Literature DB >> 26076429

Reducing hydrophobicity of homogeneous antibody-drug conjugates improves pharmacokinetics and therapeutic index.

Robert P Lyon1, Tim D Bovee1, Svetlana O Doronina1, Patrick J Burke1, Joshua H Hunter1, Haley D Neff-LaFord2, Mechthild Jonas3, Martha E Anderson4, Jocelyn R Setter1, Peter D Senter1.   

Abstract

The in vitro potency of antibody-drug conjugates (ADCs) increases with the drug-to-antibody ratio (DAR); however, ADC plasma clearance also increases with DAR, reducing exposure and in vivo efficacy. Here we show that accelerated clearance arises from ADC hydrophobicity, which can be modulated through drug-linker design. We exemplify this using hydrophilic auristatin drug linkers and PEGylated ADCs that yield uniform, high-DAR ADCs with superior in vivo performance.

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Year:  2015        PMID： 26076429     DOI： 10.1038/nbt.3212

Source DB:  PubMed          Journal:  Nat Biotechnol        ISSN： 1087-0156            Impact factor:   54.908


  17 in total

1.  Synthesis and evaluation of hydrophilic linkers for antibody-maytansinoid conjugates.

Authors:  Robert Y Zhao; Sharon D Wilhelm; Charlene Audette; Gregory Jones; Barbara A Leece; Alexandru C Lazar; Victor S Goldmacher; Rajeeva Singh; Yelena Kovtun; Wayne C Widdison; John M Lambert; Ravi V J Chari
Journal:  J Med Chem       Date:  2011-05-04       Impact factor: 7.446

2.  Structural characterization of the maytansinoid-monoclonal antibody immunoconjugate, huN901-DM1, by mass spectrometry.

Authors:  Lintao Wang; Godfrey Amphlett; Walter A Blättler; John M Lambert; Wei Zhang
Journal:  Protein Sci       Date:  2005-08-04       Impact factor: 6.725

3.  Enhanced activity of monomethylauristatin F through monoclonal antibody delivery: effects of linker technology on efficacy and toxicity.

Authors:  Svetlana O Doronina; Brian A Mendelsohn; Tim D Bovee; Charles G Cerveny; Stephen C Alley; Damon L Meyer; Ezogelin Oflazoglu; Brian E Toki; Russell J Sanderson; Roger F Zabinski; Alan F Wahl; Peter D Senter
Journal:  Bioconjug Chem       Date:  2006 Jan-Feb       Impact factor: 4.774

4.  Location matters: site of conjugation modulates stability and pharmacokinetics of antibody drug conjugates.

Authors:  Pavel Strop; Shu-Hui Liu; Magdalena Dorywalska; Kathy Delaria; Russell G Dushin; Thomas-Toan Tran; Wei-Hsien Ho; Santiago Farias; Meritxell Galindo Casas; Yasmina Abdiche; Dahui Zhou; Ramalakshmi Chandrasekaran; Caroline Samain; Carole Loo; Andrea Rossi; Mathias Rickert; Stellanie Krimm; Teresa Wong; Sherman Michael Chin; Jessica Yu; Jeanette Dilley; Javier Chaparro-Riggers; Gary F Filzen; Christopher J O'Donnell; Fang Wang; Jeremy S Myers; Jaume Pons; David L Shelton; Arvind Rajpal
Journal:  Chem Biol       Date:  2013-02-21

5.  Engineered antibody-drug conjugates with defined sites and stoichiometries of drug attachment.

Authors:  Charlotte F McDonagh; Eileen Turcott; Lori Westendorf; Jennifer B Webster; Stephen C Alley; Kristine Kim; Jamie Andreyka; Ivan Stone; Kevin J Hamblett; Joseph A Francisco; Paul Carter
Journal:  Protein Eng Des Sel       Date:  2006-04-27       Impact factor: 1.650

6.  Development and properties of beta-glucuronide linkers for monoclonal antibody-drug conjugates.

Authors:  Scott C Jeffrey; Jamie B Andreyka; Starr X Bernhardt; Kim M Kissler; Toni Kline; Joel S Lenox; Ruth F Moser; Minh T Nguyen; Nicole M Okeley; Ivan J Stone; Xinqun Zhang; Peter D Senter
Journal:  Bioconjug Chem       Date:  2006 May-Jun       Impact factor: 4.774

7.  The anti-CD30 monoclonal antibody SGN-30 promotes growth arrest and DNA fragmentation in vitro and affects antitumor activity in models of Hodgkin's disease.

Authors:  Alan F Wahl; Kerry Klussman; Jennifer D Thompson; Judy H Chen; Leigh V Francisco; Grant Risdon; Dana F Chace; Clay B Siegall; Joseph A Francisco
Journal:  Cancer Res       Date:  2002-07-01       Impact factor: 12.701

8.  Phase I biodistribution and pharmacokinetic study of Lewis Y-targeting immunoconjugate CMD-193 in patients with advanced epithelial cancers.

Authors:  Rebecca A Herbertson; Niall C Tebbutt; Fook-Thean Lee; David J MacFarlane; Bridget Chappell; Noel Micallef; Sze-Ting Lee; Timothy Saunder; Wendie Hopkins; Fiona E Smyth; David K Wyld; John Bellen; Daryl S Sonnichsen; Martin W Brechbiel; Carmel Murone; Andrew M Scott
Journal:  Clin Cancer Res       Date:  2009-10-13       Impact factor: 12.531

9.  Antibody conjugates of 7-ethyl-10-hydroxycamptothecin (SN-38) for targeted cancer chemotherapy.

Authors:  Sung-Ju Moon; Serengulam V Govindan; Thomas M Cardillo; Christopher A D'Souza; Hans J Hansen; David M Goldenberg
Journal:  J Med Chem       Date:  2008-10-22       Impact factor: 7.446

10.  Synthesis of taxoids with improved cytotoxicity and solubility for use in tumor-specific delivery.

Authors:  Michael L Miller; Elizabeth E Roller; Robert Y Zhao; Barbara A Leece; Olga Ab; Erkan Baloglu; Victor S Goldmacher; Ravi V J Chari
Journal:  J Med Chem       Date:  2004-09-23       Impact factor: 7.446
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  101 in total

1.  Cathepsin-Mediated Cleavage of Peptides from Peptide Amphiphiles Leads to Enhanced Intracellular Peptide Accumulation.

Authors:  Handan Acar; Ravand Samaeekia; Mathew R Schnorenberg; Dibyendu K Sasmal; Jun Huang; Matthew V Tirrell; James L LaBelle
Journal:  Bioconjug Chem       Date:  2017-08-24       Impact factor: 4.774

2.  Site-Selective Antibody Functionalization via Orthogonally Reactive Arginine and Lysine Residues.

Authors:  Dobeen Hwang; Napon Nilchan; Alex R Nanna; Xiaohai Li; Michael D Cameron; William R Roush; HaJeung Park; Christoph Rader
Journal:  Cell Chem Biol       Date:  2019-06-20       Impact factor: 8.116

Review 3.  Considerations for the Design of Antibody-Based Therapeutics.

Authors:  Dennis R Goulet; William M Atkins
Journal:  J Pharm Sci       Date:  2019-06-04       Impact factor: 3.534

4.  Site Selection: a Case Study in the Identification of Optimal Cysteine Engineered Antibody Drug Conjugates.

Authors:  L Nathan Tumey; Fengping Li; Brian Rago; Xiaogang Han; Frank Loganzo; Sylvia Musto; Edmund I Graziani; Sujiet Puthenveetil; Jeffrey Casavant; Kimberly Marquette; Tracey Clark; Jack Bikker; Eric M Bennett; Frank Barletta; Nicole Piche-Nicholas; Amy Tam; Christopher J O'Donnell; Hans Peter Gerber; Lioudmila Tchistiakova
Journal:  AAPS J       Date:  2017-04-24       Impact factor: 4.009

Review 5.  Strategies and challenges for the next generation of antibody-drug conjugates.

Authors:  Alain Beck; Liliane Goetsch; Charles Dumontet; Nathalie Corvaïa
Journal:  Nat Rev Drug Discov       Date:  2017-03-17       Impact factor: 84.694

Review 6.  Antibody-drug conjugates and other nanomedicines: the frontier of gynaecological cancer treatment.

Authors:  David Howard; Jetzabel Garcia-Parra; Gareth D Healey; Cynthia Amakiri; Lavinia Margarit; Lewis W Francis; Deyarina Gonzalez; R Steven Conlan
Journal:  Interface Focus       Date:  2016-12-06       Impact factor: 3.906

7.  Antibody-Drug Conjugates (ADCs) Derived from Interchain Cysteine Cross-Linking Demonstrate Improved Homogeneity and Other Pharmacological Properties over Conventional Heterogeneous ADCs.

Authors:  Christopher R Behrens; Edward H Ha; Lawrence L Chinn; Simeon Bowers; Gary Probst; Maureen Fitch-Bruhns; Jorge Monteon; Amanda Valdiosera; Abel Bermudez; Sindy Liao-Chan; Tiffany Wong; Jonathan Melnick; Jan-Willem Theunissen; Mark R Flory; Derrick Houser; Kristy Venstrom; Zoia Levashova; Paul Sauer; Thi-Sau Migone; Edward H van der Horst; Randall L Halcomb; David Y Jackson
Journal:  Mol Pharm       Date:  2015-10-02       Impact factor: 4.939

8.  Site-Specific Bioconjugation and Multi-Bioorthogonal Labeling via Rapid Formation of a Boron-Nitrogen Heterocycle.

Authors:  Tak Ian Chio; Han Gu; Kamalika Mukherjee; L Nathan Tumey; Susan L Bane
Journal:  Bioconjug Chem       Date:  2019-05-03       Impact factor: 4.774

9.  Improved Tumor Penetration and Single-Cell Targeting of Antibody-Drug Conjugates Increases Anticancer Efficacy and Host Survival.

Authors:  Cornelius Cilliers; Bruna Menezes; Ian Nessler; Jennifer Linderman; Greg M Thurber
Journal:  Cancer Res       Date:  2017-12-07       Impact factor: 12.701

10.  Site-Specific In Vivo Bioorthogonal Ligation via Chemical Modulation.

Authors:  Heebeom Koo; Jeong Heon Lee; Kai Bao; Yunshan Wu; Georges El Fakhri; Maged Henary; Seok Hyun Yun; Hak Soo Choi
Journal:  Adv Healthc Mater       Date:  2016-08-29       Impact factor: 9.933
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