Discovery of ABBV-3373, an Anti-TNF Glucocorticoid Receptor Modulator Immunology Antibody Drug ConjugateClick to copy article linkArticle link copied!
- Adrian D. Hobson*Adrian D. Hobson*Email: [email protected]AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Adrian D. Hobson
- Michael J. McPhersonMichael J. McPhersonAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Michael J. McPherson
- Martin E. HayesMartin E. HayesAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Martin E. Hayes
- Christian GoessChristian GoessAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Christian Goess
- Xiang LiXiang LiWuXi AppTec, 168 Nanhai Road, Tianjin Economic-Technological Development Area TEDA, Tianjin 300457, ChinaMore by Xiang Li
- Jian ZhouJian ZhouWuXi AppTec, 168 Nanhai Road, Tianjin Economic-Technological Development Area TEDA, Tianjin 300457, ChinaMore by Jian Zhou
- Zhongyuan WangZhongyuan WangWuXi AppTec, 168 Nanhai Road, Tianjin Economic-Technological Development Area TEDA, Tianjin 300457, ChinaMore by Zhongyuan Wang
- Yajie YuYajie YuWuXi AppTec, 168 Nanhai Road, Tianjin Economic-Technological Development Area TEDA, Tianjin 300457, ChinaMore by Yajie Yu
- Jindong YangJindong YangWuXi AppTec, 168 Nanhai Road, Tianjin Economic-Technological Development Area TEDA, Tianjin 300457, ChinaMore by Jindong Yang
- Liang SunLiang SunWuXi AppTec, 168 Nanhai Road, Tianjin Economic-Technological Development Area TEDA, Tianjin 300457, ChinaMore by Liang Sun
- Qiang ZhangQiang ZhangWuXi AppTec, 168 Nanhai Road, Tianjin Economic-Technological Development Area TEDA, Tianjin 300457, ChinaMore by Qiang Zhang
- Pei QuPei QuWuXi AppTec, 168 Nanhai Road, Tianjin Economic-Technological Development Area TEDA, Tianjin 300457, ChinaMore by Pei Qu
- Shi YangShi YangWuXi AppTec, 168 Nanhai Road, Tianjin Economic-Technological Development Area TEDA, Tianjin 300457, ChinaMore by Shi Yang
- Axel Hernandez Jr.Axel Hernandez, Jr.AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Axel Hernandez, Jr.
- Shaughn H. BryantShaughn H. BryantAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Shaughn H. Bryant
- Suzanne L. MathieuSuzanne L. MathieuAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Suzanne L. Mathieu
- Agnieszka K. BischoffAgnieszka K. BischoffAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Agnieszka K. Bischoff
- Julia FitzgibbonsJulia FitzgibbonsAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Julia Fitzgibbons
- Ling C. SantoraLing C. SantoraAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Ling C. Santora
- Lu WangLu WangAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Lu Wang
- Lu WangLu WangAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Lu Wang
- Margaret M. FettisMargaret M. FettisAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Margaret M. Fettis
- Xiaofeng LiXiaofeng LiWuXi AppTec, 168 Nanhai Road, Tianjin Economic-Technological Development Area TEDA, Tianjin 300457, ChinaMore by Xiaofeng Li
- Christopher C. MarvinChristopher C. MarvinAbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United StatesMore by Christopher C. Marvin
- Zhi WangZhi WangAbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United StatesMore by Zhi Wang
- Meena V. PatelMeena V. PatelAbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United StatesMore by Meena V. Patel
- Diana L. SchmidtDiana L. SchmidtAbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United StatesMore by Diana L. Schmidt
- Tongmei LiTongmei LiAbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United StatesMore by Tongmei Li
- John T. RandolphJohn T. RandolphAbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United StatesMore by John T. Randolph
- Rodger F. HenryRodger F. HenryAbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United StatesMore by Rodger F. Henry
- Candace GraffCandace GraffAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Candace Graff
- Yu TianYu TianAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Yu Tian
- Ana L. AguirreAna L. AguirreAbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United StatesMore by Ana L. Aguirre
- Anurupa ShresthaAnurupa ShresthaAbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United StatesMore by Anurupa Shrestha
Abstract
![Abstract Image](/cms/10.1021/acs.jmedchem.2c01579/asset/images/medium/jm2c01579_0036.gif)
Using a convergent synthetic route to enable multiple points of diversity, a series of glucocorticoid receptor modulators (GRM) were profiled for potency, selectivity, and drug-like properties in vitro. Despite covering a large range of diversity, profiling the nonconjugated small molecule was suboptimal and they were conjugated to a mouse antitumor necrosis factor (TNF) antibody using the MP-Ala-Ala linker. Screening of the resulting antibody drug conjugates (ADCs) provided a better assessment of efficacy and physical properties, reinforcing the need to conduct structure–activity relationship studies on the complete ADC. DAR4 ADCs were screened in an acute mouse contact hypersensitivity model measuring biomarkers to ensure a sufficient therapeutic window. In a chronic mouse arthritis model, mouse anti-TNF GRM ADCs were efficacious after a single dose of 10 mg/kg i.p. for over 30 days. Data on the unconjugated payloads and mouse surrogate anti-TNF ADCs identified payload 17 which was conjugated to a human anti-TNF antibody and advanced to the clinic as ABBV-3373.
Cited By
This article is cited by 7 publications.
- Nathan B. Bennett, Xiaoqiang Shen, Bradley D. Gates, Dennie S. Welch, Mark A. Servos, Justin A. Simanis, Ryan G. Ellis, Haixiao Qiu, Eric G. Moschetta, Jiajie Feng, Moussa Boukerche, Michael Rasmussen, Laura A. McKee, Laurie B. Mlinar, Shuang Chen, Zhe Wang. Development and Execution of a Scalable Route to an Immunology ADC Drug-Linker for ABBV-154. Organic Process Research & Development 2024, 28
(7)
, 2499-2517. https://doi.org/10.1021/acs.oprd.4c00142
- Nathan B. Bennett, Laurie B. Mlinar, Eric G. Moschetta, Ryan G. Ellis, Ryan Chung, Onkar Manjrekar, Michael Rasmussen, Laura A. McKee, Mark A. Servos, Justin A. Simanis, Bradley D. Gates, Xiaoqiang Shen, Dennie S. Welch, Zhe Wang. Use of Impinging Jet to Improve Scalability in the Preparation of the ABBV-154 Drug-Linker. Organic Process Research & Development 2024, 28
(7)
, 2518-2533. https://doi.org/10.1021/acs.oprd.4c00143
- Nathan B. Bennett, Bradley D. Gates, Justin A. Simanis, James W. Treadway, Steven M. Richter, Dennie S. Welch. Development of a Scalable Synthesis of a Drug-Linker for ABBV-3373. Organic Process Research & Development 2024, 28
(6)
, 2237-2246. https://doi.org/10.1021/acs.oprd.3c00447
- Christopher C. Marvin, Adrian D. Hobson, Michael J. McPherson, Martin E. Hayes, Meena V. Patel, Diana L. Schmidt, Tongmei Li, John T. Randolph, Agnieszka K. Bischoff, Julia Fitzgibbons, Lu Wang, Lu Wang, Axel Hernandez, Jr, Ying Jia, Christian A. Goess, Shaughn H. Bryant, Suzanne L. Mathieu, Jianwen Xu. Anti-TNF Thioester Glucocorticoid Antibody–Drug Conjugate Fully Inhibits Inflammation with Minimal Effect on Systemic Corticosterone Levels in a Mouse Arthritis Model. Journal of Medicinal Chemistry 2024, 67
(11)
, 9495-9515. https://doi.org/10.1021/acs.jmedchem.4c00598
- Christopher C. Marvin, Adrian D. Hobson, Michael McPherson, Theresa A. Dunstan, Thomas R. Vargo, Martin E. Hayes, Margaret M. Fettis, Agnieszka Bischoff, Lu Wang, Lu Wang, Axel Hernandez, Jr., Ying Jia, Jason Z. Oh, Yu Tian. Self-Immolative Carbamate Linkers for CD19-Budesonide Antibody–Drug Conjugates. Bioconjugate Chemistry 2023, 34
(10)
, 1835-1850. https://doi.org/10.1021/acs.bioconjchem.3c00354
- Adrian D. Hobson, Jianwen Xu, Dennie S. Welch, Christopher C. Marvin, Michael J. McPherson, Bradley Gates, Xiaoli Liao, Markus Hollmann, Michael J. Gattner, Kristina Dzeyk, Hetal Sarvaiya, Vikram M. Shenoy, Margaret M. Fettis, Agnieszka K. Bischoff, Lu Wang, Ling C. Santora, Lu Wang, Julia Fitzgibbons, Paulin Salomon, Axel Hernandez, Jr., Ying Jia, Christian A. Goess, Suzanne L. Mathieu, Shaughn H. Bryant, Mary E. Larsen, Baoliang Cui, Yu Tian. Discovery of ABBV-154, an anti-TNF Glucocorticoid Receptor Modulator Immunology Antibody-Drug Conjugate (iADC). Journal of Medicinal Chemistry 2023, 66
(17)
, 12544-12558. https://doi.org/10.1021/acs.jmedchem.3c01174
- Adrian D. Hobson, Jianwen Xu, Christopher C. Marvin, Michael J. McPherson, Markus Hollmann, Michael Gattner, Kristina Dzeyk, Margaret M. Fettis, Agnieszka K. Bischoff, Lu Wang, Julia Fitzgibbons, Lu Wang, Paulin Salomon, Axel Hernandez, Jr., Ying Jia, Hetal Sarvaiya, Christian A. Goess, Suzanne L. Mathieu, Ling C. Santora. Optimization of Drug-Linker to Enable Long-term Storage of Antibody–Drug Conjugate for Subcutaneous Dosing. Journal of Medicinal Chemistry 2023, 66
(13)
, 9161-9173. https://doi.org/10.1021/acs.jmedchem.3c00794
Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.
Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.
The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.