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 |
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creator | 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 |
description | 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. |
doi_str_mv | 10.1158/0008-5472.CAN-20-2178 |
format | Article |
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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.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-20-2178</identifier><identifier>PMID: 33687950</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Antineoplastic Agents - pharmacology ; Apoptosis ; Cell Proliferation ; Colorectal Neoplasms - drug therapy ; Colorectal Neoplasms - genetics ; Colorectal Neoplasms - metabolism ; Colorectal Neoplasms - pathology ; Factor IX - pharmacology ; Female ; Humans ; Immunoglobulin Fc Fragments - pharmacology ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - metabolism ; Pancreatic Neoplasms - pathology ; Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics ; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism ; Recombinant Fusion Proteins - pharmacology ; TNF-Related Apoptosis-Inducing Ligand - genetics ; TNF-Related Apoptosis-Inducing Ligand - metabolism ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays</subject><ispartof>Cancer research (Chicago, Ill.), 2021-06, Vol.81 (12), p.3402-3414</ispartof><rights>2021 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-869ed3f2961414bf688876f3e08484b7002fc5cbf584efd3f3a9c013da0f42573</citedby><cites>FETCH-LOGICAL-c356t-869ed3f2961414bf688876f3e08484b7002fc5cbf584efd3f3a9c013da0f42573</cites><orcidid>0000-0002-0089-0416 ; 0000-0002-9683-3562</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3356,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33687950$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Phillips, Darren C</creatorcontrib><creatorcontrib>Buchanan, Fritz G</creatorcontrib><creatorcontrib>Cheng, Dong</creatorcontrib><creatorcontrib>Solomon, Larry R</creatorcontrib><creatorcontrib>Xiao, Yu</creatorcontrib><creatorcontrib>Xue, John</creatorcontrib><creatorcontrib>Tahir, Stephen K</creatorcontrib><creatorcontrib>Smith, Morey L</creatorcontrib><creatorcontrib>Zhang, Haichao</creatorcontrib><creatorcontrib>Widomski, Deborah</creatorcontrib><creatorcontrib>Abraham, Vivek C</creatorcontrib><creatorcontrib>Xu, Nan</creatorcontrib><creatorcontrib>Liu, Zhihong</creatorcontrib><creatorcontrib>Zhou, Li</creatorcontrib><creatorcontrib>DiGiammarino, Enrico</creatorcontrib><creatorcontrib>Lu, Xin</creatorcontrib><creatorcontrib>Rudra-Ganguly, Nandini</creatorcontrib><creatorcontrib>Trela, Bruce</creatorcontrib><creatorcontrib>Morgan-Lappe, Susan E</creatorcontrib><title>Hexavalent TRAIL Fusion Protein Eftozanermin Alfa Optimally Clusters Apoptosis-Inducing TRAIL Receptors to Induce On-Target Antitumor Activity in Solid Tumors</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>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.</description><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Cell Proliferation</subject><subject>Colorectal Neoplasms - drug therapy</subject><subject>Colorectal Neoplasms - genetics</subject><subject>Colorectal Neoplasms - metabolism</subject><subject>Colorectal Neoplasms - pathology</subject><subject>Factor IX - pharmacology</subject><subject>Female</subject><subject>Humans</subject><subject>Immunoglobulin Fc Fragments - pharmacology</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>Pancreatic Neoplasms - drug therapy</subject><subject>Pancreatic Neoplasms - genetics</subject><subject>Pancreatic Neoplasms - metabolism</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics</subject><subject>Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism</subject><subject>Recombinant Fusion Proteins - pharmacology</subject><subject>TNF-Related Apoptosis-Inducing Ligand - genetics</subject><subject>TNF-Related Apoptosis-Inducing Ligand - metabolism</subject><subject>Tumor Cells, Cultured</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kc9u3CAQxlHVqNmmfYRWHHshBQM2Plqr_Flpla2S7RmxGCIqbFzAUbcPk2ctTrY5jWbmNzOa7wPgC8GXhHDxHWMsEGdNdbnu7lCFUUUa8Q6sCKcCNYzx92D1xpyDjyn9KiknmH8A55TWomk5XoHnW_NHPSlvxgz3991mC6_n5MIIf8SQjRvhlc3hrxpNHErSeavgbspuUN4f4drPKZuYYDeFKYfkEtqM_azd-Hhadm-0KZ2C5ABfegbuRrRX8dFk2I3Z5XkIEXY6uyeXj7AceQje9XC_1NMncGaVT-bzKV6An9dX-_Ut2u5uNutuizTldUaibk1PbdXWhBF2sLUQoqktNVgwwQ4NxpXVXB8sF8zYQlLVakxor7BlFW_oBfj2uneK4fdsUpaDS9p4Xz4Pc5IVa9uWkoZXBeWvqI4hpWisnGLRIx4lwXKxRi6yy0V2WayRFZaLNWXu6-nEfBhM_zb13wv6D7dTi_Q</recordid><startdate>20210615</startdate><enddate>20210615</enddate><creator>Phillips, Darren C</creator><creator>Buchanan, Fritz G</creator><creator>Cheng, Dong</creator><creator>Solomon, Larry R</creator><creator>Xiao, Yu</creator><creator>Xue, John</creator><creator>Tahir, Stephen K</creator><creator>Smith, Morey L</creator><creator>Zhang, Haichao</creator><creator>Widomski, Deborah</creator><creator>Abraham, Vivek C</creator><creator>Xu, Nan</creator><creator>Liu, Zhihong</creator><creator>Zhou, Li</creator><creator>DiGiammarino, Enrico</creator><creator>Lu, Xin</creator><creator>Rudra-Ganguly, Nandini</creator><creator>Trela, Bruce</creator><creator>Morgan-Lappe, Susan E</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-0089-0416</orcidid><orcidid>https://orcid.org/0000-0002-9683-3562</orcidid></search><sort><creationdate>20210615</creationdate><title>Hexavalent TRAIL Fusion Protein Eftozanermin Alfa Optimally Clusters Apoptosis-Inducing TRAIL Receptors to Induce On-Target Antitumor Activity in Solid Tumors</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-869ed3f2961414bf688876f3e08484b7002fc5cbf584efd3f3a9c013da0f42573</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis</topic><topic>Cell Proliferation</topic><topic>Colorectal Neoplasms - drug therapy</topic><topic>Colorectal Neoplasms - genetics</topic><topic>Colorectal Neoplasms - metabolism</topic><topic>Colorectal Neoplasms - pathology</topic><topic>Factor IX - pharmacology</topic><topic>Female</topic><topic>Humans</topic><topic>Immunoglobulin Fc Fragments - pharmacology</topic><topic>Mice</topic><topic>Mice, Inbred NOD</topic><topic>Mice, SCID</topic><topic>Pancreatic Neoplasms - drug therapy</topic><topic>Pancreatic Neoplasms - genetics</topic><topic>Pancreatic Neoplasms - metabolism</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics</topic><topic>Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism</topic><topic>Recombinant Fusion Proteins - pharmacology</topic><topic>TNF-Related Apoptosis-Inducing Ligand - genetics</topic><topic>TNF-Related Apoptosis-Inducing Ligand - metabolism</topic><topic>Tumor Cells, Cultured</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Phillips, Darren C</creatorcontrib><creatorcontrib>Buchanan, Fritz G</creatorcontrib><creatorcontrib>Cheng, Dong</creatorcontrib><creatorcontrib>Solomon, Larry R</creatorcontrib><creatorcontrib>Xiao, Yu</creatorcontrib><creatorcontrib>Xue, John</creatorcontrib><creatorcontrib>Tahir, Stephen K</creatorcontrib><creatorcontrib>Smith, Morey L</creatorcontrib><creatorcontrib>Zhang, Haichao</creatorcontrib><creatorcontrib>Widomski, Deborah</creatorcontrib><creatorcontrib>Abraham, Vivek C</creatorcontrib><creatorcontrib>Xu, Nan</creatorcontrib><creatorcontrib>Liu, Zhihong</creatorcontrib><creatorcontrib>Zhou, Li</creatorcontrib><creatorcontrib>DiGiammarino, Enrico</creatorcontrib><creatorcontrib>Lu, Xin</creatorcontrib><creatorcontrib>Rudra-Ganguly, Nandini</creatorcontrib><creatorcontrib>Trela, Bruce</creatorcontrib><creatorcontrib>Morgan-Lappe, Susan E</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Phillips, Darren C</au><au>Buchanan, Fritz G</au><au>Cheng, Dong</au><au>Solomon, Larry R</au><au>Xiao, Yu</au><au>Xue, John</au><au>Tahir, Stephen K</au><au>Smith, Morey L</au><au>Zhang, Haichao</au><au>Widomski, Deborah</au><au>Abraham, Vivek C</au><au>Xu, Nan</au><au>Liu, Zhihong</au><au>Zhou, Li</au><au>DiGiammarino, Enrico</au><au>Lu, Xin</au><au>Rudra-Ganguly, Nandini</au><au>Trela, Bruce</au><au>Morgan-Lappe, Susan E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hexavalent TRAIL Fusion Protein Eftozanermin Alfa Optimally Clusters Apoptosis-Inducing TRAIL Receptors to Induce On-Target Antitumor Activity in Solid Tumors</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2021-06-15</date><risdate>2021</risdate><volume>81</volume><issue>12</issue><spage>3402</spage><epage>3414</epage><pages>3402-3414</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><abstract>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.</abstract><cop>United States</cop><pmid>33687950</pmid><doi>10.1158/0008-5472.CAN-20-2178</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-0089-0416</orcidid><orcidid>https://orcid.org/0000-0002-9683-3562</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Animals Antineoplastic Agents - pharmacology Apoptosis Cell Proliferation Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics Colorectal Neoplasms - metabolism Colorectal Neoplasms - pathology Factor IX - pharmacology Female Humans Immunoglobulin Fc Fragments - pharmacology Mice Mice, Inbred NOD Mice, SCID Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - genetics Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism Recombinant Fusion Proteins - pharmacology TNF-Related Apoptosis-Inducing Ligand - genetics TNF-Related Apoptosis-Inducing Ligand - metabolism Tumor Cells, Cultured Xenograft Model Antitumor Assays |
title | Hexavalent TRAIL Fusion Protein Eftozanermin Alfa Optimally Clusters Apoptosis-Inducing TRAIL Receptors to Induce On-Target Antitumor Activity in Solid Tumors |
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