Zynlonta (loncastuximab tesirine-lpyl)

Zynlonta (loncastuximab tesirine-lpyl)

Published by BroadPharm on July 21, 2021

Antibody-Drug Conjugates (ADCs) are made up of a drug linked to an mAbs (antibody) that is designed to specifically release their payload at a tumor.

A key technological development in ADCs has been the ADC Linker Design. Zynlonta, similarly to Trodelvy, has incorporated monodispersed polyethylene glycol (PEG) chains into its linker.

diagram of antibody drug conjugate linker as well as a description
Figure 1. Zynlonta, shown above, has several unique features including a maleimide group for attachment to the mAbs, a PEG8 linker for solubility, and a cleavable Val-Ala section bound to the drug SG3199.

Zynlonta (loncastuximab tesirine) has been approved by the US FDA for use in treating diffuse large B-cell lymphoma (DLBCL). DLBCL is the most common type of non-Hodgkin lymphoma, a rapidly progressing aggressive disease.

Zynlonta works by targeting human CD19 using a humanized monoclonal antibody conjugated through a linker to a pyrrolobenzodiazepine (PBD) dimer payload. The ADC has an average of 2.3 linked PBD per anti-body.

Upon binding to CD19, Zynlonta is internalized where enzymes release the 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.

The linker used in Zynlonta is comprised of several interesting synthetic features; including monodispersed PEG8 arm, protease-cleavable Val-Ala di-Peptide, and the maleimide group that binds the linker to the antibody.

As a world leader of bioconjugation linkers, 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.

Journal Reference: