Although many multiple myeloma (MM) patients initially respond to cytotoxic therapy, most eventually relapse. Novel therapeutic strategies employing a combination of chemotherapy with targeted biologics may significantly enhance the response of tumor cells to treatment. We tested a fully human anti-IGF-IR antibody (A12) against MM, and showed specific inhibition of IGF-I or serum-induced IGF-IR signaling in MM cells in vitro. The A12 as a single agent was demonstrated to exert modest to significant inhibition of tumor growth in vivo in various subcutaneous xenograft MM models. The A12 was also evaluated in a disseminated xenograft MM.1S NOD/SCID model as monotherapy or in combination with other drugs (bortezomib, melphalan) currently in clinical use. The tumor burden, as determined by luciferase bioimaging, was sharply decreased, and overall survival significantly prolonged when the therapies were combined. Immunohistochemical analysis demonstrated that the A12 treated tumors had significantly decreased vascularization compared to control tumors. Furthermore, most MM lines constitutively secreted significant quantities of VEGF, and this was enhanced following IGF-I treatment. Inhibition of IGF-IR by the A12 in vitro suppressed both constitutive and IGF-I-induced secretion of VEGF, indicating that a putative anti-angiogenic mechanism associated with the A12 treatment may contribute to its anti-tumor effect.

译文

:尽管许多多发性骨髓瘤(MM)患者最初对细胞毒性疗法有反应,但大多数最终会复发。采用化学疗法与靶向生物制剂相结合的新型治疗策略可以显着增强肿瘤细胞对治疗的反应。我们测试了针对MM的完全人源抗IGF-IR抗体(A12),并显示了MM细胞在体外对IGF-1或血清诱导的IGF-1R信号的特异性抑制。在各种皮下异种移植MM模型中,A12作为单一药剂被证明在体内对肿瘤生长具有中等至显着的抑制作用。还以单一疗法或与目前临床上使用的其他药物(硼替佐米,美法仑)联用的弥漫性异种移植MM.1S NOD / SCID模型评估了A12。通过萤光素酶生物显像确定的肿瘤负荷显着降低,并且当联合治疗时,总生存期显着延长。免疫组织化学分析表明,与对照肿瘤相比,A12治疗的肿瘤的血管形成明显减少。此外,大多数MM系组成型地分泌大量的VEGF,并且在IGF-I处理后其增强。在体外通过A12抑制IGF-IR抑制了组成型和IGF-I诱导的VEGF分泌,这表明与A12治疗相关的推定抗血管生成机制可能有助于其抗肿瘤作用。

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