Systemic and local delivery of siRNA to the CNS and periphery via anti-IGF1R antibody conjugation.
- 1Ionis Pharmaceuticals Inc., 2855 Gazelle Ct, Carlsbad, CA 92010, USA.
- 2ABL Bio Inc., 456, Bongeunsa-ro, Gangnam-gu, Seoul 06153, Republic of Korea.
Abstract
siRNA delivery platforms capable of accessing both central and peripheral tissues are critically needed to expand the therapeutic potential of oligonucleotides. To address this, we developed an siRNA-antibody conjugate by attaching an Hprt-targeting siRNA to an engineered antibody shuttle. This shuttle targets the insulin-like growth factor 1 receptor (IGF1R) using a fused antibody fragment (Clone F) and utilizes an antibody backbone with no tissue-relevant binding in this study. The resulting conjugate, designated Clone F-Hprt, demonstrated robust in vivo knockdown across multiple tissues. Clone F-Hprt demonstrated enhanced penetration into central nervous system (CNS) tissues compared to unconjugated siRNA following intracerebroventricular (ICV) and intravenous (IV) administration. In peripheral tissues, Clone F-Hprt achieved widespread knockdown in the muscle, heart, and lung, consistent with IGF1R expression. Under the conditions tested, no overt tolerability findings were observed based on home-cage behavior, body weight monitoring, and CNS inflammatory marker expression. The substantial progress of transferrin receptor (TfR)-targeted receptor-mediated delivery underscores the translational potential of blood-brain barrier (BBB) shuttle strategies and supports the exploration of complementary receptors such as IGF1R. Our findings highlight IGF1R as an alternative receptor capable of supporting delivery across both central and peripheral tissues, offering a complementary strategy for expanding the therapeutic landscape of oligonucleotide delivery.
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BibTeX
@article{tian2026systemic,
title = {{Systemic and local delivery of siRNA to the CNS and periphery via anti-IGF1R antibody conjugation.}},
author = {Mengnan Tian and Mehran Nikan and Miran Yoo and Stephanie Klein and Seung-Hwan Kwon and John Matson and Dongin Kim and Jinwon Jung and Sumin Hyeon and Byeong Min Yoo and Hyeon Ji Park and Michael Tanowitz and Asa Wahlander and Weon-Kyoo You and Hakju Kwon and Janel Huffman and Thazha P Prakash and Sang Hoon Lee and Hien Zhao and Sungwon An},
journal = {Molecular therapy. Nucleic acids},
year = {2026},
month = sep,
doi = {10.1016/j.omtn.2026.103105},
url = {https://europepmc.org/article/MED/42927339},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Systemic and local delivery of siRNA to the CNS and periphery via anti-IGF1R antibody conjugation.
AU - Mengnan Tian
AU - Mehran Nikan
AU - Miran Yoo
AU - Stephanie Klein
AU - Seung-Hwan Kwon
AU - John Matson
AU - Dongin Kim
AU - Jinwon Jung
AU - Sumin Hyeon
AU - Byeong Min Yoo
AU - Hyeon Ji Park
AU - Michael Tanowitz
AU - Asa Wahlander
AU - Weon-Kyoo You
AU - Hakju Kwon
AU - Janel Huffman
AU - Thazha P Prakash
AU - Sang Hoon Lee
AU - Hien Zhao
AU - Sungwon An
PY - 2026
DA - 2026/09/18
JO - Molecular therapy. Nucleic acids
DO - 10.1016/j.omtn.2026.103105
UR - https://europepmc.org/article/MED/42927339
AB - siRNA delivery platforms capable of accessing both central and peripheral tissues are critically needed to expand the therapeutic potential of oligonucleotides. To address this, we developed an siRNA-antibody conjugate by attaching an Hprt-targeting siRNA to an engineered antibody shuttle. This shuttle targets the insulin-like growth factor 1 receptor (IGF1R) using a fused antibody fragment (Clone F) and utilizes an antibody backbone with no tissue-relevant binding in this study. The resulting conjugate, designated Clone F-Hprt, demonstrated robust in vivo knockdown across multiple tissues. Clone F-Hprt demonstrated enhanced penetration into central nervous system (CNS) tissues compared to unconjugated siRNA following intracerebroventricular (ICV) and intravenous (IV) administration. In peripheral tissues, Clone F-Hprt achieved widespread knockdown in the muscle, heart, and lung, consistent with IGF1R expression. Under the conditions tested, no overt tolerability findings were observed based on home-cage behavior, body weight monitoring, and CNS inflammatory marker expression. The substantial progress of transferrin receptor (TfR)-targeted receptor-mediated delivery underscores the translational potential of blood-brain barrier (BBB) shuttle strategies and supports the exploration of complementary receptors such as IGF1R. Our findings highlight IGF1R as an alternative receptor capable of supporting delivery across both central and peripheral tissues, offering a complementary strategy for expanding the therapeutic landscape of oligonucleotide delivery.
SN - 2162-2531
ER -