Leucine-rich Alpha-2-glycoprotein 1 (LRG1) As a Novel ADC Target

Overview

Journal RSC Chem Biol

Publisher Royal Society of Chemistry

Specialty Biology

Date 2021 Aug 30

PMID 34458833

Citations 15

Authors

Faiza Javaid

Camilla Pilotti

Carlotta Camilli

David Kallenberg

Calise Bahou

Jack Blackburn

James R Baker

John Greenwood

Stephen E Moss

Vijay Chudasama

Affiliations

Soon will be listed here.

Abstract

Leucine-rich alpha-2-glycoprotein 1 (LRG1) is present abundantly in the microenvironment of many tumours where it contributes to vascular dysfunction, which impedes the delivery of therapeutics. In this work we demonstrate that LRG1 is predominantly a non-internalising protein. We report the development of a novel antibody-drug conjugate (ADC) comprising the anti-LRG1 hinge-stabilised IgG4 monoclonal antibody Magacizumab coupled to the anti-mitotic payload monomethyl auristatin E (MMAE) a cleavable dipeptide linker using the site-selective disulfide rebridging dibromopyridazinedione (diBrPD) scaffold. It is demonstrated that this ADC retains binding post-modification, is stable in serum and effective in cell studies. We show that the extracellular LRG1-targeting ADC provides an increase in survival when compared against antibody alone and similar anti-tumour activity when compared against standard chemotherapy, but without undesired side-effects. LRG1 targeting through this ADC presents a novel and effective proof-of-concept to improving the efficacy of cancer therapeutics.

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