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Harnessing a catalytic lysine residue for the one-step preparation of homogeneous antibody-drug conjugates

Current strategies to produce homogeneous antibody-drug conjugates (ADCs) rely on mutations or inefficient conjugation chemistries. Here we present a strategy to produce site-specific ADCs using a highly reactive natural buried lysine embedded in a dual variable domain (DVD) format. This approach is...

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Autores principales: Nanna, Alex R., Li, Xiuling, Walseng, Even, Pedzisa, Lee, Goydel, Rebecca S., Hymel, David, Burke Jr., Terrence R., Roush, William R., Rader, Christoph
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5653646/
https://www.ncbi.nlm.nih.gov/pubmed/29062027
http://dx.doi.org/10.1038/s41467-017-01257-1
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author Nanna, Alex R.
Li, Xiuling
Walseng, Even
Pedzisa, Lee
Goydel, Rebecca S.
Hymel, David
Burke Jr., Terrence R.
Roush, William R.
Rader, Christoph
author_facet Nanna, Alex R.
Li, Xiuling
Walseng, Even
Pedzisa, Lee
Goydel, Rebecca S.
Hymel, David
Burke Jr., Terrence R.
Roush, William R.
Rader, Christoph
author_sort Nanna, Alex R.
collection PubMed
description Current strategies to produce homogeneous antibody-drug conjugates (ADCs) rely on mutations or inefficient conjugation chemistries. Here we present a strategy to produce site-specific ADCs using a highly reactive natural buried lysine embedded in a dual variable domain (DVD) format. This approach is mutation free and drug conjugation proceeds rapidly at neutral pH in a single step without removing any charges. The conjugation chemistry is highly robust, enabling the use of crude DVD for ADC preparation. In addition, this strategy affords the ability to precisely monitor the efficiency of drug conjugation with a catalytic assay. ADCs targeting HER2 were prepared and demonstrated to be highly potent and specific in vitro and in vivo. Furthermore, the modular DVD platform was used to prepare potent and specific ADCs targeting CD138 and CD79B, two clinically established targets overexpressed in multiple myeloma and non-Hodgkin lymphoma, respectively.
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spelling pubmed-56536462017-10-25 Harnessing a catalytic lysine residue for the one-step preparation of homogeneous antibody-drug conjugates Nanna, Alex R. Li, Xiuling Walseng, Even Pedzisa, Lee Goydel, Rebecca S. Hymel, David Burke Jr., Terrence R. Roush, William R. Rader, Christoph Nat Commun Article Current strategies to produce homogeneous antibody-drug conjugates (ADCs) rely on mutations or inefficient conjugation chemistries. Here we present a strategy to produce site-specific ADCs using a highly reactive natural buried lysine embedded in a dual variable domain (DVD) format. This approach is mutation free and drug conjugation proceeds rapidly at neutral pH in a single step without removing any charges. The conjugation chemistry is highly robust, enabling the use of crude DVD for ADC preparation. In addition, this strategy affords the ability to precisely monitor the efficiency of drug conjugation with a catalytic assay. ADCs targeting HER2 were prepared and demonstrated to be highly potent and specific in vitro and in vivo. Furthermore, the modular DVD platform was used to prepare potent and specific ADCs targeting CD138 and CD79B, two clinically established targets overexpressed in multiple myeloma and non-Hodgkin lymphoma, respectively. Nature Publishing Group UK 2017-10-24 /pmc/articles/PMC5653646/ /pubmed/29062027 http://dx.doi.org/10.1038/s41467-017-01257-1 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Nanna, Alex R.
Li, Xiuling
Walseng, Even
Pedzisa, Lee
Goydel, Rebecca S.
Hymel, David
Burke Jr., Terrence R.
Roush, William R.
Rader, Christoph
Harnessing a catalytic lysine residue for the one-step preparation of homogeneous antibody-drug conjugates
title Harnessing a catalytic lysine residue for the one-step preparation of homogeneous antibody-drug conjugates
title_full Harnessing a catalytic lysine residue for the one-step preparation of homogeneous antibody-drug conjugates
title_fullStr Harnessing a catalytic lysine residue for the one-step preparation of homogeneous antibody-drug conjugates
title_full_unstemmed Harnessing a catalytic lysine residue for the one-step preparation of homogeneous antibody-drug conjugates
title_short Harnessing a catalytic lysine residue for the one-step preparation of homogeneous antibody-drug conjugates
title_sort harnessing a catalytic lysine residue for the one-step preparation of homogeneous antibody-drug conjugates
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5653646/
https://www.ncbi.nlm.nih.gov/pubmed/29062027
http://dx.doi.org/10.1038/s41467-017-01257-1
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