Development programs

Our Treatments Pipeline

Development pipeline

AVI001 Beta1 Integrin (hybrid domain 1) Parkinson’s Disease, metastatic cancer, replicative senescence Pre-clinical
AVI002 Beta1 integrin (hybrid domain 2) Replicative senescence Discovery
AVI002+Ezetimibe (benzylic derivative) Beta1 integrin (hybrid domain 2 + Neimann Pick protein C1 “NPC”). Anti-viral (Ebola) Discovery
drops
science

AVI001 (Cancer and age-related diseases)

  • Beta1 integrin subunit pairs with at least 11 α subunits to produce heterodimers that mediate adhesion to various (e.g. matrix molecules and cell surface proteins) (Desgrosellier JS & Cheresh DA, 2010).
  • Metastasis is an umbrella description of multiple processes: migration, invasion, metastasis, extravasation and colonisation
    During the dynamics of such processes, different beta1 integrin heterodimers interplay with some even serving as tumour suppressor.
  • AVI001 (lead compound) and similar inhibitory anti beta1 integrin antibody inhibited tumour growth in models of breast cancer in vitro and in vivo (Weaver et al. 1997)
  •  Ablation of beta1 integrin in tumor cells in vivo led to (Kren et al. 2007):
    • the dissemination of tumor cell into lymphatic blood vessels yet inhibited metastasis.
    • impaired primary tumor growth by reducing tumor cell proliferation and the acquisition of senescence.
  • Anti-beta1 integrin antibody:
    • Completely inhibited invasion of triple negative breast carcinoma cells with dual effect on proliferation in vitro and in vivo (Zhang et al. 2022, Yin et al. 2016, Lau et al. 2021).
    • Prevents lung seeding of single osteosarcoma cells in vivo (Kimura et al, 2012).
    • Inhibits tumour growth (Grzesiak et al. 2011, Carbonell et al. 2013) , and
    • Selective for malignant cells (in vitro and in vivo) (Thibaudeau et al, 2015 and Jahangiri et al., 2017).

AVI001 enhances cartilage and skin regrowth in vivo and show repair in skin rejuvenation

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AVI001/ PEG emulsion

Control

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AVI002 (senescence)

Replicative senescence is related to aging and decline in function with age. Beta1 integrin levels are down-regulated in aged skin, and upregulation of beta1 integrin synthesis could have an anti-aging effect. AVIPERO identified AVI002 as a treatment for inhibiting and reversing replicative senescence in replicative senescence and injury models.

science
doctor

AVI002+EZE (Ebola)

Various viruses utilize cell adhesion receptors for entry and infection of host cells. Beta1 integrin is known to facilitate entry and is affected by various viral infections. By targeting host mechanisms utilized by the Ebola virus, AVI002 showed positive anti-viral activity against Ebola. The strategy entailed: a combination of AVI002 and a modified derivative of the marketed cholesterol-lowering drug ezetimibe. The treatment combination demonstrated a synergistic mode of action reducing viremia by 80% in cell culture models. In addition, the treatment showed no toxicity.

REFERENCES

1. The characteristics and the multiple functions of integrin beta1 in human cancers. Sun L, et al. J Transl Med. 2023 Nov 6;21(1):787. doi: 10.1186/s12967-023-04696-1. PMID: 37932738

2.  Integrin regulation by tissue factor promotes cancer stemness and metastatic dissemination in breast cancer. Ünlü B, et al. Oncogene. 2022 Nov;41(48):5176-5185. doi: 10.1038/s41388-022-02511-7. PMID: 36271029

3. Proteomic Analysis of HCC-1954 and MCF-7 Cell Lines Highlights Crosstalk between αv and β1 Integrins, E-Cadherin and HER-2. de Abreu Pereira D, et al. Int J Mol Sci. 2022 Sep 5;23(17):10194. doi: 10.3390/ijms231710194. PMID: 36077593

4. Binding blockade between TLN1 and integrin β1 represses triple-negative breast cancer. Zhang Y, et al. Elife. 2022 Mar 14;11:e68481. doi: 10.7554/eLife.68481. PMID: 35285795.

5. Role of c-Met/β1 integrin complex in the metastatic cascade in breast cancer. Lau D, et al. JCI Insight. 2021 Jun 22;6(12):e138928. doi: 10.1172/jci.insight.138928. PMID: 3400380

6. Targeting Discoidin Domain Receptor 1 (DDR1) Signaling and Its Crosstalk with β1-integrin Emerges as a Key Factor for Breast Cancer Chemosensitization upon Collagen Type 1 Binding. Baltes F, et al. Int J Mol Sci. 2020 Jul 13;21(14):4956. doi: 10.3390/ijms21144956. PMID: 32668815

7. Rab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth. Howe EN, et al. Nat Commun. 2020 Jun 15;11(1):3017. doi: 10.1038/s41467-020-16832-2. PMID: 32541798

8. Podoplanin-Expressing Macrophages Promote Lymphangiogenesis and Lymphoinvasion in Breast Cancer. Bieniasz-Krzywiec P, et al. Cell Metab. 2019 Nov 5;30(5):917-936.e10. doi: 10.1016/j.cmet.2019.07.015. PMID: 31447322

9. Enhancing Therapeutic Efficacy of Oncolytic Herpes Simplex Virus-1 with Integrin β1 Blocking Antibody OS2966. Lee TJ, et al.Mol Cancer Ther. 2019 Jun;18(6):1127-1136. doi: 10.1158/1535-7163.MCT-18-0953. PMID: 30926634

10. Integrin-Mediated Macrophage Adhesion Promotes Lymphovascular Dissemination in Breast Cancer. Evans R, et al. Cell Rep. 2019 May 14;27(7):1967-1978.e4. doi: 10.1016/j.celrep.2019.04.076. PMID: 31091437

11. Shear stress promotes anoikis resistance of cancer cells via caveolin-1-dependent extrinsic and intrinsic apoptotic pathways. Li S, et al. J Cell Physiol. 2019 Apr;234(4):3730-3743. doi: 10.1002/jcp.27149. PMID: 30171601

12. β1 and β3 integrins in breast, prostate and pancreatic cancer: A novel implication. Pan B, et al. Oncol Lett. 2018 Apr;15(4):5412-5416. doi: 10.3892/ol.2018.8076. PMID: 29556293

13. Overexpression of β1 integrin contributes to polarity reversal and a poor prognosis of breast invasive micropapillary carcinoma. Liu B, et al. Oncotarget. 2017 Nov 30;9(4):4338-4353. doi: 10.18632/oncotarget.22774. PMID: 29435106

14. Cross-activating c-Met/β1 integrin complex drives metastasis and invasive resistance in cancer. Jahangiri A, et al. Proc Natl Acad Sci U S A. 2017 Oct 10;114(41):E8685-E8694. doi: 10.1073/pnas.1701821114. PMID: 28973887

15. FOXM1 transcriptionally regulates expression of integrin β1 in triple-negative breast cancer. Hamurcu Z, et al. Breast Cancer Res Treat. 2017 Jun;163(3):485-493. doi: 10.1007/s10549-017-4207-7. PMID: 28361350

16. β1 Integrin as a Prognostic and Predictive Marker in Triple-Negative Breast Cancer. Yin HL, et al. Int J Mol Sci. 2016 Aug 31;17(9):1432. doi: 10.3390/ijms17091432. PMID: 27589736

17. Gene expression profiling combined with functional analysis identify integrin beta1 (ITGB1) as a potential prognosis biomarker in triple negative breast cancer. Klahan S, et al. Pharmacol Res. 2016 Feb;104:31-7. doi: 10.1016/j.phrs.2015.12.004. PMID: 26675717

18. 3,4-Methylenedioxy-β-nitrostyrene inhibits adhesion and migration of human triple-negative breast cancer cells by suppressing β1 integrin function and surface protein disulfide isomerase. Chen IH, et al. Biochimie. 2015 Mar;110:81-92. doi: 10.1016/j.biochi.2015.01.006. PMID: 25593085

19. New mechanistic insights of integrin β1 in breast cancer bone colonization. Thibaudeau L, et al. Oncotarget. 2015 Jan 1;6(1):332-44. doi: 10.18632/oncotarget.2788. PMID: 25426561

20. ß1 integrin binding phosphorylates ezrin at T567 to activate a lipid raft signalsome driving invadopodia activity and invasion. Antelmi E, et al. PLoS One. 2013 Sep 24;8(9):e75113. doi: 10.1371/journal.pone.0075113. PMID: 24086451

21. FER kinase promotes breast cancer metastasis by regulating α6- and β1-integrin-dependent cell adhesion and anoikis resistance. Ivanova IA, et al. Oncogene. 2013 Dec 12;32(50):5582-92. doi: 10.1038/onc.2013.277. PMID: 23873028

22. β1 integrin targeting potentiates antiangiogenic therapy and inhibits the growth of bevacizumab-resistant glioblastoma. Carbonell WS, et al. Cancer Res. 2013 May 15;73(10):3145-54. doi: 10.1158/0008-5472.CAN-13-0011. PMID: 23644530

23. β1 integrin regulates Arg to promote invadopodial maturation and matrix degradation. Beaty BT, et al. Mol Biol Cell. 2013 Jun;24(11):1661-75, S1-11. doi: 10.1091/mbc.E12-12-0908. PMID: 23552693

24. Delineating breast cancer cell interactions with engineered bone microenvironments. Taubenberger AV, et al. J Bone Miner Res. 2013 Jun;28(6):1399-411. doi: 10.1002/jbmr.1875. PMID: 23362043

25. Imaging the inhibition by anti-β1 integrin antibody of lung seeding of single osteosarcoma cells in live mice. Kimura H, et al. Int J Cancer. 2012 Nov 1;131(9):2027-33. doi: 10.1002/ijc.27475. PMID: 22323248

26. The primacy of β1 integrin activation in the metastatic cascade. Kato H, et al. PLoS One. 2012;7(10):e46576. doi: 10.1371/journal.pone.0046576. PMID: 23056350

27. Beta 1 integrin predicts survival in breast cancer: a clinicopathological and immunohistochemical study. dos Santos PB, et al. Diagn Pathol. 2012 Aug 16;7:104. doi: 10.1186/1746-1596-7-104. PMID: 22894137

28. β1-integrins signaling and mammary tumor progression in transgenic mouse models: implications for human breast cancer. Lahlou H, Muller WJ. Breast Cancer Res. 2011;13(6):229. doi: 10.1186/bcr2905. PMID: 22264244

29. Norepinephrine promotes the β1-integrin-mediated adhesion of MDA-MB-231 cells to vascular endothelium by the induction of a GROα release. Strell C, et al. Mol Cancer Res. 2012 Feb;10(2):197-207. doi: 10.1158/1541-7786.MCR-11-0130. PMID: 22127496

30. β1-integrin: a potential therapeutic target in the battle against cancer recurrence. Barkan D, Chambers AF. Clin Cancer Res. 2011 Dec 1;17(23):7219-23. doi: 10.1158/1078-0432.CCR-11-0642. PMID: 21900388

31. The α₂β₁ integrin is a metastasis suppressor in mouse models and human cancer. Ramirez NE, et al. J Clin Invest. 2011 Jan;121(1):226-37. doi: 10.1172/JCI42328. PMID: 21135504

32. Integrins in cancer: biological implications and therapeutic opportunities. Desgrosellier JS, Cheresh DA. Nat Rev Cancer. 2010 Jan;10(1):9-22. doi: 10.1038/nrc2748. PMID: 20029421

33. beta1 integrin targeting to enhance radiation therapy. Nam JM, et al. Int J Radiat Biol. 2009 Nov;85(11):923-8. doi: 10.3109/09553000903232876. PMID: 19895268

34. Beta1 integrin in tissue remodelling and repair: from phenomena to concepts. Al-Jamal R, Harrison DJ. Pharmacol Ther. 2008 Nov;120(2):81-101. doi: 10.1016/j.pharmthera.2008.07.002. PMID: 18708090

35. Increased tumor cell dissemination and cellular senescence in the absence of beta1-integrin function. Angelika Kren, et al. EMBO J. 2007 Jun 20;26(12):2832-42. doi: 10.1038/sj.emboj.7601738. PMID: 17541405

36. beta1 integrin as a molecular therapeutic target. Cordes N, Park CC. Int J Radiat Biol. 2007 Nov-Dec;83(11-12):753-60. doi: 10.1080/09553000701639694. PMID: 18058364

37. Increased beta1 integrin is associated with decreased survival in invasive breast cancer. Yao ES, et al. Cancer Res. 2007 Jan 15;67(2):659-64. doi: 10.1158/0008-5472.CAN-06-2768. PMID: 17234776

38. Tissue structure, nuclear organization, and gene expression in normal and malignant breast. Bissell MJ, et al. Cancer Res. 1999 Apr 1;59(7 Suppl):1757-1763s; discussion 1763s-1764s. PMID: 10197593

39. Reciprocal interactions between beta1-integrin and epidermal growth factor receptor in three-dimensional basement membrane breast cultures: a different perspective in epithelial biology. Wang F, et al. Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14821-6. doi: 10.1073/pnas.95.25.14821. PMID: 9843973

40. Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. Weaver VM, et al. J Cell Biol. 1997 Apr 7;137(1):231-45. doi: 10.1083/jcb.137.1.231. PMID: 9105051