Subasic Christopher N, Ardana Aditya, Chan Linda J, Huang Fei, Scoble Judith A, Butcher Neville J, Meagher Laurence, Chiefari John, Kaminskas Lisa M, Williams Charlotte C
School of Biomedical Sciences, University of Queensland, St Lucia, QLD 4072, Australia.
CSIRO Manufacturing, 343 Royal Parade, Parkville, Victoria 3052, Australia.
Int J Pharm. 2021 Oct 25;608:121075. doi: 10.1016/j.ijpharm.2021.121075. Epub 2021 Sep 2.
PEGylation is the standard approach for prolonging the plasma exposure of protein therapeutics but has limitations. We explored whether polymers prepared by Reversible Addition-Fragmentation chain-Transfer (RAFT) may provide better alternatives to polyethylene glycol (PEG). Four RAFT polymers were synthesised with varying compositions, molar mass (M), and structures, including a homopolymer of N-(2-hydroxypropyl)methacrylamide, (pHPMA) and statistical copolymers of HPMA with poly(ethylene glycol methyl ether acrylate) p(HPMA-co-PEGA); HPMA and N-acryloylmorpholine, p(HPMA-co-NAM); and HPMA and N-isopropylacrylamide, p(HPMA-co-NIPAM). The intravenous pharmacokinetics of the polymers were then evaluated in rats. The in vitro activity and in vivo pharmacokinetics of p(HPMA-co-NIPAM)-conjugated trastuzumab Fab' and full length mAb were then evaluated. p(HPMA-co-NIPAM) prolonged plasma exposure more avidly compared to the other p(HPMA) polymers or PEG, irrespective of molecular weight. When conjugated to trastuzumab-Fab', p(HPMA-co-NIPAM) prolonged plasma exposure of the Fab' similar to PEG-Fab'. The generation of anti-PEG IgM in rats 7 days after intravenous and subcutaneous dosing of p(HPMA-co-NIPAM) conjugated trastuzumab mAb was also examined and was shown to exhibit lower immunogenicity than the PEGylated construct. These data suggest that p(HPMA-co-NIPAM) has potential as a promising copolymer for use as an alternative conjugation strategy to PEG, to prolong the plasma exposure of therapeutic proteins.
聚乙二醇化是延长蛋白质治疗药物血浆暴露时间的标准方法，但存在局限性。我们探讨了通过可逆加成-断裂链转移（RAFT）制备的聚合物是否可以提供比聚乙二醇（PEG）更好的替代物。合成了四种具有不同组成、摩尔质量（M）和结构的RAFT聚合物，包括N-（2-羟丙基）甲基丙烯酰胺的均聚物（pHPMA）以及HPMA与聚（乙二醇甲基醚丙烯酸酯）p（HPMA-co-PEGA）的统计共聚物；HPMA与N-丙烯酰基吗啉，p（HPMA-co-NAM）；以及HPMA与N-异丙基丙烯酰胺，p（HPMA-co-NIPAM）。然后在大鼠中评估了这些聚合物的静脉药代动力学。随后评估了p（HPMA-co-NIPAM）缀合的曲妥珠单抗Fab'和全长单克隆抗体的体外活性和体内药代动力学。与其他p（HPMA）聚合物或PEG相比，无论分子量如何，p（HPMA-co-NIPAM）都更有效地延长了血浆暴露时间。当与曲妥珠单抗-Fab'缀合时，p（HPMA-co-NIPAM）延长了Fab'的血浆暴露时间，类似于PEG-Fab'。还检查了在静脉内和皮下注射p（HPMA-co-NIPAM）缀合的曲妥珠单抗单克隆抗体7天后大鼠体内抗PEG IgM的产生，结果显示其免疫原性低于聚乙二醇化构建体。这些数据表明，p（HPMA-co-NIPAM）作为一种有前景的共聚物，有潜力作为PEG的替代缀合策略，以延长治疗性蛋白质的血浆暴露时间。
