Antibody–drug conjugates (ADCs) are composed in a modular manner with a payload attached to an antibody via an appropriate linker. The properties that an optimal linker needs to fulfill are manifold: for efficient delivery of the payload to the tumor, the linker has to be stable in circulation, but at the site of the tumor, it has to be cleaved to release the active payload catabolite from the antibody. Depending on the target biology of the antibody, the linker may be cleaved either extracellularly in the tumor microenvironment or intracellularly after internalization and trafficking to the lysosomes, and thus the linker chemistry needs to be designed accordingly. To release the active metabolite from an ADC, linkers can be designed either for chemical cleavage, e.g. for hydrolysis at lower pH within the lysosomes, or for enzymatic cleavage by tumor-associated enzymes such as glycosidases and proteases. As a third strategy, stable (uncleavable) linkers have been employed successfully in ADCs, particularly when the target biology of the payload allows for some modification of the payload itself. In this case, the active metabolite is formed only after the degradation of the antibody, and the amino acid residue utilized for conjugation to the antibody stays attached to the non-cleavable linker-payload metabolite. A crucial prerequisite for this strategy is that the linker fragment that resides with the toxophore needs to be tolerated in a way that the entire linker-fragment-payload retains high on-target potency.
Antibody Drug Conjugates (ADCs) use the targeting ability of monoclonal antibodies to deliver potent cytototoxic payloads to their intended target. The linker encompasses a conjugating functionality suitable for attachment to the antibody, a spacer unit that typically incorporates a hydrophilic element and a trigger that releases the potent cytototoxic warhead. ALL Chemistry Inc. understands the conflicting requirements of ADC design, provides stability in systemic circulation but efficient payload release once the ADC reaches its intended target, which is crucial to effective linker development. ALL Chemistry Inc. has approached ADC linker design in a variety of different ways, with increasingly elegant solutions continuing to be reported as understanding of the intricate design complexities increases. We focus on the synthetic approaches used in ADC linkers, and the impact of linker design on antibody conjugation, ADC pharmacokinetics and payload release. ALL Chemistry Inc. offers linkers for solid-phase chemistry, ADC linkers and various other linker molecules, with a wide variety of functional groups, as well as custom synthesized linkers to suit your needs.
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