Mandler R, Kobayashi H, Hinson ER, Brechbiel MW, Waldmann TA.
Herceptin- geldanamycin immunoconjugates: pharmacokinetics,
biodistribution, and enhanced antitumor activity.
Cancer Res. 2004 Feb 15;64(4):1460-7.
Metabolism Branch, Center for Cancer Research, National
Cancer Institute/NIH, 6701 Rockledge Drive, Room 5217, MSC 7840,
Bethesda, MD 20892, USA.
rayam@mail.nih.gov
The efficacy of monoclonal antibodies (mAbs) as single agents
in targeted cancer therapy has proven to be limited. Arming mAbs
with a potent toxic drug could enhance their activity. Here we
report that conjugating geldanamycin (GA) to the anti-HER2 mAb
Herceptin improved the activity of Herceptin. The IC(50)s of the
immunoconjugate H-GA were 10-200-fold lower than that of
Herceptin in antiproliferative assays, depending on the cell
line. The H-GA mode of action involved HER2 degradation, which
was partially lactacystin sensitive and thus proteasome
dependent. The linkage between GA and Herceptin remained stable
in the circulation, as suggested by the pharmacokinetics of
Herceptin and conjugated GA, which were almost identical and
significantly different from that of free GA. Tumor uptake of
Herceptin and H-GA were similar (52 +/- 7 and 43 +/- 7% of the
initial injected dose per gram tissue, respectively; P = 0.077),
indicating no apparent damage attributable to conjugation.
Therapy experiments in xenograft-bearing mice consisted of
weekly i.p. doses, 4 mg/kg for 4 months. H-GA showed a greater
antitumor effect than Herceptin because it induced tumor
regression in 69% of the recipients compared with 7% by
Herceptin alone. Median survival time was 145 days as opposed to
78 days, and 31% of the recipients remained tumor free 2 months
after therapy was terminated versus 0% in the Herceptin group.
Enhancement of Herceptin activity could be of significant
clinical value. In addition, the chemical linkage and the
considerations in therapeutic regimen described here could be
applied to other immunoconjugates for targeted therapy of a
broad spectrum of cancers.
PMID: 14973048
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