Loxo Oncology at Lilly, Indianapolis, Indiana, USA.
Lilly Research Laboratories, Corporate Center, Indianapolis, Indiana, USA.
Birth Defects Res. 2023 Apr 15;115(7):782-796. doi: 10.1002/bdr2.2169. Epub 2023 Mar 14.
Olaratumab (Lartruvo™) is a recombinant human IgG1 monoclonal antibody that specifically binds PDGFRα. In order to support use of Lartruvo in pediatric patients, a definitive juvenile animal study in neonatal mice was conducted with a human anti-mouse PDGFRα antibody analog of olaratumab (LSN3338786).
A pilot study was used to set doses for the definitive juvenile mouse study. In the definitive study, juvenile mice were administered vehicle, 50, 100, or 150 mg/kg LSN3338786 by subcutaneous (SC) injection every 3 days between postnatal days (PND) 1 and 49, for a total of 17 doses. Blood samples were collected on PND 49 for antibody analysis and toxicokinetic evaluation. Tissues were collected on PND 52 for histopathologic examination.
Results of the pilot study indicated that dosing neonatal mice starting on PND 1 via SC administration every 3 days was logistically feasible, produced exposures consistent with prior animal studies, and the selected dose levels were well tolerated by juvenile mice. In the definitive juvenile study, there were no LSN3338786-related deaths, clinical findings, and no effects on mean body weights, body weight gains, or food consumption. Additionally, there were no adverse LSN3338786-related hematology findings, and no macroscopic, organ weight, or microscopic findings of note. The highest dose evaluated, 150 mg/kg, was considered the NOAEL for juvenile toxicity.
In conclusion, the juvenile animal studies did not identify any new toxicities or increased sensitivities for the intended pediatric patient population. The use of the surrogate antibody approach in a standard rodent model enabled the de-risking of theoretical concerns for toxicity in pediatric patients due to disruption of the PDGFRα pathway during early human development, such as pulmonary development.
奥拉单抗（Lartruvo）是一种针对 PDGFRα 的重组人 IgG1 单克隆抗体。为了支持在儿科患者中使用 Lartruvo，我们用一种人源抗鼠 PDGFRα 抗体类似物（LSN3338786）对新生小鼠进行了一项明确的幼年动物研究。
采用一项初步研究来确定明确的幼年小鼠研究的剂量。在明确的研究中，通过皮下（SC）注射，于新生后第 1 天至 49 天（PND）之间每 3 天给幼年小鼠给药，共 17 次，剂量分别为 50、100 或 150mg/kg LSN3338786。在 PND49 时采集血样进行抗体分析和毒代动力学评估。在 PND52 时采集组织进行组织病理学检查。
初步研究的结果表明，从 PND1 开始，通过 SC 给药，每 3 天给新生小鼠一次，在操作上是可行的，产生的暴露量与先前的动物研究一致，所选剂量水平可被幼年小鼠耐受。在明确的幼年动物研究中，未观察到 LSN3338786 相关的死亡、临床发现，以及对平均体重、体重增加或食物消耗无影响。此外，未观察到 LSN3338786 相关的血液学发现，也未观察到明显的大体、器官重量或显微镜下的发现。评价的最高剂量 150mg/kg 被认为是幼年毒性的无观察不良作用水平（NOAEL）。
总之，幼年动物研究未发现任何新的毒性或增加了预期儿科患者人群的敏感性。在标准啮齿动物模型中使用替代抗体方法，可降低因 PDGFRα 通路在人类早期发育过程中中断而导致的儿科患者毒性的理论风险，例如肺发育。
