Development programs

Our Treatments Pipeline

Development pipeline

Drug	Target	Indication(s)	Stage
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

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

AVI001/ PEG emulsion

Control

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.

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.

1.	Integrin regulation by tissue factor promotes cancer stemness and metastatic dissemination in breast cancer. Ünlü B, Kocatürk B, Rondon AMR, Lewis CS, Swier N, van den Akker RFP, Krijgsman D, Noordhoek I, Blok EJ, Bogdanov VY, Ruf W, Kuppen PJK, Versteeg HH. Oncogene. 2022 Nov;41(48):5176-5185. doi: 10.1038/s41388-022-02511-7. Epub 2022 Oct 21. PMID: 36271029
2.	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, Sandim V, Fernandes TFB, Almeida VH, Rocha MR, do Amaral RJFC, Rossi MID, Kalume DE, Zingali RB. Int J Mol Sci. 2022 Sep 5;23(17):10194. doi: 10.3390/ijms231710194. PMID: 36077593 Free PMC article.
3.	Binding blockade between TLN1 and integrin β1 represses triple-negative breast cancer. Zhang Y, Sun L, Li H, Ai L, Ma Q, Qiao X, Yang J, Zhang H, Ou X, Wang Y, Chen G, Xue J, Zhu X, Zhao Y, Yang Y, Liu C. Elife. 2022 Mar 14;11:e68481. doi: 10.7554/eLife.68481. PMID: 35285795 Free PMC article.
4.	Role of c-Met/β1 integrin complex in the metastatic cascade in breast cancer. Lau D, Wadhwa H, Sudhir S, Chang AC, Jain S, Chandra A, Nguyen AT, Spatz JM, Pappu A, Shah SS, Cheng J, Safaee MM, Yagnik G, Jahangiri A, Aghi MK. JCI Insight. 2021 Jun 22;6(12):e138928. doi: 10.1172/jci.insight.138928. PMID: 34003803 Free PMC article.
5.	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, Caspers J, Henze S, Schlesinger M, Bendas G. Int J Mol Sci. 2020 Jul 13;21(14):4956. doi: 10.3390/ijms21144956. PMID: 32668815 Free PMC article.
6.	Rab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth. Howe EN, Burnette MD, Justice ME, Schnepp PM, Hedrick V, Clancy JW, Guldner IH, Lamere AT, Li J, Aryal UK, D'Souza-Schorey C, Zartman JJ, Zhang S. Nat Commun. 2020 Jun 15;11(1):3017. doi: 10.1038/s41467-020-16832-2. PMID: 32541798 Free PMC article.
7.	Podoplanin-Expressing Macrophages Promote Lymphangiogenesis and Lymphoinvasion in Breast Cancer. Bieniasz-Krzywiec P, Martín-Pérez R, Ehling M, García-Caballero M, Pinioti S, Pretto S, Kroes R, Aldeni C, Di Matteo M, Prenen H, Tribulatti MV, Campetella O, Smeets A, Noel A, Floris G, Van Ginderachter JA, Mazzone M. Cell Metab. 2019 Nov 5;30(5):917-936.e10. doi: 10.1016/j.cmet.2019.07.015. Epub 2019 Aug 22. PMID: 31447322
8.	Enhancing Therapeutic Efficacy of Oncolytic Herpes Simplex Virus-1 with Integrin β1 Blocking Antibody OS2966. Lee TJ, Nair M, Banasavadi-Siddegowda Y, Liu J, Nallanagulagari T, Jaime-Ramirez AC, Guo JY, Quadri H, Zhang J, Bockhorst KH, Aghi MK, Carbonell WS, Kaur B, Yoo JY. Mol Cancer Ther. 2019 Jun;18(6):1127-1136. doi: 10.1158/1535-7163.MCT-18-0953. Epub 2019 Mar 29. PMID: 30926634 Free PMC article.
9.	Integrin-Mediated Macrophage Adhesion Promotes Lymphovascular Dissemination in Breast Cancer. Evans R, Flores-Borja F, Nassiri S, Miranda E, Lawler K, Grigoriadis A, Monypenny J, Gillet C, Owen J, Gordon P, Male V, Cheung A, Noor F, Barber P, Marlow R, Francesch-Domenech E, Fruhwirth G, Squadrito M, Vojnovic B, Tutt A, Festy F, De Palma M, Ng T. Cell Rep. 2019 May 14;27(7):1967-1978.e4. doi: 10.1016/j.celrep.2019.04.076. PMID: 31091437 Free PMC article.
10.	Shear stress promotes anoikis resistance of cancer cells via caveolin-1-dependent extrinsic and intrinsic apoptotic pathways. Li S, Chen Y, Zhang Y, Jiang X, Jiang Y, Qin X, Yang H, Wu C, Liu Y. J Cell Physiol. 2019 Apr;234(4):3730-3743. doi: 10.1002/jcp.27149. Epub 2018 Aug 31. PMID: 30171601
11.	β1 and β3 integrins in breast, prostate and pancreatic cancer: A novel implication. Pan B, Guo J, Liao Q, Zhao Y. Oncol Lett. 2018 Apr;15(4):5412-5416. doi: 10.3892/ol.2018.8076. Epub 2018 Feb 16. PMID: 29556293 Free PMC article. Review.
12.	Overexpression of β1 integrin contributes to polarity reversal and a poor prognosis of breast invasive micropapillary carcinoma. Liu B, Zheng X, Meng F, Han Y, Song Y, Liu F, Li S, Zhang L, Gu F, Zhang X, Fu L. Oncotarget. 2017 Nov 30;9(4):4338-4353. doi: 10.18632/oncotarget.22774. eCollection 2018 Jan 12. PMID: 29435106 Free PMC article.
13.	Cross-activating c-Met/β1 integrin complex drives metastasis and invasive resistance in cancer. Jahangiri A, Nguyen A, Chandra A, Sidorov MK, Yagnik G, Rick J, Han SW, Chen W, Flanigan PM, Schneidman-Duhovny D, Mascharak S, De Lay M, Imber B, Park CC, Matsumoto K, Lu K, Bergers G, Sali A, Weiss WA, Aghi MK. Proc Natl Acad Sci U S A. 2017 Oct 10;114(41):E8685-E8694. doi: 10.1073/pnas.1701821114. Epub 2017 Sep 26. PMID: 28973887 Free PMC article.
14.	FOXM1 transcriptionally regulates expression of integrin β1 in triple-negative breast cancer. Hamurcu Z, Kahraman N, Ashour A, Ozpolat B. Breast Cancer Res Treat. 2017 Jun;163(3):485-493. doi: 10.1007/s10549-017-4207-7. Epub 2017 Mar 30. PMID: 28361350
15.	β1 Integrin as a Prognostic and Predictive Marker in Triple-Negative Breast Cancer. Yin HL, Wu CC, Lin CH, Chai CY, Hou MF, Chang SJ, Tsai HP, Hung WC, Pan MR, Luo CW. Int J Mol Sci. 2016 Aug 31;17(9):1432. doi: 10.3390/ijms17091432. PMID: 27589736 Free PMC article.
16.	Gene expression profiling combined with functional analysis identify integrin beta1 (ITGB1) as a potential prognosis biomarker in triple negative breast cancer. Klahan S, Huang WC, Chang CM, Wong HS, Huang CC, Wu MS, Lin YC, Lu HF, Hou MF, Chang WC. Pharmacol Res. 2016 Feb;104:31-7. doi: 10.1016/j.phrs.2015.12.004. Epub 2015 Dec 8. PMID: 26675717
17.	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, Chang FR, Wu YC, Kung PH, Wu CC. Biochimie. 2015 Mar;110:81-92. doi: 10.1016/j.biochi.2015.01.006. Epub 2015 Jan 13. PMID: 25593085
18.	New mechanistic insights of integrin β1 in breast cancer bone colonization. Thibaudeau L, Taubenberger AV, Theodoropoulos C, Holzapfel BM, Ramuz O, Straub M, Hutmacher DW. Oncotarget. 2015 Jan 1;6(1):332-44. doi: 10.18632/oncotarget.2788. PMID: 25426561 Free PMC article.
19.	ß1 integrin binding phosphorylates ezrin at T567 to activate a lipid raft signalsome driving invadopodia activity and invasion. Antelmi E, Cardone RA, Greco MR, Rubino R, Di Sole F, Martino NA, Casavola V, Carcangiu M, Moro L, Reshkin SJ. PLoS One. 2013 Sep 24;8(9):e75113. doi: 10.1371/journal.pone.0075113. eCollection 2013. PMID: 24086451 Free PMC article.
20.	FER kinase promotes breast cancer metastasis by regulating α6- and β1-integrin-dependent cell adhesion and anoikis resistance. Ivanova IA, Vermeulen JF, Ercan C, Houthuijzen JM, Saig FA, Vlug EJ, van der Wall E, van Diest PJ, Vooijs M, Derksen PW. Oncogene. 2013 Dec 12;32(50):5582-92. doi: 10.1038/onc.2013.277. Epub 2013 Jul 22. PMID: 23873028 Free PMC article.
21.	β1 integrin targeting potentiates antiangiogenic therapy and inhibits the growth of bevacizumab-resistant glioblastoma. Carbonell WS, DeLay M, Jahangiri A, Park CC, Aghi MK. Cancer Res. 2013 May 15;73(10):3145-54. doi: 10.1158/0008-5472.CAN-13-0011. Epub 2013 May 3. PMID: 23644530 Free PMC article.
22.	β1 integrin regulates Arg to promote invadopodial maturation and matrix degradation. Beaty BT, Sharma VP, Bravo-Cordero JJ, Simpson MA, Eddy RJ, Koleske AJ, Condeelis J. Mol Biol Cell. 2013 Jun;24(11):1661-75, S1-11. doi: 10.1091/mbc.E12-12-0908. Epub 2013 Apr 3. PMID: 23552693 Free PMC article.
23.	Delineating breast cancer cell interactions with engineered bone microenvironments. Taubenberger AV, Quent VM, Thibaudeau L, Clements JA, Hutmacher DW. J Bone Miner Res. 2013 Jun;28(6):1399-411. doi: 10.1002/jbmr.1875. PMID: 23362043
24.	Imaging the inhibition by anti-β1 integrin antibody of lung seeding of single osteosarcoma cells in live mice. Kimura H, Tome Y, Momiyama M, Hayashi K, Tsuchiya H, Bouvet M, Hoffman RM. Int J Cancer. 2012 Nov 1;131(9):2027-33. doi: 10.1002/ijc.27475. Epub 2012 Mar 14. PMID: 22323248
25.	The primacy of β1 integrin activation in the metastatic cascade. Kato H, Liao Z, Mitsios JV, Wang HY, Deryugina EI, Varner JA, Quigley JP, Shattil SJ. PLoS One. 2012;7(10):e46576. doi: 10.1371/journal.pone.0046576. Epub 2012 Oct 3. PMID: 23056350 Free PMC article.
26.	Beta 1 integrin predicts survival in breast cancer: a clinicopathological and immunohistochemical study. dos Santos PB, Zanetti JS, Ribeiro-Silva A, Beltrão EI. Diagn Pathol. 2012 Aug 16;7:104. doi: 10.1186/1746-1596-7-104. PMID: 22894137 Free PMC article.
27.	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. Epub 2011 Nov 30. PMID: 22264244 Free PMC article. Review.
28.	Norepinephrine promotes the β1-integrin-mediated adhesion of MDA-MB-231 cells to vascular endothelium by the induction of a GROα release. Strell C, Niggemann B, Voss MJ, Powe DG, Zänker KS, Entschladen F. Mol Cancer Res. 2012 Feb;10(2):197-207. doi: 10.1158/1541-7786.MCR-11-0130. Epub 2011 Nov 29. PMID: 22127496
29.	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. Epub 2011 Sep 7. PMID: 21900388 Review.
30.	The α₂β₁ integrin is a metastasis suppressor in mouse models and human cancer. Ramirez NE, Zhang Z, Madamanchi A, Boyd KL, O'Rear LD, Nashabi A, Li Z, Dupont WD, Zijlstra A, Zutter MM. J Clin Invest. 2011 Jan;121(1):226-37. doi: 10.1172/JCI42328. Epub 2010 Dec 6. PMID: 21135504 Free PMC article.
31.	beta1 integrin targeting to enhance radiation therapy. Nam JM, Chung Y, Hsu HC, Park CC. Int J Radiat Biol. 2009 Nov;85(11):923-8. doi: 10.3109/09553000903232876. PMID: 19895268 Review.
32.	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. Epub 2008 Jul 24. PMID: 18708090 Review.
33.	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 Review.
34.	Increased beta1 integrin is associated with decreased survival in invasive breast cancer. Yao ES, Zhang H, Chen YY, Lee B, Chew K, Moore D, Park C. Cancer Res. 2007 Jan 15;67(2):659-64. doi: 10.1158/0008-5472.CAN-06-2768. PMID: 17234776
35.	Tissue structure, nuclear organization, and gene expression in normal and malignant breast. Bissell MJ, Weaver VM, Lelièvre SA, Wang F, Petersen OW, Schmeichel KL. Cancer Res. 1999 Apr 1;59(7 Suppl):1757-1763s; discussion 1763s-1764s. PMID: 10197593 Review.
36.	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, Weaver VM, Petersen OW, Larabell CA, Dedhar S, Briand P, Lupu R, Bissell MJ. Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14821-6. doi: 10.1073/pnas.95.25.14821. PMID: 9843973 Free PMC article.
37.	Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. Weaver VM, Petersen OW, Wang F, Larabell CA, Briand P, Damsky C, Bissell MJ. J Cell Biol. 1997 Apr 7;137(1):231-45. doi: 10.1083/jcb.137.1.231. PMID: 9105051 Free PMC article.