ADME and Safety Aspects of Non-cleavable Linkers in Drug Discovery and Development

Author(s): M. Walles , A. Connor , D. Hainzl * .

Journal Name: Current Topics in Medicinal Chemistry

Volume 17 , Issue 32 , 2017

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Graphical Abstract:


Non-cleavable linkers are used in a number of different modalities for various reasons, such as linking an active drug moiety to half-life extending molecules, to groups that enable a specific tissue or cell targeting or to facilitate active uptake into target cells. Non-cleavable linkers do not have a designated weak point in their structure that can lead to cleavage by proteases, hydrolases or chemically by pH changes. Consequently, when designing a conjugate, the choice of a non-cleavable over a cleavable linker is usually a consequence of pursuing a certain mode of action where the stability of the complex is more important than a fast liberation of the active moiety.

Linkers of various length, polarity, stability and flexibility are used for different types of conjugates and the linker design is mostly driven by the particular purpose and desired mode of action. This article reviews non-cleavable linkers applied predominantly in Antibody Drug Conjugates (ADCs), and how they influence these conjugates in terms of ADME properties (absorption, distribution, metabolism and elimination) and safety.

Keywords: Non-cleavable linker, Antibody-drug conjugate, Catabolism, Bystander activity, ADME, Polyethylene glycol.

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Article Details

Year: 2017
Page: [3463 - 3475]
Pages: 13
DOI: 10.2174/1568026618666180118153502
Price: $58

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PDF: 78