title: Multivalent scaffold proteins as superagonists of TRAIL receptor 2-induced apoptosis.
abstract: Activation of TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2) can induce apoptosis in a variety of human cancer cell lines and xenografts, while lacking toxicity in normal cells. The natural ligand and agonistic antibodies show antitumor activity in preclinical models of cancer, and this had led to significant excitement in the clinical potential of these agents. Unfortunately, this optimism has been tempered by trial data that, thus far, are not showing clear signs of efficacy in cancer patients. The reasons for discrepant preclinical and clinical observations are not understood, but one possibility is that the current TRAILR2 agonists lack sufficient potency to achieve a meaningful response in patients. Toward addressing that possibility, we have developed multivalent forms of a new binding scaffold (Tn3) that are superagonists of TRAILR2 and can induce apoptosis in tumor cell lines at subpicomolar concentrations. The monomer Tn3 unit was a fibronectin type III domain engineered for high-affinity TRAILR2 binding. Multivalent presentation of this basic unit induced cell death in TRAILR2-expressing cell lines. Optimization of binding affinity, molecular format, and valency contributed to cumulative enhancements of agonistic activity. An optimized multivalent agonist consisting of 8 tandem Tn3 repeats was highly potent in triggering cell death in TRAIL-sensitive cell lines and was 1 to 2 orders of magnitude more potent than TRAIL. Enhanced potency was also observed in vivo in a tumor xenograft setting. The TRAILR2 superagonists described here have the potential for superior clinical activity in settings insensitive to the current therapeutic agonists that target this pathway.
authors: Department of Antibody Discovery and Protein Engineering, MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
authors: Jeffery S
authors: JS
authors: Swers
authors: Luba
authors: L
authors: Grinberg
authors: Lin
authors: L
authors: Wang
authors: Hui
authors: H
authors: Feng
authors: Kristen
authors: K
authors: Lekstrom
authors: Rosa
authors: R
authors: Carrasco
authors: Zhan
authors: Z
authors: Xiao
authors: Ivan
authors: I
authors: Inigo
authors: Ching Ching
authors: CC
authors: Leow
authors: Herren
authors: H
authors: Wu
authors: David A
authors: DA
authors: Tice
authors: Manuel
authors: M
authors: Baca
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011993:Recombinant Fusion Proteins