Issue 4, 2021

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


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.

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

Supplementary files

Article information

Article type
06 May 2021
27 May 2021
First published
31 May 2021
This article is Open Access
Creative Commons BY license

RSC Chem. Biol., 2021,2, 1206-1220

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

F. Javaid, C. Pilotti, C. Camilli, D. Kallenberg, C. Bahou, J. Blackburn, J. R. Baker, J. Greenwood, S. E. Moss and V. Chudasama, RSC Chem. Biol., 2021, 2, 1206 DOI: 10.1039/D1CB00104C

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