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

Javaid, Faiza; Pilotti, Camilla; Camilli, Carlotta; Kallenberg, David; Bahou, Calise; Blackburn, Jack W. D.; Baker, James R.; Greenwood, John A.; Moss, Stephen E.; Chudasama, Vijay

doi:10.1039/d1cb00104c

Cited by 21 publications

(22 citation statements)

References 62 publications

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“…By directly blocking the downstream angiopathic molecule LRG1, either by using a function-blocking antibody or potentially by genetic manipulation, it may be possible to normalise the vascular phenotype. Our data highlight the potential of using LRG1 as a new therapeutic target to treat conditions with prominent pathological angiogenesis and dysfunctional vessels, such as age-related macular degeneration, cancer, and COVID-19-related pulmonary complications 44 , 78 .…”

Section: Discussionmentioning

confidence: 73%

Angiopathic activity of LRG1 is induced by the IL-6/STAT3 pathway

Dritsoula

Dowsett

Pilotti

et al. 2022

Sci Rep

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Leucine-rich α-2-glycoprotein 1 (LRG1) is a secreted glycoprotein that under physiological conditions is produced predominantly by the liver. In disease, its local induction promotes pathogenic neovascularisation while its inhibition leads to reduced dysfunctional angiogenesis. Here we examine the role of interleukin-6 (IL-6) in defective angiogenesis mediated by LRG1. IL-6 treatment induced LRG1 expression in endothelial cells and ex vivo angiogenesis cultures and promoted vascular growth with reduced mural cell coverage. In Lrg1−/− explants, however, IL-6 failed to stimulate angiogenesis and vessels exhibited improved mural cell coverage. IL-6 activated LRG1 transcription through the phosphorylation and binding of STAT3 to a conserved consensus site in the LRG1 promoter, the deletion of which abolished activation. Blocking IL-6 signalling in human lung endothelial cells, using the anti-IL6 receptor antibody Tocilizumab, significantly reduced LRG1 expression. Our data demonstrate that IL-6, through STAT3 phosphorylation, activates LRG1 transcription resulting in vascular destabilisation. This observation is especially timely in light of the potential role of IL-6 in COVID-19 patients with severe pulmonary microvascular complications, where targeting IL-6 has been beneficial. However, our data suggest that a therapy directed towards blocking the downstream angiopathic effector molecule LRG1 may be of greater utility.

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Section: Discussionmentioning

confidence: 73%

Angiopathic activity of LRG1 is induced by the IL-6/STAT3 pathway

Dritsoula

Dowsett

Pilotti

et al. 2022

Sci Rep

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“…This, together with the observation that inhibiting LRG1 function attenuates disease progression through restoration of vascular homeostasis, has paved the way for the development of a humanized anti-LRG1 antibody that may be tested clinically in the near future. In particular, Magacizumab is an IgG4 antibody specifically designed to minimize the risk of inflammatory reactions and whose efficacy in limiting vascular leakage and tumour progression has been already demonstrated in murine models of nvAMD [ 5 ] and melanoma [ 6 ], respectively. These encouraging results were followed by the development of an anti-LRG1 Fab fragment exhibiting even higher therapeutic benefits, especially in the context of ocular injections where the lack of the Fc fragment, and the reduced molecular weight, lend themselves to intraocular delivery [ 5 ].…”

Section: Conclusion and Future Prospectivesmentioning

confidence: 99%

“…As a role for LRG1 in disease gains traction, there is now considerable interest in targeting its activity therapeutically. Accordingly, the recent development of a function-blocking antibody [ 5 ] might provide researchers with tools to counteract aberrant LRG1 biological activities in a wide range of pathological settings [ 6 ]. Here, we provide an overview of the LRG1 literature considering its role as a contributing factor in disease and discussing its potential clinical application as a novel biomarker and therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

LRG1: an emerging player in disease pathogenesis

et al. 2022

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The secreted glycoprotein leucine-rich α-2 glycoprotein 1 (LRG1) was first described as a key player in pathogenic ocular neovascularization almost a decade ago. Since then, an increasing number of publications have reported the involvement of LRG1 in multiple human conditions including cancer, diabetes, cardiovascular disease, neurological disease, and inflammatory disorders. The purpose of this review is to provide, for the first time, a comprehensive overview of the LRG1 literature considering its role in health and disease. Although LRG1 is constitutively expressed by hepatocytes and neutrophils, Lrg1−/− mice show no overt phenotypic abnormality suggesting that LRG1 is essentially redundant in development and homeostasis. However, emerging data are challenging this view by suggesting a novel role for LRG1 in innate immunity and preservation of tissue integrity. While our understanding of beneficial LRG1 functions in physiology remains limited, a consistent body of evidence shows that, in response to various inflammatory stimuli, LRG1 expression is induced and directly contributes to disease pathogenesis. Its potential role as a biomarker for the diagnosis, prognosis and monitoring of multiple conditions is widely discussed while dissecting the mechanisms underlying LRG1 pathogenic functions. Emphasis is given to the role that LRG1 plays as a vasculopathic factor where it disrupts the cellular interactions normally required for the formation and maintenance of mature vessels, thereby indirectly contributing to the establishment of a highly hypoxic and immunosuppressive microenvironment. In addition, LRG1 has also been reported to affect other cell types (including epithelial, immune, mesenchymal and cancer cells) mostly by modulating the TGFβ signalling pathway in a context-dependent manner. Crucially, animal studies have shown that LRG1 inhibition, through gene deletion or a function-blocking antibody, is sufficient to attenuate disease progression. In view of this, and taking into consideration its role as an upstream modifier of TGFβ signalling, LRG1 is suggested as a potentially important therapeutic target. While further investigations are needed to fill gaps in our current understanding of LRG1 function, the studies reviewed here confirm LRG1 as a pleiotropic and pathogenic signalling molecule providing a strong rationale for its use in the clinic as a biomarker and therapeutic target.

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“…To date, several antibody platforms have been shown to be compatible with the DiBrPD re-bridging approach including IgG1, IgG2a (mouse), IgG2b (rat), and IgG4. [52][53][54][55] In addition, a wide variety of functionalities have been added through efficient and quantitative "click" reactions (e.g. Doxorubicin, MMAE, porphyrins, etc.…”

Section: Clinically Relevant Antibody-conjugatesmentioning

confidence: 99%

“…Fig.8(a) Formation of anti-LRG1-MMAE ADC using DiBrPDs to re-bridge disulfide bonds 55. (b) Using DiBrPDs and click chemistry to chemically construct bi-specific antibodies 59.…”

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confidence: 99%