UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Leucine-rich alpha-2-glycoprotein 1 (LRG1) as a novel ADC target

Javaid, F; Pilotti, C; Camilli, C; Kallenberg, D; Bahou, C; Blackburn, J; R. Baker, J; ... Chudasama, V; + view all (2021) Leucine-rich alpha-2-glycoprotein 1 (LRG1) as a novel ADC target. RSC Chemical Biology , 2 (4) pp. 1206-1220. 10.1039/d1cb00104c. Green open access

[thumbnail of Chudasama_d1cb00104c.pdf]
Preview
Text
Chudasama_d1cb00104c.pdf - Published Version

Download (7MB) | Preview

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) via 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 in vitro cell studies. We show that the extracellular LRG1-targeting ADC provides an increase in survival in vivo 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 en route to improving the efficacy of cancer therapeutics.

Type: Article
Title: Leucine-rich alpha-2-glycoprotein 1 (LRG1) as a novel ADC target
Open access status: An open access version is available from UCL Discovery
DOI: 10.1039/d1cb00104c
Publisher version: https://doi.org/10.1039/d1cb00104c
Language: English
Additional information: This article is licensed under a Creative Commons Attribution 3.0 Unported Licence (http://creativecommons.org/licenses/by/3.0/).
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > CRUK Cancer Trials Centre
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10129730
Downloads since deposit
34Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item