Hexavalent TRAIL Fusion Protein Eftozanermin Alfa Optimally Clusters Apoptosis-Inducing TRAIL Receptors to Induce On-Target Antitumor Activity in Solid Tumors

TRAIL can activate cell surface death receptors, resulting in potent tumor cell death via induction of the extrinsic apoptosis pathway. Eftozanermin alfa (ABBV-621) is a second generation TRAIL receptor agonist engineered as an IgG1-Fc mutant backbone linked to two sets of trimeric native single-cha...

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Veröffentlicht in:Cancer research (Chicago, Ill.) Ill.), 2021-06, Vol.81 (12), p.3402-3414
Hauptverfasser: Phillips, Darren C, Buchanan, Fritz G, Cheng, Dong, Solomon, Larry R, Xiao, Yu, Xue, John, Tahir, Stephen K, Smith, Morey L, Zhang, Haichao, Widomski, Deborah, Abraham, Vivek C, Xu, Nan, Liu, Zhihong, Zhou, Li, DiGiammarino, Enrico, Lu, Xin, Rudra-Ganguly, Nandini, Trela, Bruce, Morgan-Lappe, Susan E
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Sprache:eng
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Zusammenfassung:TRAIL can activate cell surface death receptors, resulting in potent tumor cell death via induction of the extrinsic apoptosis pathway. Eftozanermin alfa (ABBV-621) is a second generation TRAIL receptor agonist engineered as an IgG1-Fc mutant backbone linked to two sets of trimeric native single-chain TRAIL receptor binding domain monomers. This hexavalent agonistic fusion protein binds to the death-inducing DR4 and DR5 receptors with nanomolar affinity to drive on-target biological activity with enhanced caspase-8 aggregation and death-inducing signaling complex formation independent of FcγR-mediated cross-linking, and without clinical signs or pathologic evidence of toxicity in nonrodent species. ABBV-621 induced cell death in approximately 36% (45/126) of solid cancer cell lines at subnanomolar concentrations. An patient-derived xenograft (PDX) screen of ABBV-621 activity across 15 different tumor indications resulted in an overall response (OR) of 29% (47/162). Although DR4 ( ) and/or DR5 ( ) expression levels did not predict the level of response to ABBV-621 activity mutations were associated with elevated and and were enriched in ABBV-621-responsive colorectal carcinoma PDX models. To build upon the OR of ABBV-621 monotherapy in colorectal cancer (45%; 10/22) and pancreatic cancer (35%; 7/20), we subsequently demonstrated that inherent resistance to ABBV-621 treatment could be overcome in combination with chemotherapeutics or with selective inhibitors of BCL-X . In summary, these data provide a preclinical rationale for the ongoing phase 1 clinical trial (NCT03082209) evaluating the activity of ABBV-621 in patients with cancer. SIGNIFICANCE: This study describes the activity of a hexavalent TRAIL-receptor agonistic fusion protein in preclinical models of solid tumors that mechanistically distinguishes this molecular entity from other TRAIL-based therapeutics.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-20-2178