Palm Stig, Bäck Tom, Aneheim Emma, Hallqvist Andreas, Hultborn Ragnar, Jacobsson Lars, Jensen Holger, Lindegren Sture, Albertsson Per
Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Transl Oncol. 2021 Jan;14(1):100873. doi: 10.1016/j.tranon.2020.100873. Epub 2020 Sep 25.
Antibodies labeled with alpha-emitter astatine-211 have previously shown effective in intraperitoneal (i.p.) treatments of ovarian cancer. In the present work we explore the use of investigational farletuzumab, aimed at the folate receptor alpha. The aim was to evaluate the biodistribution and therapeutic effect of At-farletuzumab in in-vitro and in-vivo experiments and, using models for radiation dosimetry, to translate the findings to expected clinical result. The activity concentration used for therapy in mice (170 kBq/mL) was chosen to be in agreement with an activity concentration that is anticipated to be clinically relevant in patients (200 MBq/L).
For biodistribution, using intravenous injections and mice carrying subcutaneous (s.c.) tumors, the animals were administered either At-farletuzumab (n = 16); or with a combination of I-farletuzumab and At-MX35 (n = 12). At 1, 3, 10 and 22 h, mice were euthanized and s.c.-tumors and organs weighted and measured for radioactivity. To evaluate therapeutic efficacy, mice were inoculated i.p. with 2 × 10 NIH:OVCAR-3 cells. Twelve days later, the treatments were initiated by i.p.-administration. Specific treatment was given by At-labeled farletuzumab (group A; n = 22, 170 kBq/mL) which is specific for OVCAR-3 cells. Control treatments were given by either At-labeled rituximab which is unspecific for OVCAR-3 (group B; n = 22, 170 kBq/mL), non-radiolabeled farletuzumab (group C; n = 11) or PBS only (group D; n = 8).
The biodistribution of At-farletuzumab was similar to that with I as radiolabel, and also to that of At-labeled MX35 antibody. The tumor-free fraction (TFF) of the three control groups were all low (PBS 12%, unlabeled specific farletuzumab 9% and unspecific At-rituximab 14%). TFF following treatment with At-farletuzumab was 91%.
The current investigation of intraperitoneal therapy with At-farletuzumab, delivered at clinically relevant At-mAb radioactivity concentrations and specific activities, showed a 6 to 10-fold increase (treated versus controls) in antitumor efficacy. This observation warrants further clinical testing.
先前已证明，用α发射体砹-211标记的抗体在卵巢癌的腹腔内（i.p.）治疗中有效。在本研究中，我们探索了针对叶酸受体α的研究性药物法乐妥珠单抗的用途。目的是在体外和体内实验中评估At-法乐妥珠单抗的生物分布和治疗效果，并使用辐射剂量测定模型将研究结果转化为预期的临床结果。选择用于小鼠治疗的活度浓度（170 kBq/mL），使其与预期在患者中具有临床相关性的活度浓度（200 MBq/L）一致。
为了进行生物分布研究，通过静脉注射，对携带皮下（s.c.）肿瘤的小鼠给药At-法乐妥珠单抗（n = 16）；或给予I-法乐妥珠单抗和At-MX35的组合（n = 12）。在1、3、10和22小时时，对小鼠实施安乐死，并对皮下肿瘤和器官进行称重并测量放射性。为了评估治疗效果，通过腹腔注射接种2×10 NIH:OVCAR-3细胞。十二天后，通过腹腔给药开始治疗。特异性治疗由对OVCAR-3细胞具有特异性的At标记的法乐妥珠单抗（A组；n = 22，170 kBq/mL）给予。对照治疗由对OVCAR-3无特异性的At标记的利妥昔单抗（B组；n = 22，170 kBq/mL）、未放射性标记的法乐妥珠单抗（C组；n = 11）或仅给予PBS（D组；n = 8）。
At-法乐妥珠单抗的生物分布与以I作为放射性标记时相似，也与At标记的MX35抗体相似。三个对照组的无瘤率（TFF）均较低（PBS组为12%，未标记的特异性法乐妥珠单抗组为9%，非特异性At-利妥昔单抗组为14%）。用At-法乐妥珠单抗治疗后的无瘤率为91%。
目前对At-法乐妥珠单抗进行的腹腔内治疗研究，在具有临床相关性的At-单克隆抗体放射性浓度和比活度下进行，结果显示抗肿瘤疗效提高了6至10倍（治疗组与对照组相比）。这一观察结果值得进一步进行临床试验。
