Nordic Nanovector ASA, Oslo, Norway.
Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
J Nucl Med. 2020 Oct;61(10):1468-1475. doi: 10.2967/jnumed.119.237230. Epub 2020 Apr 3.
Patients with non-Hodgkin lymphoma (NHL) who are treated with rituximab may develop resistant disease, often associated with changes in expression of CD20. The next-generation β-particle-emitting radioimmunoconjugate Lu-lilotomab-satetraxetan (Betalutin) was shown to up-regulate CD20 expression in different rituximab-sensitive NHL cell lines and to act synergistically with rituximab in a rituximab-sensitive NHL animal model. We hypothesized that Lu-lilotomab-satetraxetan may be used to reverse rituximab resistance in NHL. The rituximab-resistant Raji2R and the parental Raji cell lines were used. CD20 expression was measured by flow cytometry. Antibody-dependent cellular cytotoxicity (ADCC) was measured by a bioluminescence reporter assay. The efficacies of combined treatments with Lu-lilotomab-satetraxetan (150 or 350 MBq/kg) and rituximab (4 × 10 mg/kg) were compared with those of single agents or phosphate-buffered saline in a Raji2R-xenograft model. Cox regression and the Bliss independence model were used to assess synergism. Rituximab binding in Raji2R cells was 36% ± 5% of that in the rituximab-sensitive Raji cells. Lu-lilotomab-satetraxetan treatment of Raji2R cells increased the binding to 53% ± 3% of the parental cell line. Rituximab ADCC induction in Raji2R cells was 20% ± 2% of that induced in Raji cells, whereas treatment with Lu-lilotomab-satetraxetan increased the ADCC induction to 30% ± 3% of that in Raji cells, representing a 50% increase ( < 0.05). The combination of rituximab with 350 MBq/kg Lu-lilotomab-satetraxetan synergistically suppressed Raji2R tumor growth in athymic Foxn1 mice. Lu-lilotomab-satetraxetan has the potential to reverse rituximab resistance; it can increase rituximab binding and ADCC activity and can synergistically improve antitumor efficacy .
接受利妥昔单抗治疗的非霍奇金淋巴瘤 (NHL) 患者可能会出现耐药疾病，通常与 CD20 表达的变化有关。下一代β粒子发射放射性免疫偶联物 Lu-lilotomab-satetraxetan（Betalutin）被证明可上调不同利妥昔单抗敏感 NHL 细胞系中的 CD20 表达，并在利妥昔单抗敏感 NHL 动物模型中与利妥昔单抗协同作用。我们假设 Lu-lilotomab-satetraxetan 可用于逆转 NHL 中的利妥昔单抗耐药性。使用利妥昔单抗耐药的 Raji2R 和亲本 Raji 细胞系。通过流式细胞术测量 CD20 表达。通过生物发光报告测定法测量抗体依赖性细胞毒性 (ADCC)。在 Raji2R-异种移植模型中，比较 Lu-lilotomab-satetraxetan（150 或 350MBq/kg）与利妥昔单抗（4×10mg/kg）联合治疗与单药或磷酸盐缓冲盐水的疗效。使用 Cox 回归和 Bliss 独立性模型评估协同作用。Raji2R 细胞中利妥昔单抗的结合率为利妥昔单抗敏感 Raji 细胞的 36%±5%。Lu-lilotomab-satetraxetan 处理 Raji2R 细胞可将结合率提高至亲本细胞系的 53%±3%。Raji2R 细胞中利妥昔单抗的 ADCC 诱导率为 Raji 细胞的 20%±2%，而 Lu-lilotomab-satetraxetan 处理可将 ADCC 诱导率提高至 Raji 细胞的 30%±3%，增加 50%（<0.05）。利妥昔单抗与 350MBq/kg Lu-lilotomab-satetraxetan 联合可协同抑制裸鼠 Raji2R 肿瘤生长。Lu-lilotomab-satetraxetan 具有逆转利妥昔单抗耐药的潜力；它可以增加利妥昔单抗结合和 ADCC 活性，并可以协同提高抗肿瘤疗效。
