1. Poly-l-glutamic acid modification modulates the bio-nano interface of a therapeutic anti-IGF-1R antibody in prostate cancer.
- Author
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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, and Vicent, María J.
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PROSTATE cancer , *BIOPOLYMERS , *MITOGEN-activated protein kinases , *PHOSPHATIDYLINOSITOL 3-kinases , *CANCER cell proliferation , *INSULIN receptors - Abstract
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. Poly- l -glutamic acid (PGA) conjugation alters the biological properties of a human monoclonal antibody against IGFR (AVE1642), increasing its antitumoral activity due to the capability to alter the bio-nano interaction between PGA-AVE1642 conjugate and IGF-1R in aggressive prostate cancer. These differential bio-nano interactions result in differential effects on critical cellular signaling pathways and the tumor microenvironment. [Display omitted] [ABSTRACT FROM AUTHOR]
- Published
- 2023
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