Rozga Piotr, Kloska Damian, Pawlak Sebastian, Teska-Kaminska Malgorzata, Galazka Marlena, Bukato Katarzyna, Pieczykolan Anna, Jaworski Albert, Molga-Kaczmarska Anna, Kopacz Aleksandra, Badyra Bogna, Kachamakova-Trojanowska Neli, Zolnierkiewicz Olga, Targosz-Korecka Marta, Poleszak Katarzyna, Szymanik Michal, Zerek Bartlomiej, Pieczykolan Jerzy, Jozkowicz Alicja, Grochot-Przeczek Anna
Department of Drug Discovery, Adamed Pharma S.A. Pienkow, Czosnow, Poland.
Department of Medical Biotechnology, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
Int J Cancer. 2020 Aug 15;147(4):1117-1130. doi: 10.1002/ijc.32845. Epub 2020 Jan 24.
Targeting of the TRAIL-DR4/5 pathway was proposed as a promising approach for specific induction of apoptosis in cancer cells. Clinical trials, however, showed inadequate efficiency of TRAIL as a monotherapy. It is a widely held view that the application of multifunctional molecules or combination therapy may lead to substantial improvement. Here, we demonstrate the effectiveness and safety of a novel chimeric protein, AD-O51.4, which is a TRAIL equipped with positively charged VEGFA-derived effector peptides. The study was performed in multiple cancer cell line- and patient-derived xenografts. A pharmacokinetic profile was established in monkeys. AD-O51.4 strongly inhibits tumor growth, even leading to complete long-term tumor remission. Neither mice nor monkeys treated with AD-O51.4 demonstrate symptoms of drug toxicity. AD-O51.4 exhibits a satisfactory half-life in plasma and accumulates preferentially in tumors. The cellular mechanism of AD-O51.4 activity involves both cytotoxic effects in tumor cells and antiangiogenic effects on the endothelium. The presence of DRs in cancer cells is crucial for AD-O51.4-driven apoptosis execution. The TRAIL component of the fusion molecule serves as an apoptosis inducer and a cellular anchor for the effector peptides in TRAIL-sensitive and TRAIL-resistant cancer cells, respectively. The FADD-dependent pathway, however, seems to be not indispensable in death signal transduction; thus, AD-O51.4 is capable of bypassing the refractoriness of TRAIL. AD-O51.4-driven cell death, which exceeds TRAIL activity, is achieved due to the N-terminally fused polypeptide, containing VEGFA-derived effector peptides. The high anticancer efficiency of AD-O51.4 combined with its safety has led to the entry of AD-O51.4 into toxicological studies.
靶向肿瘤坏死因子相关凋亡诱导配体（TRAIL）-死亡受体4/5（DR4/5）通路被认为是一种在癌细胞中特异性诱导凋亡的有前景的方法。然而，临床试验表明，TRAIL作为单一疗法的效率不足。人们普遍认为，应用多功能分子或联合疗法可能会带来显著改善。在此，我们证明了一种新型嵌合蛋白AD-O51.4的有效性和安全性，它是一种配备了带正电荷的血管内皮生长因子A（VEGFA）衍生效应肽的TRAIL。该研究在多种癌细胞系和患者来源的异种移植模型中进行。在猴子中建立了药代动力学特征。AD-O51.4强烈抑制肿瘤生长，甚至导致长期完全肿瘤缓解。用AD-O51.4治疗的小鼠和猴子均未表现出药物毒性症状。AD-O51.4在血浆中具有令人满意的半衰期，并优先在肿瘤中蓄积。AD-O51.4活性的细胞机制涉及对肿瘤细胞的细胞毒性作用和对内皮细胞的抗血管生成作用。癌细胞中DRs的存在对于AD-O51.4驱动的凋亡执行至关重要。融合分子的TRAIL成分分别作为TRAIL敏感和TRAIL耐药癌细胞中效应肽的凋亡诱导剂和细胞锚定物。然而，FADD依赖性途径似乎在死亡信号转导中并非不可或缺；因此，AD-O51.4能够绕过TRAIL的难治性。由于N端融合了含有VEGFA衍生效应肽的多肽，AD-O51.4驱动的细胞死亡超过了TRAIL活性。AD-O51.4的高抗癌效率及其安全性已使其进入毒理学研究阶段。
