An optimal “Click” formulation strategy for antibody-drug conjugate synthesis
An optimal “Click” formulation strategy for antibody-drug conjugate synthesis
As a versatile reaction for bioconjugation, Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC) has enormous potential in the synthesis of antibody-drug conjugates (ADCs). In order to optimize CuAAC-based ADC synthesis, we characterized kinetically different formulation processes by mimicking ADC synthesis using small molecules and subsequently revealed unique kinetic behaviors of different combinations of alkyne and azide conditions. Our results indicate that under ADC synthesis conditions, for an alkyne-containing drug, its concentration has minimal impact on the reaction rate when an antibody has a non-metal-chelating azide but is proportional to concentration when an antibody contains a metal-chelating azide; however, for an alkyne-containing antibody, the ADC synthesis rate is proportional to the concentration of a drug with a non-metal-chelating azide but displays almost no dependence on drug concentration with a metal-chelating azide. Based on our results, we designed and tested an optimal “click” formulation strategy that allowed rapid and cost-effective synthesis of a new ADC.
Antibody-drug conjugate, Click reaction, Copper(I)-catalyzed alkyne-azide cycloaddition, Kinetic formulation, Metal-chelating azide
Ward, E. Sally
b31c0877-8abe-485f-b800-244a9d3cd6cc
Vatansever, E.C.
200cfffa-85da-4052-acfb-2bf03fc59818
Kang, Jeffrey C.
a3dfd242-a85c-475e-9b98-a6a79db7a93c
Tuley, Alfred
c9b4bff7-8e33-4d5e-a8c9-90d7cc2ce891
Liu, Wenshe Ray
5655ff5d-8c28-4093-b765-845d4ee83b6c
15 December 2020
Ward, E. Sally
b31c0877-8abe-485f-b800-244a9d3cd6cc
Vatansever, E.C.
200cfffa-85da-4052-acfb-2bf03fc59818
Kang, Jeffrey C.
a3dfd242-a85c-475e-9b98-a6a79db7a93c
Tuley, Alfred
c9b4bff7-8e33-4d5e-a8c9-90d7cc2ce891
Liu, Wenshe Ray
5655ff5d-8c28-4093-b765-845d4ee83b6c
Ward, E. Sally, Vatansever, E.C., Kang, Jeffrey C., Tuley, Alfred and Liu, Wenshe Ray
(2020)
An optimal “Click” formulation strategy for antibody-drug conjugate synthesis.
Bioorganic & Medicinal Chemistry, 28 (24), [115808].
(doi:10.1016/j.bmc.2020.115808).
Abstract
As a versatile reaction for bioconjugation, Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC) has enormous potential in the synthesis of antibody-drug conjugates (ADCs). In order to optimize CuAAC-based ADC synthesis, we characterized kinetically different formulation processes by mimicking ADC synthesis using small molecules and subsequently revealed unique kinetic behaviors of different combinations of alkyne and azide conditions. Our results indicate that under ADC synthesis conditions, for an alkyne-containing drug, its concentration has minimal impact on the reaction rate when an antibody has a non-metal-chelating azide but is proportional to concentration when an antibody contains a metal-chelating azide; however, for an alkyne-containing antibody, the ADC synthesis rate is proportional to the concentration of a drug with a non-metal-chelating azide but displays almost no dependence on drug concentration with a metal-chelating azide. Based on our results, we designed and tested an optimal “click” formulation strategy that allowed rapid and cost-effective synthesis of a new ADC.
Text
bioorgmedchem-submitted-final-version
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More information
Accepted/In Press date: 1 October 2020
e-pub ahead of print date: 6 October 2020
Published date: 15 December 2020
Additional Information:
Funding Information:
This work was supported in part by National Institutes of Health (grant R01GM127575 ), Cancer Prevention and Research Institute of Texas (grants RP170797, RP140141) and Welch Foundation (grant A-1715). We thank Sunshine Z. Leeuwon for proofreading the manuscript.
Publisher Copyright:
© 2020 Elsevier Ltd
Keywords:
Antibody-drug conjugate, Click reaction, Copper(I)-catalyzed alkyne-azide cycloaddition, Kinetic formulation, Metal-chelating azide
Identifiers
Local EPrints ID: 445468
URI: http://eprints.soton.ac.uk/id/eprint/445468
ISSN: 0968-0896
PURE UUID: cc3a21c6-4317-4a04-b41f-73a51d40aac8
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Date deposited: 10 Dec 2020 17:31
Last modified: 17 Mar 2024 06:08
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Contributors
Author:
E.C. Vatansever
Author:
Jeffrey C. Kang
Author:
Alfred Tuley
Author:
Wenshe Ray Liu
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