改造生物药物用聚合物（如聚乙二醇）已经表明具有临床益处；然而，对PEG化衍生物的市场后监测揭示出PEG相关的毒性问题，引发对替代物的寻找。我们探讨聚-L-谷氨酸（PGA）与抗胰岛素样生长因子1受体抗体（AVE1642）的共轭如何调节生物纳米界面和抗肿瘤活性，在临床前前列腺癌模型中。原始和PGA修饰的AVE1642在体外表现出类似的抗肿瘤活性；但是，AVE1642促进IGF-1R内化，而PGA共轭则促进了更高亲和力的IGF-1R结合，从而抑制了IGF-1R的内化和改变了细胞的运输。AVE1642减弱了磷酸肌醇3-激酶信号，而PGA-AVE1642则抑制了磷酸肌醇3-激酶和丝裂原活化蛋白激酶信号。PGA共轭还增强了AVE1642在原位前列腺癌小鼠模型中的抗肿瘤活性，而PGA-AVE1642比AVE1642更显著地抑制了癌细胞的增殖/血管生成。这些发现表明PGA共轭调节了抗体的生物纳米界面、作用机制和治疗活性。版权所有©2023 Elsevier Ltd.发表。

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.Copyright © 2023. Published by Elsevier Ltd.