Clinical Pharmacology & Quantitative Pharmacology, BioPharmaceuticals R&D, AstraZeneca, Waltham, Massachusetts, USA.
Early Oncology DMPK, Oncology R&D, AstraZeneca, Cambridge, UK.
CPT Pharmacometrics Syst Pharmacol. 2024 Oct;13(10):1670-1681. doi: 10.1002/psp4.13204. Epub 2024 Jul 23.
AZD0171 (INN: Falbikitug) is being developed as a humanized monoclonal antibody (mAb), immunoglobulin G subclass 1 (IgG1), which binds specifically to the immunosuppressive human cytokine leukemia inhibitory factor (LIF) and inhibits downstream signaling by blocking recruitment of glycoprotein 130 (gp130) to the LIF receptor (LIFR) subunit (gp190) and the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and is intended to treat adult participants with advanced solid tumors. LIF is a pleiotropic cytokine (and a member of the IL-6 family of cytokines) involved in many physiological and pathological processes and is highly expressed in a subset of solid tumors, including non-small cell lung cancer (NSCLC), colon, ovarian, prostate, and pancreatic cancer. The aim of this work was to develop a mechanistic PK/PD model to investigate the effect of AZD0171 on tumor LIF levels, predict the level of downstream signaling complex (LIF:LIFR:gp130) inhibition, and examine the dose-response relationship to support dose selection for a Phase II clinical study. Modeling results show that tumor LIF is inhibited in a dose-dependent manner with >90% inhibition for 95% of patients at the Phase II clinical dose of 1500 mg Q2W.
AZD0171（商品名：Falbikitug）正在被开发为一种人源化单克隆抗体（mAb），免疫球蛋白 G 亚类 1（IgG1），它特异性地结合免疫抑制性人类细胞因子白血病抑制因子（LIF），并通过阻断糖蛋白 130（gp130）募集到 LIF 受体（LIFR）亚基（gp190）和信号转导和转录激活因子 3（STAT3）的磷酸化来抑制下游信号传导，旨在治疗患有晚期实体瘤的成年参与者。LIF 是一种多效细胞因子（也是细胞因子家族中的 IL-6 家族成员），参与许多生理和病理过程，在包括非小细胞肺癌（NSCLC）、结肠、卵巢、前列腺和胰腺癌在内的一部分实体瘤中高度表达。这项工作的目的是开发一种机制性 PK/PD 模型，以研究 AZD0171 对肿瘤 LIF 水平的影响，预测下游信号复合物（LIF:LIFR:gp130）抑制的水平，并检查剂量反应关系，以支持 II 期临床研究的剂量选择。模型结果表明，肿瘤 LIF 以剂量依赖性方式被抑制，在 II 期临床剂量 1500mg Q2W 下，95%的患者有超过 90%的抑制率。
