Sarah Cannon Research Institute, Nashville, Tenessee 37203-1632, USA.
Clin Cancer Res. 2010 Mar 1;16(5):1673-81. doi: 10.1158/1078-0432.CCR-09-2263. Epub 2010 Feb 23.
RAV12 is a high affinity, internalizing, chimeric IgG1 monoclonal antibody that binds RAAG12, a novel primate-restricted N-linked carbohydrate epitope present on multiple cell surface proteins. RAAG12 is highly expressed on many adenocarcinomas, particularly those of gastrointestinal origin. A phase 1 dose-escalation safety and pharmacokinetics trial was conducted in patients with metastatic or recurrent adenocarcinomas.
RAV12 was initially given i.v. weekly x4, then by fractionated dosing twice or thrice weekly. Thirty-three patients were treated in the dose escalation segment of the trial in the following cohorts: 0.3 mg/kg qw (6), 1.0 mg/kg qw (8), 1.5 mg/kg qw (7); and 0.5 mg/kg biw (3), 0.75 mg/kg biw (3), and 0.5 mg/kg tiw (6). Twenty patients were enrolled in a maximum tolerated dose cohort expansion at 0.75 mg/kg biw.
Two clinical syndromes were associated with drug administration: abdominal cramping pain with diarrhea, and asymptomatic, self-limited increases of liver function tests. These effects were partially ameliorated with fractionated dosing. Pharmacokinetics was dose dependent. Maximum concentration was reduced, whereas area under the concentration versus time curve was maintained with fractionated dosing. One patient with colorectal cancer experienced a durable partial remission, with a time to progression (TTP) of >8 months. Three additional patients experienced a TTP of >4 months.
RAV12 has activity in recurrent adenocarcinomas. However, the safety profile of the antibody seems to preclude the delivery of highly efficacious doses. Re-engineering the molecule to remove FcRn binding (while maintaining FcgammaR binding) and to humanize it may improve the toxicity profile and efficacy.
RAV12 是一种高亲和力、内化的嵌合 IgG1 单克隆抗体，可与 RAAG12 结合，RAAG12 是一种新型灵长类动物限制性 N 连接糖基化表位，存在于多种细胞表面蛋白上。RAAG12 在许多腺癌中高度表达，特别是胃肠道来源的腺癌。一项 1 期递增剂量安全性和药代动力学试验在转移性或复发性腺癌患者中进行。
RAV12 最初以静脉注射每周 4 次的剂量给药，然后以分次剂量每周 2 次或 3 次给药。33 名患者在该试验的剂量递增部分接受治疗，分为以下几个队列：0.3mg/kg 每周 1 次（6 例）、1.0mg/kg 每周 1 次（8 例）、1.5mg/kg 每周 1 次（7 例）；0.5mg/kg 每周 2 次（3 例）、0.75mg/kg 每周 2 次（3 例）和 0.5mg/kg 每周 3 次（6 例）。20 名患者在 0.75mg/kg 每周 2 次的最大耐受剂量扩展队列中入组。
两种与药物给药相关的临床综合征：腹痛伴腹泻，以及无症状、自限性的肝功能试验升高。这些影响通过分次剂量给药部分得到改善。药代动力学呈剂量依赖性。最大浓度降低，而与时间的浓度-时间曲线下面积通过分次剂量给药得以维持。1 名结直肠癌患者经历了持久的部分缓解，无进展生存期（TTP）超过 8 个月。另外 3 名患者的 TTP 超过 4 个月。
RAV12 在复发性腺癌中具有活性。然而，抗体的安全性似乎排除了高疗效剂量的应用。对该分子进行工程改造以去除 FcRn 结合（同时保持 FcγR 结合）并使其人源化可能会改善其毒性谱和疗效。
