Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) binds to death receptors and induces apoptosis in various cancer cell lines while sparing normal cells. Recombinant TRAIL has shown good safety and efficacy profiles in preclinical cancer models. However, clinical success has been limited due to poor PK and development of resistance to death receptor-induced apoptosis. We have addressed these issues by creating a fusion protein of TRAIL and arginine deiminase (ADI). The fusion protein benefits from structural and functional synergies between its two components and has an extended half-life in vivo. ADI downregulates survivin, upregulates DR5 receptor and sensitizes cancer cells to TRAIL induced apoptosis. ADI-TRAIL fusion protein was efficacious in a number of cell lines and synergized with some standard of care drugs. In an HCT116 xenograft model ADI-TRAIL localized to the tumor and induced dose-dependent tumor regression, the fusion protein was superior to rhTRAIL administered at the same molar amounts.
Highlights
TRAIL, is a trimeric protein, a Tumor necrosis factor (TNF) superfamily member, expressed as a typeII transmembrane protein and plays a physiological role in anti-tumor immune surveillance [1,2,3,4,5,6]
Clinical success has been limited due to poor PK and development of resistance to death receptor-induced apoptosis. We have addressed these issues by creating a fusion protein of TRAIL and arginine deiminase (ADI)
A number of cancer cell lines were treated with serially diluted ADI-PEG 20 or serially diluted recombinant human TRAIL (rhTRAIL) or the combination of the two
Summary
TRAIL ( known as Apo ligand), is a trimeric protein, a TNF superfamily member, expressed as a typeII transmembrane protein and plays a physiological role in anti-tumor immune surveillance [1,2,3,4,5,6]. Active soluble TRAIL can be generated after cleavage at the stalk domain. TRAIL receptor agonists, soluble recombinant TRAIL and antibodies against DR4 and DR5 receptors, have been pursued as a promising anti-cancer strategy and showed favorable activity in pre-clinical studies [5,6,7,8,9,10,11]. A number of groups addressed this issue through protein engineering (e.g. PEGylation, single chain Fc fusion, etc.) with the resulting molecules having improved PK with differential effect on activity ranging from less potent to more potent than the unmodified rhTRAIL trimer [14,15,16,17,18,19,20]
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