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Int. J. Mol. Sci. 2017, 18(11), 2284; https://doi.org/10.3390/ijms18112284

A Versatile Chemo-Enzymatic Conjugation Approach Yields Homogeneous and Highly Potent Antibody-Drug Conjugates

1
Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, Institute of Drug Metabolism and Drug Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
2
College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
3
Formulation and Analysis Laboratory, HisunPharma (Hangzhou) Co. Ltd., Xialian Village, Xukou Town, Fuyang, Hangzhou 311404, China
*
Authors to whom correspondence should be addressed.
Received: 7 October 2017 / Revised: 27 October 2017 / Accepted: 27 October 2017 / Published: 31 October 2017
(This article belongs to the Section Materials Science)
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Abstract

The therapeutic efficacy of antibodies can be successfully improved through targeted delivery of potent cytotoxic drugs in the form of antibody-drug conjugates. However, conventional conjugation strategies lead to heterogeneous conjugates with undefined stoichiometry and sites, even with considerable batch-to-batch variability. In this study, we have developed a chemo-enzymatic strategy by equipping the C-terminus of anti-CD20 ofatumumab with a click handle using Sortase A, followed by ligation of the payload based on a strain-promoted azide-alkyne cycloaddition to produce homogeneous conjugates. The resulting antibody-drug conjugates fully retained their antigen binding capability and proved to be internalized and trafficked to the lysosome, which released the payload with a favorable efficacy in vitro and in vivo. Thus, this reported method is a versatile tool with maximum flexibility for development of antibody-drug conjugates and protein modification. View Full-Text
Keywords: antibody-drug conjugate; site-specific; chemo-enzymatic conjugation; click chemistry antibody-drug conjugate; site-specific; chemo-enzymatic conjugation; click chemistry
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Xu, Y.; Jin, S.; Zhao, W.; Liu, W.; Ding, D.; Zhou, J.; Chen, S. A Versatile Chemo-Enzymatic Conjugation Approach Yields Homogeneous and Highly Potent Antibody-Drug Conjugates. Int. J. Mol. Sci. 2017, 18, 2284.

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