Nuclear Medicine Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
J Nucl Med. 2011 Aug;52(8):1173-80. doi: 10.2967/jnumed.110.086165. Epub 2011 Jul 15.
Humanized A33 (huA33) is a promising monoclonal antibody that recognizes A33 antigen, which is present in more than 95% of colorectal cancers and in normal bowel. In this study, we took advantage of quantitative PET to evaluate (124)I huA33 targeting, biodistribution, and safety in patients with colorectal cancer. We also determined the biodistribution of (124)I-huA33 when a large dose of human intravenous IgG (IVIG) was administered to manipulate the Fc receptor or when (124)I-huA33 was given via hepatic arterial infusion (HAI).
We studied 25 patients with primary or metastatic colorectal cancer; 19 patients had surgical exploration or resection. Patients received a median of 343 MBq (44.4-396 MBq) and 10 mg of (124)I-huA33. Nineteen patients received the antibody intravenously and 6 patients via HAI, and 5 patients also received IVIG.
Ten of 12 primary tumors were visualized in 11 patients. The median concentration in primary colon tumors was 0.016% injected dose per gram, compared with 0.004% in normal colon. The PET-based median ratio of hepatic tumor uptake to normal-liver uptake was 3.9 (range, 1.8-22.2). Quantitation using PET, compared with well counting of serum and tissue, showed little difference. Prominent uptake in bowel hindered tumor identification in some patients. Pharmacokinetics showed that patients receiving IVIG had a significantly shorter serum half-time (41.6 ± 14.0 h) than those without (65.2 ± 9.8 h). There were no differences in clearance rates among the intravenous group, IVIG group, and HAI group, nor was there any difference in serum area under the curve, maximum serum concentration, or volume of distribution. Weak titers of human-antihuman antibodies were observed in 6 of 25 patients. No acute side effects or significant toxicities were associated with huA33.
Good localization of (124)I-huA33 in colorectal cancer with no significant toxicity has been observed. PET-derived (124)I concentrations agreed well with those obtained by well counting of surgically resected tissue and blood, confirming the quantitative accuracy of (124)I-huA33 PET. The HAI route had no advantage over the intravenous route. No clinically significant changes in blood clearance were induced by IVIG.
人源化 A33（huA33）是一种有前途的单克隆抗体，可识别 A33 抗原，该抗原存在于超过 95%的结直肠癌和正常肠中。在这项研究中，我们利用定量 PET 评估了结直肠癌患者中（124）I huA33 的靶向、生物分布和安全性。我们还确定了当给予大剂量人静脉内免疫球蛋白（IVIG）以操纵 Fc 受体或当通过肝动脉输注（HAI）给予（124）I-huA33 时，（124）I-huA33 的生物分布。
我们研究了 25 例原发性或转移性结直肠癌患者；19 例患者接受了手术探查或切除。患者接受了中位数为 343MBq（44.4-396MBq）和 10mg（124）I-huA33 的治疗。19 例患者静脉内给予抗体，6 例患者经 HAI 给予，5 例患者还给予 IVIG。
11 例患者中的 12 个原发肿瘤中有 10 个可见。原发性结肠肿瘤的中位数浓度为 0.016%注入剂量/克，而正常结肠为 0.004%。基于 PET 的肝肿瘤摄取与正常肝摄取的中位数比值为 3.9（范围，1.8-22.2）。与血清和组织的-well 计数相比，使用 PET 进行定量显示出差异不大。一些患者的肠后摄取明显阻碍了肿瘤的识别。药代动力学显示，接受 IVIG 的患者的血清半衰期（41.6±14.0 h）明显短于未接受 IVIG 的患者（65.2±9.8 h）。静脉内组、IVIG 组和 HAI 组之间的清除率无差异，血清 AUC、最大血清浓度或分布容积也无差异。25 例患者中有 6 例观察到人类抗人抗体的弱滴度。huA33 未引起明显的急性副作用或毒性。
已观察到结直肠癌中（124）I-huA33 的良好定位，且无明显毒性。通过手术切除组织和血液的-well 计数获得的 PET 衍生（124）I 浓度与放射性碘-124 人源化 A33 PET 定量准确一致。HAI 途径与静脉途径相比没有优势。IVIG 未引起血液清除率的临床显著变化。
