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Broadpharm提供可切割和不可切割Linker

更新時(shí)間:2023-08-28   點(diǎn)擊次數(shù):886次

Antibody-Drug Conjugates (ADCs) are composed of a drug (payload) and antibody (mAbs) that are bound using linkages that are specifically designed to deliver the payload to the intended target environment. ADCs are designed to sparing healthy cells by targeting specific cancer types.

This article expands upon the linker information in the ADC Linker Technology in 2021 article. Specifically, the cleavable and non-cleavable categories of ADC linkers. Cleavable linkers use inherent properties of tumor cells for selective release of payloads from the ADCs. There are three commonly used mechanisms for cleavable linkers; protease-sensitive peptide linkers, acid sensitive hydrazone linkers, and glutathione-sensitive disulfide linkers.

Protease-sensitive cleavable linkers use the dominant proteases found in tumor cell lysosomes for recognition and cleavage of a specific peptide sequence in the linker. A commonly used ADC linker makes use of a valine-citrulline (vc) dipeptide, first discovered by Dubowchik et al., as an intracellular cleavage mechanism by cathepsin B.

diagram of adcetris
Figure 1. Adcetris with enzymatically cleavable val-cit linkage.

Acid-sensitive linkers use a lower pH in the endosomal (pH = 5-6) and lysosomal (pH = 4.8) compartments, in contrast to cytosol (pH = 7.4) to trigger hydrolysis of acid labile groups within a linker such as hydrazone.

Glutathione-sensitive linkers use higher concentrations of intracellular glutathione that in the plasma. This causes disulfide bridges to release the payload upon reduction by glutathione.

Cleavable linkers may also help with destroying cancer cell adjacent to their targets through a process referred to as "bystander effect". The bystander effect occurs when the payload is released near the targeted cancer cell, or a payload diffuses out of one cancer cell and then is absorbed by a second cancer cell.

Non-cleavable linkers only degrade when the anti-body degrades. Release of the payload occurs mainly in the lysosome after internalization of the ADC and degradation of both the antibody and linker. This may be an advantage since it could lead to a lower risk of systemic toxicity. Figure 2 shows an example of Kadcyla, which uses SMCC crosslinker as the non-cleavable linker.

diagram of kadcyla
Figure 2. Kadcyla, shown with the linker in green and the payload in orange, was designed with a non-cleavable linkage.

BroadPharm offers a wide array of different ADC Linkers, PEG Linkers to empower our customer's advanced research worldwide. These compounds feature great aqueous solubility, smart choice of PEG length, and a broad selection of functional groups to choose from.

Journal Reference:

1.Editorial Team, "FDA Grants Accelerated Approval for Sacituzumab Govitecan in Metastatic Triple-negative Breast Cancer", ADC Review (2020)

2.FDA Press Release, "FDA grants accelerated approval to loncastuximab tesirine-lpyl for large B-cell lymphoma", (2021)

3.Staudacher, Brown, "Antibody drug conjugates and bystander killing: is antigen-dependent internalisation required?", Br J Cancer 117, (2017): 1736-1742

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