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Publication Detail
Leucine-rich alpha-2-glycoprotein 1 (LRG1) as a novel ADC target
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Javaid F, Pilotti C, Camilli C, Kallenberg D, Bahou C, Blackburn J, R. Baker J, Greenwood J, Moss SE, Chudasama V
  • Publication date:
    01/08/2021
  • Pagination:
    1206, 1220
  • Journal:
    RSC Chemical Biology
  • Volume:
    2
  • Issue:
    4
  • Status:
    Published
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. This journal is
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