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.