GX-BP2(STAT3-bioPROTAC)

Disease Indication

Atopic Dermatitis, Cancer

Development Stage

1. 1Confirmation of superior in vitro STAT3 degradation effect compared to small-molecule PROTACs.
2. 2Confirmation of enhanced effects compared to dupilumab in a multiple cytokine-induced atopic dermatitis model (in vitro): 1) Restoration of skin barrier proteins and 2) Inhibition of pro-inflammatory cytokine secretion.
3. 2Demonstration of superior in vivo efficacy compared to dupilumab in an Atopic Dermatitis (AD) model.

Summary

1. 1As a bioPROTAC agent that selectively degrades the STAT3 protein—an established therapeutic target in Atopic Dermatitis and Cancer—it holds significant therapeutic potential in STAT3-driven diseases, including inflammatory skin diseases and various cancers.
2. 2Possesses a high safety profile: Lowered off-target risk due to superior STAT3 protein selectivity, and reduced potential for side effects through local delivery to dermal cells of the skin.
3. 2Personalized combination therapies are necessary for Atopic Dermatitis patients, considering factors such as age, disease severity, and triggering factors. Atopic Dermatitis therapeutics based on a novel mechanism of action (MOA) for cases refractory to dupilumab.

Structure

This is a next-generation Targeted Protein Degrader (TPD) constructed as a direct fusion protein, comprising a nanobody that specifically binds to the STAT3 protein and an engineered E3 protein. It possesses innovative differentiators compared to first-generation TPDs, such as small-molecule-based PROTACs. This is a next-generation Targeted Protein Degrader (TPD) constructed as a direct fusion protein, comprising a nanobody that specifically binds to the STAT3 protein and an engineered E3 protein. It possesses innovative differentiators compared to first-generation TPDs, such as small-molecule-based PROTACs.

Mechanism

1. 1GX-BP2 restores skin barrier function by selectively degrading the STAT3 protein, which is activated by IL-4/IL-13 in the JAK-STAT pathway.
2. 2Targeting a promising therapeutic target in cancer treatment by degrading STAT3.
3. 2Delivery of mRNA-encoded GX-BP2 to the dermal layer of the skin via LNPs through subcutaneous injection (SC injection).

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Characteristics

Enhanced degradation efficacy and high selectivity compared to small-molecule PROTACs.

Superior STAT3 degradation efficacy compared to 'KT-333' (a small-molecule VHL-recruiting PROTAC currently in Phase 1 clinical trials by Company K***).**

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Superior in vivo efficacy compared to dupilumab.

1. 1Administration of epd4305 at 1 mg/kg via subcutaneous (s.c.) injection, twice weekly (BIW) for a total of five doses, resulted in the observed alleviation of atopic dermatitis features.
2. 2H&E staining (40X image)

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