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Appraisal of Leucine-rich alpha-2-glycoprotein 1 (LRG1) as a target for a potential antibody–drug conjugate (ADC)

Javaid, Faiza; (2021) Appraisal of Leucine-rich alpha-2-glycoprotein 1 (LRG1) as a target for a potential antibody–drug conjugate (ADC). Doctoral thesis (Ph.D), UCL (University College London). Green open access

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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. LRG1 antibody blockade leads to vascular normalisation, and represents a novel means of improving efficacy of cancer therapeutics. The aim of this research is to evaluate whether LRG1 is a suitable target for an antibody–drug conjugate (ADC) based cancer therapy. While it is generally believed that ADCs need to internalise into tumour cells in order to liberate their payload and display optimal therapeutic activity, a growing body of evidence indicates that ADCs targeting non internalising antigens also display potent activity. This work demonstrates that LRG1 is predominantly a non-internalising protein. Herein, the development of a novel 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 is reported. It is demonstrated that this ADC retains binding post modification, is stable in serum and effective in in vitro cell studies. A hLRG1 expressing B16F0 mouse melanoma cell line was developed and tumours derived from this cell line indicated localisation of Magacizumab at the site of the tumour. In vivo and in vitro studies showed that the novel extracellular LRG1-targeting ADC liberates its toxic payload, which is coupled to the antibody via a cleavable dipeptide linker, presumably upon being metabolised by appropriate proteases (e.g. cathepsin B) and provides an increase in survival when applied in mouse models of tumours when compared against standard chemotherapy and antibody alone. LRG1 targeting through this reported ADC presents a novel and effective proof-of-concept en route to improving the efficacy of cancer therapeutics.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Appraisal of Leucine-rich alpha-2-glycoprotein 1 (LRG1) as a target for a potential antibody–drug conjugate (ADC)
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
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/10125913
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