Maximizing tumour exposure to anti-neuropilin-1 antibody requires saturation of non-tumour tissue antigenic sinks in mice
Maximizing tumour exposure to anti-neuropilin-1 antibody requires saturation of non-tumour tissue antigenic sinks in mice
复制标题
DOI：
10.1111/j.1476-5381.2011.01777.x
复制
发表时间：
2012-05-01
影响因子：
7.3
通讯作者：
Shen, Ben-Quan
中科院分区：
文献类型：
--
作者：
Bumbaca, Daniela;Xiang, Hong;Shen, Ben-Quan
神经纤毛蛋白-1（Neuropilin-1，NRP 1）是一种VEGF受体，广泛表达于正常组织中，并参与肿瘤血管生成。MNRP 1685 A是一种啮齿类和灵长类交叉结合的抗NRP 1人单克隆抗体，在NPR 1表达的临床前模型中表现出肿瘤生长抑制作用。然而，NRP 1在正常组织中的广泛表达可能会影响MNRP 1685 A肿瘤的摄取。本研究的目的是评估MNRP 1685 A在荷瘤小鼠中的生物分布，以了解剂量、非肿瘤组织摄取和肿瘤摄取之间的关系。mg.kg对荷瘤小鼠给予In-111标记的MNRP 1685 A沿着增加量的未标记抗体。采集所有动物的血液和组织，以测定药物浓度（未标记）或放射性水平（放射性标记）。一些动物使用单光子发射计算机断层扫描-X射线计算机断层扫描成像。关键结果MNRP 1685 A显示出比帕妥珠单抗更快的血清清除，表明靶结合影响MNRP 1685 A清除。I. v.给荷瘤小鼠施用111 In标记的MNRP 1685 A在血浆和肿瘤中产生最小的放射性，但在肺和肝中产生高水平的放射性。共同管理的未标记的MNRP 1685 A与放射性标记的抗体是能够竞争性地阻止肺和肝脏的放射性摄取的剂量依赖性的方式，同时增加血浆和肿瘤的放射性levels.CONCLUSIONS和影响这些结果表明，非肿瘤组织的吸收饱和，以实现肿瘤的吸收和可接受的暴露于抗体。利用啮齿动物和灵长类动物交叉结合抗体可以将这些结果转化为临床环境。
BACKGROUND AND PURPOSE Neuropilin-1 (NRP1) is a VEGF receptor that is widely expressed in normal tissues and is involved in tumour angiogenesis. MNRP1685A is a rodent and primate cross-binding human monoclonal antibody against NRP1 that exhibits inhibition of tumour growth in NPR1-expressing preclinical models. However, widespread NRP1 expression in normal tissues may affect MNRP1685A tumour uptake. The objective of this study was to assess MNRP1685A biodistribution in tumour-bearing mice to understand the relationships between dose, non-tumour tissue uptake and tumour uptake.EXPERIMENTAL APPROACH Non-tumour-bearing mice were given unlabelled MNRP1685A at 10 mg.kg(-1). Tumour-bearing mice were given In-111-labelled MNRP1685A along with increasing amounts of unlabelled antibody. Blood and tissues were collected from all animals to determine drug concentration (unlabelled) or radioactivity level (radiolabelled). Some animals were imaged using single photon emission computed tomography - X-ray computed tomography.KEY RESULTS MNRP1685A displayed faster serum clearance than pertuzumab, indicating that target binding affected MNRP1685A clearance. I. v. administration of 111In-labelled MNRP1685A to tumour-bearing mice yielded minimal radioactivity in the plasma and tumour, but high levels in the lungs and liver. Co-administration of unlabelled MNRP1685A with the radiolabelled antibody was able to competitively block lungs and liver radioactivity uptake in a dose-dependent manner while augmenting plasma and tumour radioactivity levels.CONCLUSIONS AND IMPLICATIONS These results indicate that saturation of non-tumour tissue uptake is required in order to achieve tumour uptake and acceptable exposure to antibody. Utilization of a rodent and primate cross-binding antibody allows for translation of these results to clinical settings.