pH-Sensitive Self-Immolative Linkers

Conjugating potent small molecules (e.g. toxins) to highly target specific biomolecules such as antibodies by means of a linker has become a modern and sophisticated therapeutic approach, particularly in the field of cancer therapy. The list of antibody drug conjugates ADCs in clinical trials continues to grow, bolstered by the success of two pioneers in this field: Adcetris® and Kadcyla®.

An ADC circulates in plasma until it reaches the target cell which is typically a cancer cell. The antibody portion of the ADC then binds to a cell-surface antigen that is overexpressed in or ideally specific for a certain cell type. Upon binding, the ADC-antigen complex is internalized into the target cell. The linker between antibody and payload is then typically cleaved by intracellular hydrolases, by reduction, or by a difference in pH, releasing the payload which subsequently binds to its cellular target.

By design, acid-labile linkers are intended to remain stable while circulating in plasma at neutral conditions (pH 7.3. - 7.5). This stability allows conjugates to reach and accumulate at the target cells while remaining intact. Once internalized, the mildly acidic pH of the endosomal (pH 5.0 - 6.5) or lysosomal (pH 4.5 ‑ 5.0) compartments of the cell induces hydrolysis of the pH-sensitive linkers, releasing the payload.

Due to the acidic microenvironment of solid tumors, this cleavage mechanism has been proven to be equally effective against targets that suffer from poor internalization. With a smartly chosen payload, an ADC can exert its effect even on antigen-negative tumor cells present in the vicinity of antigen-positive cells through bystander killing, a feature that renders pH-sensitive linkers a valuable option in the ADC toolbox.

Our acid-labile linkers are based on silyl ether chemistry that affords stability of the corresponding conjugate during circulation while allowing for an effective linker cleavage and drug release once taken up by the target cell.

➔ Are you unable to find your desired linker derivative? Please contact us for a custom synthesis! 

➔ Interested in further information on linker technologies? ➔ Please feel free to download our new brochure on Linkerology!

References:

A versatile acid-labile linker for antibody drug conjugates; M. C. Finniss, K. S. Chu, C. J. Bowerman, J. C. Luft, Z. A. Haroon, J. M. DeSimone; Med. Chem. Commun. 2014; 5: 1355-1358. https://doi.org/10.1039/C4MD00150H.

Novel Silyl Ether-Based Acid-Cleavable Antibody-MMAE Conjugates with Appropriate Stability and Efficacy; Y. Wang, S. Fan, D. Xiao, F. Xie, W. Li, W. Zhong, X. Zhou; Cancers 2019; 11(7): 957. https://doi.org/10.3390/cancers11070957.

Acid-labile Linkers; E.A. Savoy, F.P. Olatunji. H. Yoon, N. Mesbahi, J.R. Knight, C.E. Berkman; in Chemical Linkers in Antibody-Drug Conjugates (ADCs); edited by Floris van Delft, John M. Lambert. Royal Society of Chemistry 2022; ISSN 2041-3203.