Cleavable cross linkers play a crucial role in the success of antibody-drug conjugates. It determines the fate of the cytotoxic drug in the biological system. In order to make the ADC effective, it requires the linkers to be stable enough in the blood circulation for a substantial amount of time to avoid side toxicity and to allow ADC to reach the target. It also requires the linkers to be labile so that they efficiently release corresponding payload in the tumor environment.

Acid-labile Linkers and Reducible Linkers are two types of widely used chemically labile linkers in ADCs. They undergo cleavage in the acidic endosomal–lysosomal environment or elevated concentration of glutathione inside cells.

Ala-Ala-Asn-pab peptide Linkers

Ala-ala-asn-pab peptide linkers improve physiochemical property and toxicity profiles of cytotoxic drugs by forming a peptide-drug conjugate. The peptide drug conjugate can be cleaved by cellular proteases and release the cytotoxic drugs in their active form.

Val-ala linkers

Val-Ala linkers have emerged as an effective protease-cleavable group, with numerous examples in clinical trials. Like Val-Cit, Val-Ala is effectively cleaved in cells and it is highly stable in human plasma.

Val-Cit-PAB Linkers

Val-cit-pab linkers have been widely used in Antibody drug conjugation development. They have superior plasma stability to other peptide linkers. Val-cit-pab linkers are cleavable by cathepsin. The cleavage of val-cit-PAB linked amide releases the free parent drug through a 1,6-elimination of carbon dioxide.

β-Glucuronide Linkers

β-Glucuronide Linkers is an enzyme-labile linker used in the development of antibody-drug conjugates. The β-Glucuronide and cytotoxic drug conjugate complex undergoes cleavage by β-glucuronidase and releases the cytotoxic drug. β-glucuronidase is an enzyme present in lysosomes and over expressed in some tumors.