Engineered humanized dimeric forms of IgG are more effective antibodies

doi:10.1084/jem.176.4.1191

This Article

Full Text (PDF, 523K)

Alert me when this article is cited

Citation Map

Services

Email this article

Similar articles in this journal

Similar articles in PubMed

Alert me to new content in the JEM

Download to citation manager

Citing Articles

Citing Articles via HighWire

Citing Articles via CrossRef

Citing Articles via Google Scholar

Google Scholar

Articles by Caron, P. C.

Articles by Scheinberg, D. A.

Search for Related Content

PubMed

PubMed Citation

Articles by Caron, P. C.

Articles by Scheinberg, D. A.

Pubmed/NCBI databases

Substance via MeSH

Social Bookmarking

What's this?

ARTICLES

Engineered humanized dimeric forms of IgG are more effective antibodies

PC Caron, W Laird, MS Co, NM Avdalovic, C Queen and DA Scheinberg
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.

Humanized IgG1 M195 (HuG1-M195), a complementarity determining region- grafted recombinant monoclonal antibody, is reactive with CD33, an antigen expressed on myelogenous leukemia cells. M195 is in use in trials for the therapy of acute myelogenous leukemia. Since biological activity of IgG may depend, in part, on multimeric Fab and Fc clustering, homodimeric forms of HuG1-M195 were constructed by introducing a mutation in the gamma 1 chain CH3 region gene to change a serine to a cysteine, allowing interchain disulfide bond formation at the COOH terminal of the IgG. Despite similar avidity, the homodimeric IgG showed a dramatic improvement in the ability to internalize and retain radioisotope in target leukemia cells. Moreover, homodimers were 100-fold more potent at complement-mediated leukemia cell killing and antibody-dependent cellular cytotoxicity using human effectors. Therefore, genetically engineered multimeric constructs of IgG may have advantages relative to those forms that are found naturally.
Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Add to Reddit Reddit Add to Technorati Technorati What's this?

This article has been cited by other articles:

Rossi, E. A., Goldenberg, D. M., Cardillo, T. M., Stein, R., Wang, Y., Chang, C.-H. (2008). Novel Designs of Multivalent Anti-CD20 Humanized Antibodies as Improved Lymphoma Therapeutics. Cancer Res. 68: 8384-8392 [Abstract] [Full Text]
McDonagh, C. F., Turcott, E., Westendorf, L., Webster, J. B., Alley, S. C., Kim, K., Andreyka, J., Stone, I., Hamblett, K. J., Francisco, J. A., Carter, P. (2006). Engineered antibody-drug conjugates with defined sites and stoichiometries of drug attachment. Protein Eng Des Sel 19: 299-307 [Abstract] [Full Text]
Niwa, R., Sakurada, M., Kobayashi, Y., Uehara, A., Matsushima, K., Ueda, R., Nakamura, K., Shitara, K. (2005). Enhanced Natural Killer Cell Binding and Activation by Low-Fucose IgG1 Antibody Results in Potent Antibody-Dependent Cellular Cytotoxicity Induction at Lower Antigen Density. Clin. Cancer Res. 11: 2327-2336 [Abstract] [Full Text]
Borchardt, P. E., Yuan, R. R., Miederer, M., McDevitt, M. R., Scheinberg, D. A. (2003). Targeted Actinium-225 in Vivo Generators for Therapy of Ovarian Cancer. Cancer Res. 63: 5084-5090 [Abstract] [Full Text]
Miller, K., Meng, G., Liu, J., Hurst, A., Hsei, V., Wong, W.-L., Ekert, R., Lawrence, D., Sherwood, S., DeForge, L., Gaudreault, J., Keller, G., Sliwkowski, M., Ashkenazi, A., Presta, L. (2003). Design, Construction, and In Vitro Analyses of Multivalent Antibodies. J. Immunol. 170: 4854-4861 [Abstract] [Full Text]
Nielsen, S. U., Routledge, E. G. (2002). Human T cells resistant to complement lysis by bivalent antibody can be efficiently lysed by dimers of monovalent antibody. Blood 100: 4067-4073 [Abstract] [Full Text]
Spiridon, C. I., Ghetie, M.-A., Uhr, J., Marches, R., Li, J.-L., Shen, G.-L., Vitetta, E. S. (2002). Targeting Multiple Her-2 Epitopes with Monoclonal Antibodies Results in Improved Antigrowth Activity of a Human Breast Cancer Cell Line in Vitro and in Vivo. Clin. Cancer Res. 8: 1720-1730 [Abstract] [Full Text]
Wiewrodt, R., Thomas, A. P., Cipelletti, L., Christofidou-Solomidou, M., Weitz, D. A., Feinstein, S. I., Schaffer, D., Albelda, S. M., Koval, M., Muzykantov, V. R. (2002). Size-dependent intracellular immunotargeting of therapeutic cargoes into endothelial cells. Blood 99: 912-922 [Abstract] [Full Text]
Ghetie, M.-A., Bright, H., Vitetta, E. S. (2001). Homodimers but not monomers of Rituxan (chimeric anti-CD20) induce apoptosis in human B-lymphoma cells and synergize with a chemotherapeutic agent and an immunotoxin. Blood 97: 1392-1398 [Abstract] [Full Text]
Ghetie, M.-A., Podar, E. M., Ilgen, A., Gordon, B. E., Uhr, J. W., Vitetta, E. S. (1997). Homodimerization of tumor-reactive monoclonal antibodies markedly increases their ability to induce growth arrest or apoptosis of tumor�cells. Proc. Natl. Acad. Sci. USA 94: 7509-7514 [Abstract] [Full Text]
Stimmel, J. B., Merrill, B. M., Kuyper, L. F., Moxham, C. P., Hutchins, J. T., Fling, M. E., Kull, F. C. Jr. (2000). Site-specific Conjugation on Serine right-arrow Cysteine Variant Monoclonal Antibodies. J. Biol. Chem. 275: 30445-30450 [Abstract] [Full Text]