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[D. Medicine/Translational Research] D-6

A SOCS3 Competitor Protein Overcomes Leptin Resistance By

Activating The JAK/STAT3 Signaling In Hypothalamic Neurons

Yerim Kang¹, Sukyeong Jeong¹, Sujung Lee¹, Dabin Guk¹, Moonyoung Choi¹, Eunna Chung¹,

Daewoong Jo¹*

¹Cellivery R&D Institute, Cellivery Therapeutics, Inc., Seoul 03929, Korea

The main obstacle to treat patients with obesity is inappropriate appetite regulation induced by leptin resistance.

Therapeuticmolecule Systemic Delivery Technology (TSDT) platform using an advanced macromolecule transduction
domain (aMTD), a group of optimized CPPs to improve the cell-permeability of cargos via direct penetration,

provides a powerful delivery mechanism for therapeutic proteins. Here, Cell-Permeable truncated SOCS3 SH2
domain (CP-SD) has been developed by fusing the truncated SH2 domain of human SOCS3 with aMTD and a

solubilization domain, and its therapeutic potency has been evaluated. As a result, this recombinant protein was
homogeneous and soluble at concentration of up to 8 μg/μl, and also stable at 37 degrees up to 24 hours. CP-SD

selectively bound to the activated leptin receptor and overcame leptin resistance at concentration of 100 nM
through competitively inhibiting the interaction between leptin receptor and highly expressed SOCS3. In diet-

induced obesity (DIO) mice fed high fat diet (60% calories as fat), CP-SD rapidly reduced body weight by 3.7% and
food intake by 22.2% in 6 days (20 mg/kg, IV, daily injection). These results suggest that CP-SD is a promising

therapeutic protein to treat severe obesity by restoring leptin sensitivity and suppressing abnormally elevated
appetite.