Vicente-Ruiz Sonia, Armiñán Ana, Maso Katia, Gallon Elena, Zagorodko Oleksandr, Movellan Julie, Rodríguez-Otormín Fernanda, Baues Maike, May Jan-Niklas, De Lorenzi Federica, Lammers Twan, Vicent María J
Polymer Therapeutics Laboratory, Prince Felipe Research Center (CIPF), 46012, Valencia, Spain.
Polymer Therapeutics Laboratory, Prince Felipe Research Center (CIPF), 46012, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, 28029, Madrid, Spain.
Biomaterials. 2023 Oct;301:122280. doi: 10.1016/j.biomaterials.2023.122280. Epub 2023 Aug 14.
Modifying biological agents with polymers such as polyethylene glycol (PEG) has demonstrated clinical benefits; however, post-market surveillance of PEGylated derivatives has revealed PEG-associated toxicity issues, prompting the search for alternatives. We explore how conjugating a poly-l-glutamic acid (PGA) to an anti-insulin growth factor 1 receptor antibody (AVE1642) modulates the bio-nano interface and anti-tumor activity in preclinical prostate cancer models. Native and PGA-modified AVE1642 display similar anti-tumor activity in vitro; however, AVE1642 prompts IGF-1R internalization while PGA conjugation prompts higher affinity IGF-1R binding, thereby inhibiting IGF-1R internalization and altering cell trafficking. AVE1642 attenuates phosphoinositide 3-kinase signaling, while PGA-AVE1642 inhibits phosphoinositide 3-kinase and mitogen-activated protein kinase signaling. PGA conjugation also enhances AVE1642's anti-tumor activity in an orthotopic prostate cancer mouse model, while PGA-AVE1642 induces more significant suppression of cancer cell proliferation/angiogenesis than AVE1642. These findings demonstrate that PGA conjugation modulates an antibody's bio-nano interface, mechanism of action, and therapeutic activity.
用聚乙二醇（PEG）等聚合物修饰生物制剂已显示出临床益处；然而，对聚乙二醇化衍生物的上市后监测发现了与PEG相关的毒性问题，促使人们寻找替代方案。我们探讨了将聚-L-谷氨酸（PGA）与抗胰岛素生长因子1受体抗体（AVE1642）偶联如何在临床前前列腺癌模型中调节生物纳米界面和抗肿瘤活性。天然的和PGA修饰的AVE1642在体外显示出相似的抗肿瘤活性；然而，AVE1642促使胰岛素样生长因子1受体（IGF-1R）内化，而PGA偶联促使更高亲和力的IGF-1R结合，从而抑制IGF-1R内化并改变细胞运输。AVE1642减弱磷酸肌醇3激酶信号传导，而PGA-AVE1642抑制磷酸肌醇3激酶和丝裂原活化蛋白激酶信号传导。PGA偶联还增强了AVE1642在原位前列腺癌小鼠模型中的抗肿瘤活性，而PGA-AVE1642比AVE1642诱导更显著地抑制癌细胞增殖/血管生成。这些发现表明，PGA偶联调节了抗体的生物纳米界面、作用机制和治疗活性。
