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JNCI Journal of the National Cancer Institute 2000 92(19):1573-1581; doi:10.1093/jnci/92.19.1573
© 2000 by Oxford University Press
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Journal of the National Cancer Institute, Vol. 92, No. 19, 1573-1581, October 4, 2000
© 2000 Oxford University Press

Immunoconjugates of Geldanamycin and Anti-HER2 Monoclonal Antibodies: Antiproliferative Activity on Human Breast Carcinoma Cell Lines

Raya Mandler, Chuanchu Wu, Edward A. Sausville, Alexis J. Roettinger, David J. Newman, David K. Ho, C. Richter King, Dajun Yang, Marc E. Lippman, Nicholas F. Landolfi, Ekaterina Dadachova, Martin W. Brechbiel, Thomas A. Waldmann

Affiliations of authors: R. Mandler, A. J. Roettinger, T. A. Waldmann (Metabolism Branch, Division of Clinical Sciences), C. Wu, E. Dadachova, M. W. Brechbiel (Radioimmune and Inorganic Chemistry Section, Division of Clinical Sciences), E. A. Sausville (Developmental Therapeutics Program, Division of Cancer Treatment and Diagnostics), D. J. Newman (Natural Products Branch, Division of Cancer Treatment and Diagnostics), National Cancer Institute (NCI), Bethesda, MD; D. K. Ho, Science Applications International Corporation, NCI-Frederick Cancer Research and Development Center, Frederick, MD; C. R. King, D. Yang, M. E. Lippman, Lombardi Cancer Center, Georgetown University, Washington, DC; N. F. Landolfi, Protein Design Laboratories, Fremont, CA.

Correspondence to: Raya Mandler, Ph.D., National Institutes of Health, Bldg. 10, Rm. 4N115, 10 Center Dr., Bethesda, MD 20892 (e-mail: rayam{at}box-r.nih.gov).

Background: HER2 is a membrane receptor whose overexpression is strongly associated with poor prognosis in breast carcinomas. Inhibition of HER2 activity can reduce tumor growth, which led to the development of Herceptin, an anti-HER2 monoclonal antibody (MAb) that is already in clinical use. However, the objective response rate to Herceptin monotherapy is quite low. HER2 activity can also be inhibited by the highly cytotoxic antibiotic geldanamycin (GA). However, GA is not used clinically because of its adverse toxicity. Our purpose was to enhance the inhibitory activity of anti-HER2 MAb by coupling it to GA. Methods: We synthesized 17-(3-aminopropylamino)GA (17-APA-GA) and conjugated it to the anti-HER2 MAb e21, to form e21 : GA. The noninternalizing anti-HER2 MAb AE1 was used as a control. Internalization assays and western blot analyses were used to determine whether the anti-HER2 MAbs and their immunoconjugates were internalized into HER2-expressing cells and reduced HER2 levels. All statistical tests were two-sided. Results: The immunoconjugate e21 : GA inhibited the proliferation of HER2-overexpressing cell lines better than unconjugated e21 (concentration required for 50% inhibition = 40 versus 1650 µg/mL, respectively). At 15 µg/mL, e21 : GA reduced HER2 levels by 86% within 16 hours, whereas unconjugated e21, 17-APA-GA, or AE1 : GA reduced HER2 levels by only 20%. These effects were not caused by release of 17-APA-GA from the immunoconjugate because immunoconjugates containing [3H]GA were stable in serum at 37 °C. Furthermore, e21 : GA did not significantly inhibit proliferation of the adult T-cell leukemia cell line HuT102, which is HER2 negative yet highly sensitive to GA. Conclusions: Our findings suggest that conjugating GA to internalizing MAbs enhances the inhibitory effect of the MAbs. This approach might also be applied in cellular targeting via growth factors and may be of clinical interest.


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