Sapra Puja, Allen Theresa M
Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
Clin Cancer Res. 2004 Apr 1;10(7):2530-7. doi: 10.1158/1078-0432.ccr-03-0376.
We have reported previously that successful immunoliposomal drug therapy with liposomal doxorubicin (DXR) against xenograft B-lymphoma models required targeting against an internalizing B-cell antigen, CD19 (P. Sapra and T. M. Allen. Cancer Res 2002;62:7190-4.). Here we compare targeting of immunoliposomal formulations of DXR with vincristine (VCR) targeted against CD19 versus a noninternalizing (CD20) epitope. We also examine the effect of targeting immunoliposomes with antibody combinations in an attempt to increase the total number of binding sites (apparent antigen density) at the target cell surface.
Cell association of immunoliposomes (CD19-targeted, CD20-targeted, or combinations of the two) with human B-cell lymphoma (Namalwa) cells were studied using radiolabeled liposomes. Therapeutic efficacy of the same formulations was determined in a severe combined immunodeficient murine model.
Therapeutic results in severe combined immunodeficient mice bearing Namalwa cells administered anti-CD20-targeted liposomal DXR were barely improved over those found for nontargeted liposomal DXR or free DXR but, surprisingly, administration of anti-CD20-targeted liposomal VCR resulted in a significantly improved therapeutic outcome compared with nontargeted liposomal VCR, free VCR, or anti-CD20-targeted liposomal DXR. Treatment of murine B lymphoma with single injections of combinations of anti-CD19- and anti-CD20-targeted liposomal VCR led to cures in 70% of mice. However, mice injected with similar combinations of liposomal DXR did not have improved survival rates over anti-CD19-targeted liposomal DXR by itself.
The success of immunoliposomal therapy in combination regimens varies with the type of encapsulated drug and the nature of the target epitopes.
我们之前报道过，用脂质体阿霉素（DXR）进行成功的免疫脂质体药物治疗异种移植B淋巴瘤模型需要靶向一种内化的B细胞抗原CD19（P. Sapra和T. M. Allen。《癌症研究》2002年；62：7190 - 4）。在此，我们比较了靶向CD19的阿霉素免疫脂质体制剂与靶向非内化（CD20）表位的长春新碱（VCR）免疫脂质体制剂。我们还研究了用抗体组合靶向免疫脂质体的效果，试图增加靶细胞表面结合位点的总数（表观抗原密度）。
使用放射性标记的脂质体研究免疫脂质体（靶向CD19、靶向CD20或两者组合）与人B细胞淋巴瘤（Namalwa）细胞的细胞结合。在严重联合免疫缺陷小鼠模型中测定相同制剂的治疗效果。
在携带Namalwa细胞的严重联合免疫缺陷小鼠中，给予靶向抗CD20的脂质体阿霉素的治疗效果相比非靶向脂质体阿霉素或游离阿霉素几乎没有改善，但令人惊讶的是，给予靶向抗CD20的脂质体长春新碱与非靶向脂质体长春新碱、游离长春新碱或靶向抗CD20的脂质体阿霉素相比，治疗效果有显著改善。单次注射靶向抗CD19和抗CD20的脂质体长春新碱组合治疗小鼠B淋巴瘤，70%的小鼠被治愈。然而，注射类似组合的脂质体阿霉素的小鼠与单独使用靶向抗CD19的脂质体阿霉素相比，生存率并未提高。
联合治疗方案中免疫脂质体治疗的成功与否因包封药物的类型和靶表位的性质而异。
