ADC Technology Review in 2021

ADC Technology Review in 2021

Published by BroadPharm on July 21, 2021

Antibody-Drug Conjugates (ADCs) are a class of drugs developed to selectively target cancer cells while sparing healthy cell. ADCs are composed of a payload bound to an mAbs (antibody) using a linker that is designed to specifically release their payload at a tumor.

In a General Review of ADC Drugs Development, the history of FDA approval is traced from the first release of Mylotarg to the success of compounds like Zynlonta (loncastuximab tesirine). The article also covers the three generations of technological evolution that have occurred in the development of ADCs.

Figure 1. Zynlonta, shown above, has several unique features including a maleimide group for attachment to the mAbs, a PEG8 liner for solubility, and a cleavable Val-Ala-PABA section bound to the drug SG3199.

ADC Technology Review in 2020 outlines the basic evolution and key features of ADC development up to 2020. Specifically, Zynlonta shows a combination of advanced features in ADC design. The mAbs is humanized and the attachment site is through a maleimide group to a thiol on the antibody, just like Trodelvy (Sacituzumab govitecan). Also, Zynlonta and Trodelvy both use polyethylene glycol (PEG) in their linker to increase solubility.

Both ADCs also feature a cleavable linker, but Zynlonta utilizes a valine-alanine linkage that is enzyme-cleavable instead of a benzylcarbonate site that is acid-cleavable as in Trodelvy.

Zynlonta has an average of 2.3 linked PBD per anti-body. This lower drug to antibody ratio (DAR) is indicative of the current ADC design theory that suggests a DAR of 2-4 is ideal for improving drug stability, pharmacokinetics, increase binding and drugs activity to cells with lower antigen levels.

Upon binding to CD19, Zynlonta is internalized where enzymes release the cytotoxic PBD-based dimer. The PBD-dimer has two PBD monomers that are linked through their aromatic A-ring phenolic C8-positions via a flexible propyldioxy tether. The PBD-dimer is a highly efficient DNA minor groove cross-linking agent with potent cytotoxicity.

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

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