Purpose

The development of molecularly targeted tracers is likely to improve the accuracy of diagnostic, screening, and therapeutic tools. Despite the many therapeutic antibodies that are FDA-approved with known toxicity, only a limited number of antibody-dye conjugates have been introduced to the clinic. Thorough evaluation of the safety, stability, and pharmacokinetics of antibody conjugates in the clinical setting compared with their parental components could accelerate the clinical approval of antibodies as agents for molecular imaging. Here we investigate the safety and stability of a near-infrared fluorescent dye (IRDye800CW) conjugated panitumumab, an approved therapeutic antibody, and report on the product stability, pharmacokinetics, adverse events, and QTc interval changes in patients.

Procedures

Panitumumab-IRDye800CW was made under good manufacturing practice (GMP) conditions in a single batch on March 26, 2014, and then evaluated over 4.5 years at 0, 3, and 6 months, and then at 6-month intervals thereafter. We conducted early phase trials in head and neck, lung, pancreas, and brain cancers with panitumumab-IRDye800CW. Eighty-one patients scheduled to undergo standard-of-care surgery were infused with doses between 0.06 to 2.83 mg/kg of antibody. Patient ECGs, blood samples, and adverse events were collected over 30-day post-infusion for analysis.

Results

Eighty-one patients underwent infusion of the study drug at a range of doses. Six patients (7.4 %) experienced an adverse event that was considered potentially related to the drug. The most common event was a prolonged QTc interval which occurred in three patients (3.7 %). Panitumumab-IRDye800CW had two OOS results at 42 and 54 months while meeting all other stability testing criteria.

Conclusions

Panitumumab-IRDye800CW was safe and stable to administer over a 54-month window with a low rate of adverse events (7.4 %) which is consistent with the rate associated with panitumumab alone. This data supports re-purposing therapeutic antibodies as diagnostic imaging agents with limited preclinical toxicology studies.

中文翻译：

---

抗体-染料偶联物在光学分子成像中的安全性和稳定性。

目的

分子靶向示踪剂的开发可能会提高诊断、筛查和治疗工具的准确性。尽管 FDA 批准了许多具有已知毒性的治疗性抗体，但只有有限数量的抗体-染料偶联物被引入临床。与其母体成分相比，全面评估抗体偶联物在临床环境中的安全性、稳定性和药代动力学，可以加速抗体作为分子成像试剂的临床批准。在这里，我们研究了一种经批准的治疗性抗体近红外荧光染料 (IRDye800CW) 偶联帕尼单抗的安全性和稳定性，并报告了产品稳定性、药代动力学、不良事件和患者 QTc 间期变化。

程序

Panitumumab-IRDye800CW 于 2014 年 3 月 26 日在良好生产规范 (GMP) 条件下单批生产，然后在 4.5 年的 0、3 和 6 个月进行评估，之后每隔 6 个月进行一次评估。我们使用帕尼单抗-IRDye800CW 对头颈癌、肺癌、胰腺癌和脑癌进行了早期试验。81 名计划接受标准护理手术的患者被注入 0.06 至 2.83 mg/kg 的抗体剂量。在输注后 30 天内收集患者心电图、血液样本和不良事件进行分析。

结果

81 名患者接受了一系列剂量的研究药物输注。六名患者 (7.4 %) 经历了被认为可能与药物有关的不良事件。最常见的事件是 3 名患者 (3.7 %) 发生的 QTc 间期延长。Panitumumab-IRDye800CW 在 42 个月和 54 个月有两个 OOS 结果，同时满足所有其他稳定性测试标准。

结论

Panitumumab-IRDye800CW 在 54 个月的窗口期内给药安全且稳定，不良事件发生率低 (7.4%)，这与单独使用帕尼单抗相关的发生率一致。该数据支持将治疗性抗体重新用作诊断显像剂，但临床前毒理学研究有限。