Linkers Having a Crucial Role in Antibody-Drug Conjugates.

Jun Lu,Aiping Lu,Ge Zhang,Feng Jiang

doi:10.3390/ijms17040561

Abstract

Antibody–drug conjugates (ADCs) comprised of a desirable monoclonal antibody, an active cytotoxic drug and an appropriate linker are considered to be an innovative therapeutic approach for targeted treatment of various types of tumors and cancers, enhancing the therapeutic parameter of the cytotoxic drug and reducing the possibility of systemic cytotoxicity. An appropriate linker between the antibody and the cytotoxic drug provides a specific bridge, and thus helps the antibody to selectively deliver the cytotoxic drug to tumor cells and accurately releases the cytotoxic drug at tumor sites. In addition to conjugation, the linkers maintain ADCs’ stability during the preparation and storage stages of the ADCs and during the systemic circulation period. The design of linkers for ADCs is a challenge in terms of extracellular stability and intracellular release, and intracellular circumstances, such as the acid environment, the reducing environment and cathepsin, are considered as the catalysts to activate the triggers for initiating the cleavage of ADCs. This review discusses the linkers used in the clinical and marketing stages for ADCs and details the fracture modes of the linkers for the further development of ADCs.

Highlights

Antitumor drug development has made great progress since the 20th century, especially with the emergence of biological products, promoting better selectively for the different kinds of antitumor drugs
With the development of Antibody–drug conjugates (ADCs) introduced to clinical trials or approved by the FDA, a series of typical linkers have been exploited [31]
Many non-cleavable linkers have been explored in ADC development

Summary

Introduction

Antitumor drug development has made great progress since the 20th century, especially with the emergence of biological products, promoting better selectively for the different kinds of antitumor drugs. Considerable efforts are being invested to construct the appropriate linkers, which must meet requirements for maintaining the properties of monoclonal antibodies and the cell killing activity of cytotoxic drugs, reducing systemic toxicity, maintaining the stability of ADCs and releasing in the right circumstances [4,5,36]. Among these properties, linkers should possess two crucial characteristics, including stability in plasma for an extended period of time so that the ADCs can reach and localize to the cancer cell in the original formation. With the development of ADCs introduced to clinical trials or approved by the FDA, a series of typical linkers have been exploited [31]

Types of Linkers

Cleavable Linkers

Conclusions