Sm and anti-La autoantibodies Int. Immunol., April 1, 2000; 12(4): 415 - 423. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Onda, R. J. Kreitman, G. Vasmatzis, B. Lee, and I. Pastan Reduction of the Nonspecific Animal Toxicity of Anti-Tac(Fv)-PE38 by Mutations in the Framework Regions of the Fv Which Lower the Isoelectric Point J. Immunol., December 1, 1999; 163(11): 6072 - 6077. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
