Grabody B, an IGF1 receptor-based shuttle, mediates efficient delivery of biologics across the blood-brain barrier

Effective delivery of therapeutics to the brain is challenging. Molecular shuttles use receptors expressed on brain endothelial cells to deliver therapeutics. Antibodies targeting transferrin receptor (TfR) have been widely developed as molecular shuttles. However, the TfR-based approach raises conc...

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Published in:Cell reports methods 2022-11, Vol.2 (11), p.100338, Article 100338
Main Authors: Shin, Jung-Won, An, Sungwon, Kim, Dongin, Kim, Hyunjoo, Ahn, Jinhyung, Eom, Jaehyun, You, Weon-Kyoo, Yun, Hyesu, Lee, Bora, Sung, Byungje, Jung, Jinwon, Kim, Sehyun, Son, Yonggyu, Sung, Eunsil, Lee, Hanbyul, Lee, Suyeon, Song, Daehae, Pak, Youngdon, Sandhu, Jagdeep K., Haqqani, Arsalan S., Stanimirovic, Danica B., Yoo, Jiseon, Kim, Donghwan, Maeng, Sungho, Lee, Jeonghun, Lee, Sang Hoon
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Language:English
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Summary:Effective delivery of therapeutics to the brain is challenging. Molecular shuttles use receptors expressed on brain endothelial cells to deliver therapeutics. Antibodies targeting transferrin receptor (TfR) have been widely developed as molecular shuttles. However, the TfR-based approach raises concerns about safety and developmental burden. Here, we report insulin-like growth factor 1 receptor (IGF1R) as an ideal target for the molecular shuttle. We also describe Grabody B, an antibody against IGF1R, as a molecular shuttle. Grabody B has broad cross-species reactivity and does not interfere with IGF1R-mediated signaling. We demonstrate that administration of Grabody B-fused anti-alpha-synuclein (α-Syn) antibody induces better improvement in neuropathology and behavior in a Parkinson’s disease animal model than the therapeutic antibody alone due to its superior serum pharmacokinetics and enhanced brain exposure. The results indicate that IGF1R is an ideal shuttle target and Grabody B is a safe and efficient molecular shuttle. • IGF1R is enriched higher in the CNS than in the periphery • Grabody B, an anti-IGF1R antibody-based shuttle, does not cause safety issues in animals • Grabody B increases the BBB penetration of antibody therapeutics • Grabody B increases the efficacy of an anti-α-Syn antibody in a PD animal model To overcome the limited delivery of antibody therapeutics to the central nervous system due to the blood-brain barrier (BBB), molecular shuttles have been actively developed. The molecular shuttles were designed to bind to receptors at the surface of brain endothelial cells that are major components of the BBB. Most of the conventional molecular shuttles, however, exhibit low cross-reactivity, safety issues, or poor brain-penetrating capability. Here, we report a non-neutralizing anti-insulin-like growth factor 1 receptor (IGF1R) antibody (Grabody B) as a safe and efficient molecular shuttle that can be applicable to various therapeutic modalities for CNS-related disorders. Shin et al. demonstrate that Grabody B acts as a molecular shuttle to increase the BBB penetration of antibody therapeutics, which leads to increased efficacy in a disease model. Moreover, Grabody B shows improved safety in animal models.
ISSN:2667-2375
2667-2375
DOI:10.1016/j.crmeth.2022.100338