BIVV001, a new class of factor VIII replacement for hemophilia A that is independent of von Willebrand factor in primates and mice
Factor VIII (FVIII) replacement products enable comprehensive care in hemophilia A. Treatment goals in severe hemophilia A are expanding beyond low annualized bleed rates to include long-term outcomes associated with high sustained FVIII levels. Endogenous von Willebrand factor (VWF) stabilizes and...
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| Veröffentlicht in: | Blood 2020-04, Vol.135 (17), p.1484-1496 |
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| creator | Seth Chhabra, Ekta Liu, Tongyao Kulman, John Patarroyo-White, Susannah Yang, Buyue Lu, Qi Drager, Douglas Moore, Nancy Liu, Jiayun Holthaus, Amy M. Sommer, Jurg M. Ismail, Ayman Rabinovich, Deana Liu, Zhan van der Flier, Arjan Goodman, Allison Furcht, Chris Tie, Mark Carlage, Tyler Mauldin, Randy Dobrowsky, Terrence M. Liu, Zhiqian Mercury, Oblaise Zhu, Lily Mei, Baisong Schellenberger, Volker Jiang, Haiyan Pierce, Glenn F. Salas, Joe Peters, Robert |
| description | Factor VIII (FVIII) replacement products enable comprehensive care in hemophilia A. Treatment goals in severe hemophilia A are expanding beyond low annualized bleed rates to include long-term outcomes associated with high sustained FVIII levels. Endogenous von Willebrand factor (VWF) stabilizes and protects FVIII from degradation and clearance, but it also subjects FVIII to a half-life ceiling of ∼15 to 19 hours. Increasing recombinant FVIII (rFVIII) half-life further is ultimately dependent upon uncoupling rFVIII from endogenous VWF. We have developed a new class of FVIII replacement, rFVIIIFc-VWF-XTEN (BIVV001), that is physically decoupled from endogenous VWF and has enhanced pharmacokinetic properties compared with all previous FVIII products. BIVV001 was bioengineered as a unique fusion protein consisting of a VWF-DʹD3 domain fused to rFVIII via immunoglobulin-G1 Fc domains and 2 XTEN polypeptides (Amunix Pharmaceuticals, Inc, Mountain View, CA). Plasma FVIII half-life after BIVV001 administration in mice and monkeys was 25 to 31 hours and 33 to 34 hours, respectively, representing a three- to fourfold increase in FVIII half-life. Our results showed that multifaceted protein engineering, far beyond a few amino acid substitutions, could significantly improve rFVIII pharmacokinetic properties while maintaining hemostatic function. BIVV001 is the first rFVIII with the potential to significantly change the treatment paradigm for severe hemophilia A by providing optimal protection against all bleed types, with less frequent doses. The protein engineering methods described herein can also be applied to other complex proteins.
•BIVV001 is a novel fusion protein that provides fourfold longer hemostatic control than rFVIII in preclinical hemophilia A models.•BIVV001 has the potential to allow for more optimal, extended protection against all bleeding types in patients with severe hemophilia A.
[Display omitted] |
| doi_str_mv | 10.1182/blood.2019001292 |
| format | Article |
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•BIVV001 is a novel fusion protein that provides fourfold longer hemostatic control than rFVIII in preclinical hemophilia A models.•BIVV001 has the potential to allow for more optimal, extended protection against all bleeding types in patients with severe hemophilia A.
[Display omitted]</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood.2019001292</identifier><identifier>PMID: 32078672</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Factor VIII - genetics ; Factor VIII - metabolism ; Hemophilia A - metabolism ; Hemophilia A - pathology ; Hemophilia A - therapy ; Hemorrhage - prevention & control ; Hemostasis ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Primates ; Recombinant Fusion Proteins - administration & dosage ; Thrombosis and Hemostasis ; von Willebrand Factor - genetics ; von Willebrand Factor - metabolism</subject><ispartof>Blood, 2020-04, Vol.135 (17), p.1484-1496</ispartof><rights>2020 American Society of Hematology</rights><rights>2020 by The American Society of Hematology.</rights><rights>2020 by The American Society of Hematology 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c447t-918919b76a9d78d261de032c2bb48611dca2f80c75a41266b20313cb5904ad8f3</citedby><cites>FETCH-LOGICAL-c447t-918919b76a9d78d261de032c2bb48611dca2f80c75a41266b20313cb5904ad8f3</cites><orcidid>0000-0001-8108-803X ; 0000-0002-0378-0909 ; 0000-0002-1442-3907 ; 0000-0002-8853-7560</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32078672$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Seth Chhabra, Ekta</creatorcontrib><creatorcontrib>Liu, Tongyao</creatorcontrib><creatorcontrib>Kulman, John</creatorcontrib><creatorcontrib>Patarroyo-White, Susannah</creatorcontrib><creatorcontrib>Yang, Buyue</creatorcontrib><creatorcontrib>Lu, Qi</creatorcontrib><creatorcontrib>Drager, Douglas</creatorcontrib><creatorcontrib>Moore, Nancy</creatorcontrib><creatorcontrib>Liu, Jiayun</creatorcontrib><creatorcontrib>Holthaus, Amy M.</creatorcontrib><creatorcontrib>Sommer, Jurg M.</creatorcontrib><creatorcontrib>Ismail, Ayman</creatorcontrib><creatorcontrib>Rabinovich, Deana</creatorcontrib><creatorcontrib>Liu, Zhan</creatorcontrib><creatorcontrib>van der Flier, Arjan</creatorcontrib><creatorcontrib>Goodman, Allison</creatorcontrib><creatorcontrib>Furcht, Chris</creatorcontrib><creatorcontrib>Tie, Mark</creatorcontrib><creatorcontrib>Carlage, Tyler</creatorcontrib><creatorcontrib>Mauldin, Randy</creatorcontrib><creatorcontrib>Dobrowsky, Terrence M.</creatorcontrib><creatorcontrib>Liu, Zhiqian</creatorcontrib><creatorcontrib>Mercury, Oblaise</creatorcontrib><creatorcontrib>Zhu, Lily</creatorcontrib><creatorcontrib>Mei, Baisong</creatorcontrib><creatorcontrib>Schellenberger, Volker</creatorcontrib><creatorcontrib>Jiang, Haiyan</creatorcontrib><creatorcontrib>Pierce, Glenn F.</creatorcontrib><creatorcontrib>Salas, Joe</creatorcontrib><creatorcontrib>Peters, Robert</creatorcontrib><title>BIVV001, a new class of factor VIII replacement for hemophilia A that is independent of von Willebrand factor in primates and mice</title><title>Blood</title><addtitle>Blood</addtitle><description>Factor VIII (FVIII) replacement products enable comprehensive care in hemophilia A. Treatment goals in severe hemophilia A are expanding beyond low annualized bleed rates to include long-term outcomes associated with high sustained FVIII levels. Endogenous von Willebrand factor (VWF) stabilizes and protects FVIII from degradation and clearance, but it also subjects FVIII to a half-life ceiling of ∼15 to 19 hours. Increasing recombinant FVIII (rFVIII) half-life further is ultimately dependent upon uncoupling rFVIII from endogenous VWF. We have developed a new class of FVIII replacement, rFVIIIFc-VWF-XTEN (BIVV001), that is physically decoupled from endogenous VWF and has enhanced pharmacokinetic properties compared with all previous FVIII products. BIVV001 was bioengineered as a unique fusion protein consisting of a VWF-DʹD3 domain fused to rFVIII via immunoglobulin-G1 Fc domains and 2 XTEN polypeptides (Amunix Pharmaceuticals, Inc, Mountain View, CA). Plasma FVIII half-life after BIVV001 administration in mice and monkeys was 25 to 31 hours and 33 to 34 hours, respectively, representing a three- to fourfold increase in FVIII half-life. Our results showed that multifaceted protein engineering, far beyond a few amino acid substitutions, could significantly improve rFVIII pharmacokinetic properties while maintaining hemostatic function. BIVV001 is the first rFVIII with the potential to significantly change the treatment paradigm for severe hemophilia A by providing optimal protection against all bleed types, with less frequent doses. The protein engineering methods described herein can also be applied to other complex proteins.
•BIVV001 is a novel fusion protein that provides fourfold longer hemostatic control than rFVIII in preclinical hemophilia A models.•BIVV001 has the potential to allow for more optimal, extended protection against all bleeding types in patients with severe hemophilia A.
[Display omitted]</description><subject>Animals</subject><subject>Factor VIII - genetics</subject><subject>Factor VIII - metabolism</subject><subject>Hemophilia A - metabolism</subject><subject>Hemophilia A - pathology</subject><subject>Hemophilia A - therapy</subject><subject>Hemorrhage - prevention & control</subject><subject>Hemostasis</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Primates</subject><subject>Recombinant Fusion Proteins - administration & dosage</subject><subject>Thrombosis and Hemostasis</subject><subject>von Willebrand Factor - genetics</subject><subject>von Willebrand Factor - metabolism</subject><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc1v1DAQxS1ERZfCnRPykQNpx042tjkglYqPSJW4wHK0HHvCGjlxsLOLuPKX43bbQg-92NLM7z0_-RHygsEpY5Kf9SFGd8qBKQDGFX9EVmzNZQXA4TFZAUBbNUqwY_I05x-FaWq-fkKOaw5CtoKvyJ933WZTFq-poRP-ojaYnGkc6GDsEhPddF1HE87BWBxxWuhQhlsc47z1wRt6TpetWajP1E8OZyxHgYp-Hyf6zYeAfTKTu7XzE52TH82CmV6NR2_xGTkaTMj4_OY-IV8_vP9y8am6_Pyxuzi_rGzTiKVSTCqmetEa5YR0vGUOoeaW930jW8acNXyQYMXaNIy3bc-hZrXt1woa4-RQn5C3B99514_obAmaTNDXedJvHY3X9zeT3-rvca8FkwCSF4NXNwYp_txhXvTos8UQzIRxlzWvVSOF4qIpKBxQm2LOCYe7Zxjoq-r0dXX6X3VF8vL_eHeC264K8OYAYPmkvceks_U4WXQ-oV20i_5h979LeqlP</recordid><startdate>20200423</startdate><enddate>20200423</enddate><creator>Seth Chhabra, Ekta</creator><creator>Liu, Tongyao</creator><creator>Kulman, John</creator><creator>Patarroyo-White, Susannah</creator><creator>Yang, Buyue</creator><creator>Lu, Qi</creator><creator>Drager, Douglas</creator><creator>Moore, Nancy</creator><creator>Liu, Jiayun</creator><creator>Holthaus, Amy M.</creator><creator>Sommer, Jurg M.</creator><creator>Ismail, Ayman</creator><creator>Rabinovich, Deana</creator><creator>Liu, Zhan</creator><creator>van der Flier, Arjan</creator><creator>Goodman, Allison</creator><creator>Furcht, Chris</creator><creator>Tie, Mark</creator><creator>Carlage, Tyler</creator><creator>Mauldin, Randy</creator><creator>Dobrowsky, Terrence M.</creator><creator>Liu, Zhiqian</creator><creator>Mercury, Oblaise</creator><creator>Zhu, Lily</creator><creator>Mei, Baisong</creator><creator>Schellenberger, Volker</creator><creator>Jiang, Haiyan</creator><creator>Pierce, Glenn F.</creator><creator>Salas, Joe</creator><creator>Peters, Robert</creator><general>Elsevier Inc</general><general>American Society of Hematology</general><scope>6I.</scope><scope>AAFTH</scope><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><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-8108-803X</orcidid><orcidid>https://orcid.org/0000-0002-0378-0909</orcidid><orcidid>https://orcid.org/0000-0002-1442-3907</orcidid><orcidid>https://orcid.org/0000-0002-8853-7560</orcidid></search><sort><creationdate>20200423</creationdate><title>BIVV001, a new class of factor VIII replacement for hemophilia A that is independent of von Willebrand factor in primates and mice</title><author>Seth Chhabra, Ekta ; Liu, Tongyao ; Kulman, John ; Patarroyo-White, Susannah ; Yang, Buyue ; Lu, Qi ; Drager, Douglas ; Moore, Nancy ; Liu, Jiayun ; Holthaus, Amy M. ; Sommer, Jurg M. ; Ismail, Ayman ; Rabinovich, Deana ; Liu, Zhan ; van der Flier, Arjan ; Goodman, Allison ; Furcht, Chris ; Tie, Mark ; Carlage, Tyler ; Mauldin, Randy ; Dobrowsky, Terrence M. ; Liu, Zhiqian ; Mercury, Oblaise ; Zhu, Lily ; Mei, Baisong ; Schellenberger, Volker ; Jiang, Haiyan ; Pierce, Glenn F. ; Salas, Joe ; Peters, Robert</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c447t-918919b76a9d78d261de032c2bb48611dca2f80c75a41266b20313cb5904ad8f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Factor VIII - genetics</topic><topic>Factor VIII - metabolism</topic><topic>Hemophilia A - metabolism</topic><topic>Hemophilia A - pathology</topic><topic>Hemophilia A - therapy</topic><topic>Hemorrhage - prevention & control</topic><topic>Hemostasis</topic><topic>Humans</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Primates</topic><topic>Recombinant Fusion Proteins - administration & dosage</topic><topic>Thrombosis and Hemostasis</topic><topic>von Willebrand Factor - genetics</topic><topic>von Willebrand Factor - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Seth Chhabra, Ekta</creatorcontrib><creatorcontrib>Liu, Tongyao</creatorcontrib><creatorcontrib>Kulman, John</creatorcontrib><creatorcontrib>Patarroyo-White, Susannah</creatorcontrib><creatorcontrib>Yang, Buyue</creatorcontrib><creatorcontrib>Lu, Qi</creatorcontrib><creatorcontrib>Drager, Douglas</creatorcontrib><creatorcontrib>Moore, Nancy</creatorcontrib><creatorcontrib>Liu, Jiayun</creatorcontrib><creatorcontrib>Holthaus, Amy M.</creatorcontrib><creatorcontrib>Sommer, Jurg M.</creatorcontrib><creatorcontrib>Ismail, Ayman</creatorcontrib><creatorcontrib>Rabinovich, Deana</creatorcontrib><creatorcontrib>Liu, Zhan</creatorcontrib><creatorcontrib>van der Flier, Arjan</creatorcontrib><creatorcontrib>Goodman, Allison</creatorcontrib><creatorcontrib>Furcht, Chris</creatorcontrib><creatorcontrib>Tie, Mark</creatorcontrib><creatorcontrib>Carlage, Tyler</creatorcontrib><creatorcontrib>Mauldin, Randy</creatorcontrib><creatorcontrib>Dobrowsky, Terrence M.</creatorcontrib><creatorcontrib>Liu, Zhiqian</creatorcontrib><creatorcontrib>Mercury, Oblaise</creatorcontrib><creatorcontrib>Zhu, Lily</creatorcontrib><creatorcontrib>Mei, Baisong</creatorcontrib><creatorcontrib>Schellenberger, Volker</creatorcontrib><creatorcontrib>Jiang, Haiyan</creatorcontrib><creatorcontrib>Pierce, Glenn F.</creatorcontrib><creatorcontrib>Salas, Joe</creatorcontrib><creatorcontrib>Peters, Robert</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Seth Chhabra, Ekta</au><au>Liu, Tongyao</au><au>Kulman, John</au><au>Patarroyo-White, Susannah</au><au>Yang, Buyue</au><au>Lu, Qi</au><au>Drager, Douglas</au><au>Moore, Nancy</au><au>Liu, Jiayun</au><au>Holthaus, Amy M.</au><au>Sommer, Jurg M.</au><au>Ismail, Ayman</au><au>Rabinovich, Deana</au><au>Liu, Zhan</au><au>van der Flier, Arjan</au><au>Goodman, Allison</au><au>Furcht, Chris</au><au>Tie, Mark</au><au>Carlage, Tyler</au><au>Mauldin, Randy</au><au>Dobrowsky, Terrence M.</au><au>Liu, Zhiqian</au><au>Mercury, Oblaise</au><au>Zhu, Lily</au><au>Mei, Baisong</au><au>Schellenberger, Volker</au><au>Jiang, Haiyan</au><au>Pierce, Glenn F.</au><au>Salas, Joe</au><au>Peters, Robert</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>BIVV001, a new class of factor VIII replacement for hemophilia A that is independent of von Willebrand factor in primates and mice</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>2020-04-23</date><risdate>2020</risdate><volume>135</volume><issue>17</issue><spage>1484</spage><epage>1496</epage><pages>1484-1496</pages><issn>0006-4971</issn><eissn>1528-0020</eissn><abstract>Factor VIII (FVIII) replacement products enable comprehensive care in hemophilia A. Treatment goals in severe hemophilia A are expanding beyond low annualized bleed rates to include long-term outcomes associated with high sustained FVIII levels. Endogenous von Willebrand factor (VWF) stabilizes and protects FVIII from degradation and clearance, but it also subjects FVIII to a half-life ceiling of ∼15 to 19 hours. Increasing recombinant FVIII (rFVIII) half-life further is ultimately dependent upon uncoupling rFVIII from endogenous VWF. We have developed a new class of FVIII replacement, rFVIIIFc-VWF-XTEN (BIVV001), that is physically decoupled from endogenous VWF and has enhanced pharmacokinetic properties compared with all previous FVIII products. BIVV001 was bioengineered as a unique fusion protein consisting of a VWF-DʹD3 domain fused to rFVIII via immunoglobulin-G1 Fc domains and 2 XTEN polypeptides (Amunix Pharmaceuticals, Inc, Mountain View, CA). Plasma FVIII half-life after BIVV001 administration in mice and monkeys was 25 to 31 hours and 33 to 34 hours, respectively, representing a three- to fourfold increase in FVIII half-life. Our results showed that multifaceted protein engineering, far beyond a few amino acid substitutions, could significantly improve rFVIII pharmacokinetic properties while maintaining hemostatic function. BIVV001 is the first rFVIII with the potential to significantly change the treatment paradigm for severe hemophilia A by providing optimal protection against all bleed types, with less frequent doses. The protein engineering methods described herein can also be applied to other complex proteins.
•BIVV001 is a novel fusion protein that provides fourfold longer hemostatic control than rFVIII in preclinical hemophilia A models.•BIVV001 has the potential to allow for more optimal, extended protection against all bleeding types in patients with severe hemophilia A.
[Display omitted]</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>32078672</pmid><doi>10.1182/blood.2019001292</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0001-8108-803X</orcidid><orcidid>https://orcid.org/0000-0002-0378-0909</orcidid><orcidid>https://orcid.org/0000-0002-1442-3907</orcidid><orcidid>https://orcid.org/0000-0002-8853-7560</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0006-4971 |
| ispartof | Blood, 2020-04, Vol.135 (17), p.1484-1496 |
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| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7180082 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Animals Factor VIII - genetics Factor VIII - metabolism Hemophilia A - metabolism Hemophilia A - pathology Hemophilia A - therapy Hemorrhage - prevention & control Hemostasis Humans Male Mice Mice, Inbred C57BL Primates Recombinant Fusion Proteins - administration & dosage Thrombosis and Hemostasis von Willebrand Factor - genetics von Willebrand Factor - metabolism |
| title | BIVV001, a new class of factor VIII replacement for hemophilia A that is independent of von Willebrand factor in primates and mice |
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