Carlo-Stella Carmelo, Guidetti Anna, Di Nicola Massimo, Lavazza Cristiana, Cleris Loredana, Sia Daniela, Longoni Paolo, Milanesi Marco, Magni Michele, Nagy Zoltan, Corradini Paolo, Carbone Antonino, Formelli Franca, Gianni Alessandro M
"Cristina Gandini" Medical Oncology Unit, Medical Oncology, University of Milano, Milan, Italy.
Cancer Res. 2007 Apr 1;67(7):3269-75. doi: 10.1158/0008-5472.CAN-06-3744.
To investigate the therapeutic activity of the fully human anti-HLA-DR antibody 1D09C3 in multiple myeloma (MM), we reevaluated HLA-DR expression on CD138(+) cells, analyzed the capacity of IFN-gamma to up-regulate HLA-DR expression on MM cell lines, and tested the in vitro and in vivo activity of 1D09C3 alone or in combination with IFN-gamma. CD138(+)HLA-DR(+) cells were detected in 31 of 60 patients, with 15 of 60 patients having >/=20% CD138(+)HLA-DR(+) cells (median, 50%; range, 23-100). Because primary plasma cells cannot be efficiently cultured in vitro, we used a panel of MM cell lines with a dim/negative to bright HLA-DR expression to evaluate 1D09C3-induced cell death. Annexin V/propidium iodide (PI) staining showed that 1D09C3-induced cell death correlated with constitutive HLA-DR expression. Induction of HLA-DR by IFN-gamma restored the sensitivity of HLA-DR dim cell lines to 1D09C3. In vivo, the combined IFN-gamma/1D09C3 treatment significantly increased the median survival of nonobese diabetic/severe combined immunodeficient mice xenografted with KMS-11 cell line, compared with controls (147 versus 48 days, P </= 0.0001) or mice receiving 1D09C3 alone (147 versus 92 days, P </= 0.03). The better therapeutic activity of IFN-gamma/1D09C3 treatment over 1D09C3 alone was further shown by a 2-fold increase of mice being disease-free at 150 days after xenograft (47% versus 25%). No mice experienced any apparent treatment-related toxicity. Our data show that (a) one fourth of MM patients express HLA-DR on CD138(+) cells and (b) IFN-gamma-induced up-regulation of HLA-DR results in a potent enhancement of the in vivo antimyeloma activity of 1D09C3.
为了研究全人源抗HLA - DR抗体1D09C3在多发性骨髓瘤（MM）中的治疗活性，我们重新评估了CD138(+)细胞上HLA - DR的表达，分析了IFN - γ上调MM细胞系上HLA - DR表达的能力，并测试了单独使用1D09C3或与IFN - γ联合使用时的体外和体内活性。60例患者中有31例检测到CD138(+)HLA - DR(+)细胞，60例患者中有15例的CD138(+)HLA - DR(+)细胞≥20%（中位数为50%；范围为23% - 100%）。由于原代浆细胞无法在体外有效培养，我们使用了一组HLA - DR表达从暗淡/阴性到明亮的MM细胞系来评估1D09C3诱导的细胞死亡。膜联蛋白V/碘化丙啶（PI）染色显示，1D09C3诱导的细胞死亡与组成性HLA - DR表达相关。IFN - γ诱导的HLA - DR上调恢复了HLA - DR暗淡的细胞系对1D09C3的敏感性。在体内，与对照组（147天对48天，P≤0.0001）或单独接受1D09C3的小鼠（147天对92天，P≤0.03）相比，联合IFN - γ/1D09C3治疗显著提高了移植KMS - 11细胞系的非肥胖糖尿病/严重联合免疫缺陷小鼠的中位生存期。移植后150天无疾病的小鼠数量增加了2倍（47%对25%），进一步表明IFN - γ/1D09C3治疗比单独使用1D09C3具有更好的治疗活性。没有小鼠出现任何明显的与治疗相关的毒性。我们的数据表明：（a）四分之一的MM患者在CD138(+)细胞上表达HLA - DR；（b）IFN - γ诱导的HLA - DR上调导致1D09C3体内抗骨髓瘤活性的显著增强。
