Nordic Nanovector ASA, Kjelsåsveien 168 B, 0884, Oslo, Norway.
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Eur J Nucl Med Mol Imaging. 2019 Oct;46(11):2311-2321. doi: 10.1007/s00259-019-04417-1. Epub 2019 Jul 15.
The aim of this study was to explore the β-emitting lutetium-177 labelled anti-CD37 antibody NNV003 (Lu-NNV003, Humalutin®) for the treatment of non-Hodgkin's lymphoma in in vitro studies and in animal models.
Cytotoxicity of Lu-NNV003 was measured in REC-1 (mantle cell lymphoma) and DOHH-2 (diffuse large B cell lymphoma) cell lines. Biodistribution was studied in mice bearing subcutaneous DOHH-2 or MEC-2 (chronic lymphocytic leukaemia) xenografts. The therapeutic effect of a single injection of Lu-NNV003 was measured in mice intravenously or subcutaneously injected with REC-1 cells. Haematological and histopathological assessments were used to evaluate the toxic effect of Lu-NNV003. The immunotherapeutic effect of NNV003 was assessed by measuring binding to Fcγ receptors, activation of ADCC and ADCP. NNV003's immunogenicity potential was assessed using in silico immunogenicity prediction tools.
Lu-NNV003 showed an activity dependent antiproliferative effect in all cell lines. Maximum tumour uptake in vivo was 45% of injected activity/g in MEC-2 tumours and 15% injected activity/g in DOHH-2 tumours. In mice injected intravenously with REC-1 cells, Lu-NNV003 (50-100 MBq/kg) improved survival compared to control groups (p < 0.02). In mice with subcutaneous REC-1 xenografts, 500 MBq/kg Lu-NNV003 extended survival compared to the control treatments (p < 0.005). Transient haematological toxicity was observed in all mice treated with radioactivity. NNV003 induced ADCC and ADCP and was predicted to have a lower immunogenicity potential than its murine counterpart.
Lu-NNV003 had a significant anti-tumour effect and a favourable toxicity profile. These results warrant further clinical testing in patients with CD37-expressing B cell malignancies.
本研究旨在探讨β发射体镥-177 标记的抗 CD37 抗体 NNV003（Lu-NNV003，Huma-lutin®）在体外研究和动物模型中治疗非霍奇金淋巴瘤的作用。
在 REC-1（套细胞淋巴瘤）和 DOHH-2（弥漫性大 B 细胞淋巴瘤）细胞系中测量 Lu-NNV003 的细胞毒性。在皮下接种 DOHH-2 或 MEC-2（慢性淋巴细胞白血病）异种移植瘤的小鼠中研究其生物分布。通过静脉或皮下注射 REC-1 细胞的小鼠测量单次注射 Lu-NNV003 的治疗效果。使用血液学和组织病理学评估来评估 Lu-NNV003 的毒性作用。通过测量与 Fcγ 受体的结合、ADCC 和 ADCP 的激活来评估 NNV003 的免疫治疗作用。使用计算机免疫原性预测工具评估 NNV003 的免疫原性潜力。
Lu-NNV003 在所有细胞系中均表现出活性依赖性抗增殖作用。体内最大肿瘤摄取量在 MEC-2 肿瘤中为 45%注入的活性/g，在 DOHH-2 肿瘤中为 15%注入的活性/g。在静脉注射 REC-1 细胞的小鼠中，与对照组相比（p<0.02），Lu-NNV003（50-100 MBq/kg）提高了生存率。在皮下 REC-1 异种移植瘤小鼠中，与对照治疗相比（p<0.005），500 MBq/kg Lu-NNV003 延长了生存时间。所有接受放射性治疗的小鼠均出现短暂的血液学毒性。NNV003 诱导了 ADCC 和 ADCP，并且预测其免疫原性潜力低于其鼠类对应物。
Lu-NNV003 具有显著的抗肿瘤作用和良好的毒性特征。这些结果证明了其在表达 CD37 的 B 细胞恶性肿瘤患者中进一步临床测试的合理性。
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