Death Receptor 4 & 5 (DR4 & DR5) Agonists

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Publisher: La Merie Publishing
Format: Word Table
Product Line: Target Pipeline List
Product Code: LMTPL036
Release Date: January of 2019

Death Receptor 4 & 5 (DR4 & DR5) Agonists – Target Pipeline List 01/2019

Target: TNF-related apoptosis inducing ligand receptor 1, TRAIL receptor 1, TRAIL-R1, death receptor 4, DR4, TRAIL receptor 2, TRAIL-R2, death receptor 5, DR5

This Target Pipeline list provides an overview of agonist antibodies and fusion proteins targeting death receptor 4 and/or 5 in development for treatment of cancer.

The discovery of tumor necrosis factor (TNF) superfamily members and more specifically TNF-related apoptosis-inducing ligand (TRAIL), the only cytokine of the family capable of eradicating selectively cancer cells, led to the development of numerous TRAIL derivatives targeting death receptor 4 (DR4) and death receptor 5 (DR5) for cancer therapy. With a few exceptions, preliminary attempts to use recombinant TRAIL, agonistic antibodies, or derivatives to target TRAIL agonist receptors in the clinic have been fairly disappointing. Nevertheless, efforts are ongoing to develop novel strategic options to target TRAIL receptors based on multimeric agonist molecules.

TRAIL can bind as a trimer to membrane-bound or soluble receptors, but it is only the two closely related cell surface death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5), which express intracellular functional death domains, that can preferentially trigger the extrinsic pathway of tumor cells. Trimerization of receptors leads to the formation of the death-inducing signaling complex (DISC). DISC recruits and activates initiator caspases, triggering a series of downstream events that ultimately result in apoptotic cell death.

To date, five TRAIL receptors have been identified in humans: DR4, DR5, DcR1, DcR2, and osteoprotegerin (OPG). These receptors, like all members of the TNF super family, are characterized by an extracellular domain, rich in cysteines, which are essential for the binding of their cognate ligand. Only two of them, DR4 and DR5, harbor the death domain (DD), a stretch of ~90 amino acids (aa), required and sufficient to activate the apoptotic machinery; they consequently represent promising targets for cancer treatment.

DR4, is a N-glycosylated protein of 468 aa, also known as tumor necrosis factor receptor superfamily member 10A, CD261, Apo2, TNF-related apoptosis-inducing ligand receptor 1, and TRAILR-1. DR5 is O-glycosylated. It is also known as tumor necrosis factor receptor superfamily member 10B, CD262, Killer/Ly98, TNF-related apoptosis-inducing ligand receptor 2, TRICK2A, and TRICKB.

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