Oncology Business Division, Sanofi, Vitry sur Seine, France.
Clin Cancer Res. 2011 Oct 15;17(20):6448-58. doi: 10.1158/1078-0432.CCR-11-0485.
SAR3419 is a novel anti-CD19 humanized monoclonal antibody conjugated to a maytansine derivate through a cleavable linker for the treatment of B-cell malignancies. SAR3419 combines the strengths of a high-potency tubulin inhibitor and the exquisite B-cell selectivity of an anti-CD19 antibody. The internalization and processing of SAR3419, following its binding at the surface of CD19-positive human lymphoma cell lines and xenograft models, release active metabolites that trigger cell-cycle arrest and apoptosis, leading to cell death and tumor regression. SAR3419 has also been shown to be active in different lymphoma xenograft models, including aggressive diffuse large B-cell lymphoma, resulting in complete regressions and tumor-free survival. In these models, the activity of SAR3419 compared favorably with rituximab and lymphoma standard of care chemotherapy. Two phase I trials with 2 different schedules of SAR3419 as a single agent were conducted in refractory/relapsed B-cell non-Hodgkin lymphoma. Activity was reported in both schedules, in heavily pretreated patients of both follicular and diffuse large B-cell lymphoma subtypes, with a notable lack of significant hematological toxicity, validating SAR3419 as an effective antibody-drug conjugate and opening opportunities in the future. Numerous B-cell-specific anti-CD19 biologics are available to treat B-cell non-Hodgkin lymphoma, and early phase I results obtained with SAR3419 suggest that it is a promising candidate for further development in this disease. In addition, thanks to the broad expression of CD19, SAR3419 may provide treatment options for B-cell leukemias that are often CD20-negative.
SAR3419 是一种新型抗 CD19 人源化单克隆抗体，通过可裂解接头与美登素衍生物偶联，用于治疗 B 细胞恶性肿瘤。SAR3419 结合了高活性微管抑制剂的优势和抗 CD19 抗体对 B 细胞的特异性。SAR3419 与 CD19 阳性人淋巴瘤细胞系和异种移植模型表面结合后，其内化和加工会释放出活性代谢物，触发细胞周期停滞和细胞凋亡，导致细胞死亡和肿瘤消退。SAR3419 在不同的淋巴瘤异种移植模型中也表现出活性，包括侵袭性弥漫性大 B 细胞淋巴瘤，导致完全消退和无肿瘤生存。在这些模型中，SAR3419 的活性优于利妥昔单抗和淋巴瘤标准化疗。进行了两项 I 期试验，使用 2 种不同方案的 SAR3419 作为单一药物治疗难治/复发性 B 细胞非霍奇金淋巴瘤。在这两种方案中均报告了活性，在滤泡性和弥漫性大 B 细胞淋巴瘤亚型的大量预处理患者中均有活性，且明显缺乏显著的血液学毒性，验证了 SAR3419 作为一种有效的抗体药物偶联物的有效性，并为未来提供了机会。有许多针对 B 细胞的抗 CD19 生物制剂可用于治疗 B 细胞非霍奇金淋巴瘤，SAR3419 的早期 I 期结果表明，它是该疾病进一步开发的有前途的候选药物。此外，由于 CD19 的广泛表达，SAR3419 可能为通常 CD20 阴性的 B 细胞白血病提供治疗选择。
