Mandler Raya, Kobayashi Hisataka, Hinson Ella R, Brechbiel Martin W, Waldmann Thomas A
Metabolism Branch, Center for Cancer Research, National Cancer Institute/NIH, 6701 Rockledge Drive, Room 5217, MSC 7840, Bethesda, MD 20892, USA.
Cancer Res. 2004 Feb 15;64(4):1460-7. doi: 10.1158/0008-5472.can-03-2485.
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.
单克隆抗体（mAb）作为单一药物用于靶向癌症治疗的疗效已被证明是有限的。给单克隆抗体配备一种强效毒性药物可增强其活性。在此我们报告，将格尔德霉素（GA）与抗HER2单克隆抗体赫赛汀偶联可提高赫赛汀的活性。在抗增殖试验中，免疫偶联物H-GA的半数抑制浓度（IC50）比赫赛汀低10至200倍，具体取决于细胞系。H-GA的作用模式涉及HER2降解，这部分对乳胞素敏感，因此是蛋白酶体依赖性的。赫赛汀和偶联GA的药代动力学表明，GA与赫赛汀之间的连接在循环中保持稳定，二者几乎相同，且与游离GA的药代动力学显著不同。赫赛汀和H-GA的肿瘤摄取相似（每克组织分别为初始注射剂量的52±7%和43±7%；P = 0.077），表明偶联未造成明显损害。在荷瘤异种移植小鼠中进行的治疗实验包括每周腹腔注射给药，剂量为4 mg/kg，持续4个月。H-GA显示出比赫赛汀更强的抗肿瘤作用，因为它使69%的受体肿瘤消退，而单独使用赫赛汀时这一比例为7%。中位生存时间为145天，而单独使用赫赛汀时为78天，并且在治疗终止2个月后有31%的受体无瘤，而赫赛汀组为0%。增强赫赛汀的活性可能具有重要的临床价值。此外，这里描述的化学连接和治疗方案考虑因素可应用于其他免疫偶联物，用于多种癌症的靶向治疗。
