The secreted glycoprotein leucine-rich α-2 glycoprotein 1 (LRG1) is a multifunctional pathogenic signalling molecule which, amongst other activities, modulates the TGFβ pathway in a highly context-dependent manner. LRG1 was first described as a key player in pathogenic ocular neovascularization 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. Effective blocking of LRG1 therefore offers platform therapeutic value across many disease indications.

Continued LRG1 presence leads to disease

LRG1 acts as an effective “acute phase” protein that contributes to the innate immune response. Although almost absent in healthy individuals, inflammation and infection trigger expression of LRG1. As a component of the repair mechanism it induces de-differentiation of epithelial, endothelial and pericyte cells enabling cell survival, proliferation, immune cell infiltration, vessel restoration and wound healing.

Upon restoration of homeostasis, LRG1 is switched off. However, under chronically stressed cell conditions, LRG1 continues to be expressed and has aberrant effects: Fibrosis, loss of vascular integrity and cancer cell proliferation and migration.

Main pathogenic mechanism of LRG1

Under chronic conditions LRG1 drives excessive and uncontrolled signalling of the TGFβ cascade. LRG1 binds to TGFβ receptors switching TGFβ cascade from homeostatic to pathogenic motif.

Senya’s Pipeline

Senya Therapeutics is developing proprietary biologics targeting LRG1 to provide therapeutic interventions in these key disease populations. To date, the company has developed a lead molecule, STX-002, that inhibits the activity of LRG1 and has successfully demonstrated its efficacy in a range of translational preclinical models. These results have shown that the compound is safe and well-tolerated, and that these approaches can be used to treat disease through vascular normalisation, deceleration of fibrosis, and an improved microenvironment.

In addition to STX-002, Senya is developing STX-001, a fragment of STX-002, intended for ophthalmology indications.

Publications

General LRG1 Review

• LRG1: an emerging player in disease pathogenesis.Camilli C, Hoeh AE, De Rossi G, Moss SE, Greenwood J. J Biomed Sci. 2022 Jan 21;29(1):6.doi: 10.1186/s12929-022-00790-6. PMID: 35062948

Kidney

• Urine Leucine-Rich α-2 Glycoprotein 1 (LRG1) Predicts the Risk of Progression to End-Stage Kidney Disease in Patients With Type 2 Diabetes.Liu JJ, Liu S, Wang J, Pek SLT, Lee J, Gurung RL, Ang K, Shao YM, Tavintharan S, Tang WE, Sum CF, Lim SC. Diabetes Care. 2023 Feb 1;46(2):408-415.

  doi: 10.2337/dc22-1611. PMID: 36516193

• Modulation of transforming growth factor-β-induced kidney fibrosis by leucine-rich ⍺-2 glycoprotein-1.Hong Q, Cai H, Zhang L, Li Z, Zhong F, Ni Z, Cai G, Chen XM, He JC, Lee K. Kidney Int. 2022 Feb;101(2):299-314.

  doi: 10.1016/j.kint.2021.10.023. Epub 2021 Nov 10. PMID: 34774561

• Leucine-Rich Alpha-2-Glycoprotein (LRG-1) as a Potential Kidney Injury Marker in Kidney Transplant Recipients.Popova A, Vasiļvolfa A, Rācenis K, Erts R, Šlisere B, Saulīte AJ, Ziedina I, Folkmane I, Čerņevskis H, Kroiča J, Pētersons A, Kuzema V. Ann Transplant. 2022 Sep 6;27:e936751.

  doi: 10.12659/AOT.936751. PMID: 36065144

• Association of Genetic Variants for Plasma LRG1 With Rapid Decline in Kidney Function in Patients With Type 2 Diabetes.Gurung RL, Dorajoo R, M Y, Liu JJ, Pek SLT, Wang J, Wang L, Sim X, Liu S, Shao YM, Ang K, Subramaniam T, Tang WE, Sum CF, Liu JJ, Lim SC. J Clin Endocrinol Metab. 2021 Jul 13;106(8):2384-2394.

  doi: 10.1210/clinem/dgab268. PMID: 33889958

• Plasma Leucine-Rich α-2-Glycoprotein 1 Predicts Cardiovascular Disease Risk in End-Stage Renal Disease.Yang FJ, Hsieh CY, Shu KH, Chen IY, Pan SY, Chuang YF, Chiu YL, Yang WS. Sci Rep. 2020 Apr 6;10(1):5988.

  doi: 10.1038/s41598-020-62989-7. PMID: 32249825

• Leucine-rich α2-glycoprotein-1 upregulation in plasma and kidney of patients with lupus nephritis.Yang Y, Luo R, Cheng Y, Liu T, Dai W, Li Y, Ge S, Xu G. BMC Nephrol. 2020 Apr 6;21(1):122.

  doi: 10.1186/s12882-020-01782-0. PMID: 32252660

• LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-β-Induced Angiogenesis.Hong Q, Zhang L, Fu J, Verghese DA, Chauhan K, Nadkarni GN, Li Z, Ju W, Kretzler M, Cai GY, Chen XM, D’Agati VD, Coca SG, Schlondorff D, He JC, Lee K. J Am Soc Nephrol. 2019 Apr;30(4):546-562.

  doi: 10.1681/ASN.2018060599. Epub 2019 Mar 11. PMID: 30858225

• Leucine rich α-2 glycoprotein is a potential urinary biomarker for renal tubular injury.Lee H, Fujimoto M, Ohkawara T, Honda H, Serada S, Terada Y, Naka T. Biochem Biophys Res Commun. 2018 Apr 15;498(4):1045-1051.

  doi: 10.1016/j.bbrc.2018.03.111. Epub 2018 Mar 17. PMID: 29550485

• Plasma Leucine-Rich α-2-Glycoprotein 1 Predicts Rapid eGFR Decline and Albuminuria Progression in Type 2 Diabetes Mellitus.Liu JJ, Pek SLT, Ang K, Tavintharan S, Lim SC; SMART2D study. J Clin Endocrinol Metab. 2017 Oct 1;102(10):3683-3691.

  doi: 10.1210/jc.2017-00930. PMID: 28973352

Cancer

• Systemic LRG1 Expression in Melanoma is Associated with Disease Progression and Recurrence.Hoefsmit EP, Völlmy F, Rozeman EA, Reijers ILM, Versluis JM, Hoekman L, van Akkooi ACJ, Long GV, Schadendorf D, Dummer R, Altelaar M, Blank CU. Cancer Res Commun. 2023 Apr 20;3(4):672-683.

  doi: 10.1158/2767-9764.CRC-23-0015. eCollection 2023 Apr.

• LRG1 mediated by ATF3 promotes growth and angiogenesis of gastric cancer by regulating the SRC/STAT3/VEGFA pathway.He L, Feng A, Guo H, Huang H, Deng Q, Zhao E, Yang M. Gastric Cancer. 2022 May;25(3):527-541.

  doi: 10.1007/s10120-022-01279-9. Epub 2022 Jan 30. PMID: 35094168

• Temporal multi-omics identifies LRG1 as a vascular niche instructor of metastasis.Singhal M, Gengenbacher N, Abdul Pari AA, Kamiyama M, Hai L, Kuhn BJ, Kallenberg DM, Kulkarni SR, Camilli C, Preuß SF, Leuchs B, Mogler C, Espinet E, Besemfelder E, Heide D, Heikenwalder M, Sprick MR, Trumpp A, Krijgsveld J, Schlesner M, Hu J, Moss SE, Greenwood J, Augustin HG. Sci Transl Med. 2021 Sep;13(609):eabe6805.

  doi: 10.1126/scitranslmed.abe6805. Epub 2021 Sep 1. PMID: 34516824

• LRG1 Promotes Metastatic Dissemination of Melanoma through Regulating EGFR/STAT3 Signalling.Kwan YP, Teo MHY, Lim JCW, Tan MS, Rosellinny G, Wahli W, Wang X. Cancers (Basel). 2021 Jun 30;13(13):3279.

  doi: 10.3390/cancers13133279. PMID: 34208965

• LRG1 destabilizes tumor vessels and restricts immunotherapeutic potency.O’Connor MN, Kallenberg DM, Camilli C, Pilotti C, Dritsoula A, Jackstadt R, Bowers CE, Watson HA, Alatsatianos M, Ohme J, Dowsett L, George J, Blackburn JWD, Wang X, Singhal M, Augustin HG, Ager A, Sansom OJ, Moss SE, Greenwood J. Med. 2021 Nov 12;2(11):1231-1252.e10.

  doi: 10.1016/j.medj.2021.10.002. Epub 2021 Nov 3. PMID: 35590198

• Identification and Validation of Leucine-rich α-2-glycoprotein 1 as a Noninvasive Biomarker for Improved Precision in Prostate Cancer Risk Stratification.Guldvik IJ, Zuber V, Braadland PR, Grytli HH, Ramberg H, Lilleby W, Thiede B, Zucknick M, Saatcioglu F, Gislefoss R, Kvåle R, George A, Grönberg H, Wiklund F, Neal DE, Gnanapragasam VJ, Taskén KA, Mills IG. Eur Urol Open Sci. 2020 Oct 13;21:51-60.

  doi: 10.1016/j.euros.2020.08.007. eCollection 2020 Oct. PMID: 34337468

• Prognostic Value of LRG1 in Breast Cancer: A Retrospective Study.Zhang YS, Han L, Yang C, Liu YJ, Zhang XM. Oncol Res Treat. 2021;44(1-2):36-42.

  doi: 10.1159/000510945. Epub 2020 Nov 26. PMID: 33242858

• LRG‑1 enhances the migration of thyroid carcinoma cells through promotion of the epithelial‑mesenchymal transition by activating MAPK/p38 signaling.Ban Z, He J, Tang Z, Zhang L, Xu Z. Oncol Rep. 2019 Jun;41(6):3270-3280.

  doi: 10.3892/or.2019.7123. Epub 2019 Apr 17. PMID: 31002347

• LRG-1 promotes pancreatic cancer growth and metastasis via modulation of the EGFR/p38 signaling.Xie ZB, Zhang YF, Jin C, Mao YS, Fu DL. J Exp Clin Cancer Res. 2019 Feb 13;38(1):75.

  doi: 10.1186/s13046-019-1088-0. PMID: 30760292

• Epithelial-mesenchymal transition via transforming growth factor beta in pancreatic cancer is potentiated by the inflammatory glycoprotein leucine-richalpha-2 glycoprotein.Otsuru T, Kobayashi S, Wada H, Takahashi T, Gotoh K, Iwagami Y, Yamada D, Noda T, Asaoka T, Serada S, Fujimoto M, Eguchi H, Mori M, Doki Y, Naka T. Cancer Sci. 2019 Mar;110(3):985-996.

  doi: 10.1111/cas.13918. Epub 2019 Feb 4. PMID: 30575211

• Leucine-rich alpha-2-glycoprotein-1 is up-regulated in colorectal cancer and is a tumor promoter.Zhang Q, Huang R, Tang Q, Yu Y, Huang Q, Chen Y, Wang G, Wang X. Onco Targets Ther. 2018 May 11;11:2745-2752.

  doi: 10.2147/OTT.S153375. eCollection 2018.PMID: 29785123

• Leucine-rich alpha-2-glycoprotein-1, relevant with microvessel density, is an independent survival prognostic factor for stage III colorectal cancer patients: a retrospective analysis.Sun DC, Shi Y, Wang LX, Lv Y, Han QL, Wang ZK, Dai GH. Oncotarget. 2017 Mar 16;8(39):66550-66558.

  doi: 10.18632/oncotarget.16289. eCollection 2017 Sep 12. PMID: 29029535

• Leucine-rich alpha-2-glycoprotein-1, relevant with microvessel density, is an independent survival prognostic factor for stage III colorectal cancer patients: a retrospective analysis.Sun DC, Shi Y, Wang LX, Lv Y, Han QL, Wang ZK, Dai GH. Oncotarget. 2017 Mar 16;8(39):66550-66558.

  doi: 10.18632/oncotarget.16289. eCollection 2017 Sep 12. PMID: 29029535

• LRG1 modulates epithelial-mesenchymal transition and angiogenesis in colorectal cancer via HIF-1α activation.Zhang J, Zhu L, Fang J, Ge Z, Li X. J Exp Clin Cancer Res. 2016 Feb 9;35:29.

  doi: 10.1186/s13046-016-0306-2. PMID: 26856989

• LRG1 expression indicates unfavorable clinical outcome in hepatocellular carcinoma.Wang CH, Li M, Liu LL, Zhou RY, Fu J, Zhang CZ, Yun JP. Oncotarget. 2015 Dec 8;6(39):42118-29.

  doi: 10.18632/oncotarget.5967. PMID: 26517349

• Discovery and Validation of Predictive Biomarkers of Survival for Non-small Cell Lung Cancer Patients Undergoing Radical Radiotherapy: Two Proteins With Predictive Value.Walker MJ, Zhou C, Backen A, Pernemalm M, Williamson AJ, Priest LJ, Koh P, Faivre-Finn C, Blackhall FH, Dive C, Whetton AD. EBioMedicine. 2015 Jun 19;2(8):841-50.

  doi: 10.1016/j.ebiom.2015.06.013. eCollection 2015 Aug. PMID: 26425690

• Leucine-rich α-2-glycoprotein promotes TGFβ1-mediated growth suppression in the Lewis lung carcinoma cell lines.Takemoto N, Serada S, Fujimoto M, Honda H, Ohkawara T, Takahashi T, Nomura S, Inohara H, Naka T. Oncotarget. 2015 May 10;6(13):11009-22.

  doi: 10.18632/oncotarget.3557. PMID: 25826092

• LRG1 suppresses the migration and invasion of hepatocellular carcinoma cells.Zhang Y, Luo Q, Wang N, Hu F, Jin H, Ge T, Wang C, Qin W. Med Oncol. 2015 May;32(5):146.

  doi: 10.1007/s12032-015-0598-7. Epub 2015 Mar 27. PMID: 25814288

• LRG1 is an independent prognostic factor for endometrial carcinoma.Wen SY, Zhang LN, Yang XM, Zhang YL, Ma L, Ge QL, Jiang SH, Zhu XL, Xu W, Ding WJ, Yang BQ, Zhang ZG, Teng YC. Tumour Biol. 2014 Jul;35(7):7125-33.

  doi: 10.1007/s13277-014-1953-6. Epub 2014 Apr 24. PMID: 24760273

• Increased plasma levels of the APC-interacting protein MAPRE1, LRG1, and IGFBP2 preceding a diagnosis of colorectal cancer in women.Ladd JJ, Busald T, Johnson MM, Zhang Q, Pitteri SJ, Wang H, Brenner DE, Lampe PD, Kucherlapati R, Feng Z, Prentice RL, Hanash SM. Cancer Prev Res (Phila). 2012 Apr;5(4):655-64.

  doi: 10.1158/1940-6207.CAPR-11-0412. Epub 2012 Jan 25. PMID: 22277732

Eye

• LRG1 facilitates corneal fibrotic response by inducing neutrophil chemotaxis via Stat3 signaling in alkali-burned mouse corneas.Yu B, Yang L, Song S, Li W, Wang H, Cheng J. Am J Physiol Cell Physiol. 2021 Sep 1;321(3):C415-C428.

  doi: 10.1152/ajpcell.00517.2020. Epub 2021 Jul 14. PMID: 34260299

• LRG1 Expression Is Elevated in the Eyes of Patients with Neovascular Age-Related Macular Degeneration.Mundo L, Tosi GM, Lazzi S, Pertile G, Parolini B, Neri G, Posarelli M, De Benedetto E, Bacci T, Silvestri E, Siciliano MC, Barbera S, Orlandini M, Greenwood J, Moss SE, Galvagni F. Int J Mol Sci. 2021 Aug 18;22(16):8879.

  doi: 10.3390/ijms22168879. PMID: 34445590

• LRG1 promotes angiogenesis by modulating endothelial TGF-β signalling.Wang X, Abraham S, McKenzie JAG, Jeffs N, Swire M, Tripathi VB, Luhmann UFO, Lange CAK, Zhai Z, Arthur HM, Bainbridge J, Moss SE, Greenwood J. Nature. 2013 Jul 18;499(7458):306-11.

  doi: 10.1038/nature12345. PMID: 23868260

Lung

• The involvement of leucine-rich α-2 glycoprotein in the progression of skin and lung fibrosis in bleomycin-induced systemic sclerosis model.Nakajima H, Nakajima K, Serada S, Fujimoto M, Naka T, Sano S. Mod Rheumatol. 2021 Nov;31(6):1120-1128.doi: 10.1080/14397595.2021.1883841. Epub 2021 Feb 17. PMID: 33535851
• Reversal of emphysema by restoration of pulmonary endothelial cells.Hisata S, Racanelli AC, Kermani P, Schreiner R, Houghton S, Palikuqi B, Kunar B, Zhou A, McConn K, Capili A, Redmond D, Nolan DJ, Ginsberg M, Ding BS, Martinez FJ, Scandura JM, Cloonan SM, Rafii S, Choi AMK.J Exp Med. 2021 Aug 2;218(8):e20200938.

  doi: 10.1084/jem.20200938. Epub 2021 Jul 21. PMID: 34287647

• Leucine-rich α-2 glycoprotein promotes lung fibrosis by modulating TGF-β signaling in fibroblasts.

  Honda H, Fujimoto M, Serada S, Urushima H, Mishima T, Lee H, Ohkawara T, Kohno N, Hattori N, Yokoyama A, Naka T. Physiol Rep. 2017 Dec;5(24):e13556.

  doi: 10.14814/phy2.13556. Epub 2017 Dec 26. PMID: 29279415