CELLIVERY

PIPELINE

CV-02

PIPELINE | CV-02
iCP-SOCS3

Suppressor of cytokine signaling 3 (SOCS3) functions as a negative-feedback regulator of JAK/STAT signaling that suppresses JAK kinase activity and promotes degradation of the activated cytokine receptor complex resulting in the anti-inflammatory and anti-cancer effect due to suppression of inflammation-inducing cytokine signaling. Loss of SOCS3 enhances the growth and survival of some solid tumors; therefore, methods to replenish intracellular levels of the protein may provide an effective therapy against solid tumors dependent on JAK/STAT signaling for growth or survival.

To control the JAK/STAT signaling negatively, we previously developed cell-permeable SOCS3 recombinant protein (CP-SOCS3) enabled by a previous generation of hydrophobic CPP (membrane-translocating motif: MTM) derived from FGF4 in order to explore the possibility of blocking cytokine-induced signaling pathway (Nat Med. 2005;11:892-898). However, these previously developed recombinant CP-SOCS3 proteins showed extremely low solubility, yield, and relative low cell- and tissue-permeability. To overcome these limitations, we have newly developed recombinant SOCS3 proteins fused to novel hydrophobic CPP, advanced macromolecule transduction domain (aMTD), to greatly increase their solubility, manufacturing yield, and efficiency of membrane penetrating ability named as improved cell-permeable (iCP)-SOCS3 proteins.

iCP-SOCS3 has the therapeutic applicability to treat various cancers including hepatoma, pancreatic cancer, lung cancer, colorectal cancer, gastric cancer and glioblastoma, and inflammatory disorders through protein-based intracellular replacement therapy.

iCP-SOCS3 suppressed cancer-associated phenotypes, induced apoptosis and triggered alteration in biomarker expression (e.g., cell cycle, apoptosis, angiogenesis) consistent withpreviously described effects of SOCS3. In contrast, iCP-SOCS3 did not affect proliferation and apoptosis of non-cancerous cells. In addition, iCP-SOCS3 also significantly suppressed the tumor growth in various cancer cell-derived xenograft (CDX) models and significantly inhibited tumor angiogenesis in vivo, leading to inhibition of tumor angiogenesis. Furthermore, iCP-SOCS3 inhibited STAT3 phosphorylation and reduced secretion of proinflammatory cytokines leading to attenuated progression of inflammatory bowel disease (IBD) and acute liver injury.

iCP-SOCS3 suppressed cancer-associated phenotypes, induced apoptosis and triggered alteration in biomarker expression (e.g., cell cycle, apoptosis, angiogenesis) consistent with previously described effects of SOCS3. In contrast, iCP-SOCS3 did not affect proliferation and apoptosis of non-cancerous cells. In addition, iCP-SOCS3 also significantly suppressed the tumor growth in various cancer cell-derived xenograft (CDX) models and significantly inhibited tumor angiogenesis in vivo, leading to inhibition of tumor angiogenesis. Furthermore, iCP-SOCS3 inhibited STAT3 phosphorylation and reduced secretion of proinflammatory cytokines leading to attenuated progression of inflammatory bowel disease (IBD) and acute liver injury.