Viral Safety of APOSECTM: a Novel Peripheral Blood Mononuclear Cell Derived-biological for Regenerative Medicine

Overview

Journal Blood Transfus

Specialty Hematology

Date 2019 Mar 14

PMID 30865581

Citations 10

Authors

Alfred Gugerell

Dirk Sorgenfrey

Maria Laggner

Jurgen Raimann

Anja Peterbauer

Daniel Bormann

Susanne Suessner

Christian Gabriel

Bernhard Moser

Tobias Ostler

Michael Mildner

Hendrik J Ankersmit

Affiliations

Soon will be listed here.

Abstract

Background: Viral reduction and inactivation of cell-derived biologicals is paramount for patients' safety and so viral reduction needs to be demonstrated to regulatory bodies in order to obtain marketing authorisation. Allogeneic human blood-derived biological medicinal products require special attention. APOSEC, the secretome harvested from selected human blood cells, is a new biological with promising regenerative capabilities. We evaluated the effectiveness of inactivation of model viruses by methylene blue/light treatment, lyophilisation, and gamma irradiation during the manufacturing process of APOSEC.

Materials And Methods: Samples of intermediates of APOSEC were acquired during the manufacturing process and spiked with bovine viral diarrhoea virus (BVDV), human immunodeficiency virus type 1 (HIV-1), pseudorabies virus (PRV), hepatitis A virus (HAV), and porcine parvovirus (PPV). Viral titres were assessed with suitable cell lines.

Results: Methylene blue-assisted viral reduction is mainly effective against enveloped viruses: the minimum log reduction factors for BVDV, HIV-1, and PRV were ≥6.42, ≥6.88, and ≥6.18, respectively, with no observed residual infectivity. Viral titres of both HAV and PPV were not significantly reduced, indicating minor inactivation of non-enveloped viruses. Lyophilisation had minor effects on the viability of several enveloped model viruses. Gamma irradiation contributes to the viral safety by reduction of enveloped viruses (BVDV: ≥2.42; HIV-1: 4.53; PRV: ≥4.61) and to some degree of non-enveloped viruses as seen for HAV with a minimum log10 reduction factor of 2.92. No significant reduction could be measured for the non-enveloped virus PPV (2.60).

Discussion: Three manufacturing steps of APOSEC were evaluated under Good Laboratory Practice conditions for their efficacy at reducing and inactivating potentially present viruses. It could be demonstrated that all three steps contribute to the viral safety of APOSEC.

Citing Articles

Advancing wound healing by hydrogel-based dressings loaded with cell-conditioned medium: a systematic review.

Nifontova G, Safaryan S, Khristidis Y, Smirnova O, Vosough M, Shpichka A Stem Cell Res Ther. 2024; 15(1):371.

PMID: 39420416 PMC: 11488269. DOI: 10.1186/s13287-024-03976-x.

The Secretome of Irradiated Peripheral Mononuclear Cells Attenuates Hypertrophic Skin Scarring.

Vorstandlechner V, Copic D, Klas K, Direder M, Golabi B, Radtke C Pharmaceutics. 2023; 15(4).

PMID: 37111549 PMC: 10143262. DOI: 10.3390/pharmaceutics15041065.

Comparing the efficacy of γ- and electron-irradiation of PBMCs to promote secretion of paracrine, regenerative factors.

Laggner M, Gugerell A, Copic D, Jeitler M, Springer M, Peterbauer A Mol Ther Methods Clin Dev. 2021; 21:14-27.

PMID: 33768126 PMC: 7960502. DOI: 10.1016/j.omtm.2021.02.016.

Safety and clinical efficacy of the secretome of stressed peripheral blood mononuclear cells in patients with diabetic foot ulcer-study protocol of the randomized, placebo-controlled, double-blind, multicenter, international phase II clinical trial....

Gugerell A, Gouya-Lechner G, Hofbauer H, Laggner M, Trautinger F, Almer G Trials. 2021; 22(1):10.

PMID: 33407796 PMC: 7789696. DOI: 10.1186/s13063-020-04948-1.

TGF-β in the Secretome of Irradiated Peripheral Blood Mononuclear Cells Supports In Vitro Osteoclastogenesis.

Panahipour L, Kargarpour Z, Laggner M, Mildner M, Ankersmit H, Gruber R Int J Mol Sci. 2020; 21(22).

PMID: 33202935 PMC: 7696998. DOI: 10.3390/ijms21228569.

References

Hoetzenecker K, Zimmermann M, Hoetzenecker W, Schweiger T, Kollmann D, Mildner M . Mononuclear cell secretome protects from experimental autoimmune myocarditis. Eur Heart J. 2013; 36(11):676-85. PMC: 4359357. DOI: 10.1093/eurheartj/ehs459. View

Riggert J, Humpe A, Legler T, Wolf C, Simson G, Kohler M . Filtration of methylene blue-photooxidized plasma: influence on coagulation and cellular contamination. Transfusion. 2001; 41(1):82-6. DOI: 10.1046/j.1537-2995.2001.41010082.x. View

Beer L, Nemec L, Wagner T, Ristl R, Altenburger L, Jan Ankersmit H . Ionizing radiation regulates long non-coding RNAs in human peripheral blood mononuclear cells. J Radiat Res. 2016; 58(2):201-209. PMC: 5603904. DOI: 10.1093/jrr/rrw111. View

Khelifa M, Masse D, Blanc S, Drucker M . Evaluation of the minimal replication time of Cauliflower mosaic virus in different hosts. Virology. 2009; 396(2):238-45. DOI: 10.1016/j.virol.2009.09.032. View

Moore M . Inactivation of enveloped and non-enveloped viruses on seeded human tissues by gamma irradiation. Cell Tissue Bank. 2011; 13(3):401-7. PMC: 3432196. DOI: 10.1007/s10561-011-9266-0. View

Beer L, Zimmermann M, Mitterbauer A, Ellinger A, Gruber F, Narzt M . Analysis of the Secretome of Apoptotic Peripheral Blood Mononuclear Cells: Impact of Released Proteins and Exosomes for Tissue Regeneration. Sci Rep. 2015; 5:16662. PMC: 4645175. DOI: 10.1038/srep16662. View

Unger U, Poelsler G, Modrof J, Kreil T . Virus inactivation during the freeze-drying processes as used for the manufacture of plasma-derived medicinal products. Transfusion. 2009; 49(9):1924-30. DOI: 10.1111/j.1537-2995.2009.02218.x. View

Ankersmit H, Hoetzenecker K, Dietl W, Soleiman A, Horvat R, Wolfsberger M . Irradiated cultured apoptotic peripheral blood mononuclear cells regenerate infarcted myocardium. Eur J Clin Invest. 2009; 39(6):445-56. DOI: 10.1111/j.1365-2362.2009.02111.x. View

Kasiri M, Beer L, Nemec L, Gruber F, Pietkiewicz S, Haider T . Dying blood mononuclear cell secretome exerts antimicrobial activity. Eur J Clin Invest. 2016; 46(10):853-63. PMC: 5113772. DOI: 10.1111/eci.12667. View

10.

Muniz-Diaz E, Puig L . Allergic and anaphylactic reactions to methylene-blue-treated plasma in Catalonia in the period 2008-2013. Blood Transfus. 2014; 12(4):628-30. PMC: 4212051. DOI: 10.2450/2014.0121-14. View

11.

Wagner T, Traxler D, Simader E, Beer L, Narzt M, Gruber F . Different pro-angiogenic potential of γ-irradiated PBMC-derived secretome and its subfractions. Sci Rep. 2018; 8(1):18016. PMC: 6301954. DOI: 10.1038/s41598-018-36928-6. View

12.

Simader E, Traxler D, Kasiri M, Hofbauer H, Wolzt M, Glogner C . Safety and tolerability of topically administered autologous, apoptotic PBMC secretome (APOSEC) in dermal wounds: a randomized Phase 1 trial (MARSYAS I). Sci Rep. 2017; 7(1):6216. PMC: 5524970. DOI: 10.1038/s41598-017-06223-x. View

13.

Dewachter P, Castro S, Nicaise-Roland P, Chollet-Martin S, Le Beller C, Lillo-Le-Louet A . Anaphylactic reaction after methylene blue-treated plasma transfusion. Br J Anaesth. 2011; 106(5):687-9. DOI: 10.1093/bja/aer009. View

14.

Op de Beeck A, Caillet-Fauquet P . Viruses and the cell cycle. Prog Cell Cycle Res. 1997; 3:1-19. DOI: 10.1007/978-1-4615-5371-7_1. View

15.

Reichenberg S, Gravemann U, Sumian C, Seltsam A . Challenge study of the pathogen reduction capacity of the THERAFLEX MB-Plasma technology. Vox Sang. 2015; 109(2):129-37. DOI: 10.1111/vox.12257. View

16.

Hume A, Ames J, Rennick L, Duprex W, Marzi A, Tonkiss J . Inactivation of RNA Viruses by Gamma Irradiation: A Study on Mitigating Factors. Viruses. 2016; 8(7). PMC: 4974539. DOI: 10.3390/v8070204. View

17.

Beer L, Mildner M, Gyongyosi M, Jan Ankersmit H . Peripheral blood mononuclear cell secretome for tissue repair. Apoptosis. 2016; 21(12):1336-1353. PMC: 5082595. DOI: 10.1007/s10495-016-1292-8. View

18.

Steinmann E, Gravemann U, Friesland M, Doerrbecker J, Muller T, Pietschmann T . Two pathogen reduction technologies--methylene blue plus light and shortwave ultraviolet light--effectively inactivate hepatitis C virus in blood products. Transfusion. 2012; 53(5):1010-8. DOI: 10.1111/j.1537-2995.2012.03858.x. View

19.

Haider T, Hoftberger R, Ruger B, Mildner M, Blumer R, Mitterbauer A . The secretome of apoptotic human peripheral blood mononuclear cells attenuates secondary damage following spinal cord injury in rats. Exp Neurol. 2015; 267:230-42. DOI: 10.1016/j.expneurol.2015.03.013. View

20.

Altmann P, Mildner M, Haider T, Traxler D, Beer L, Ristl R . Secretomes of apoptotic mononuclear cells ameliorate neurological damage in rats with focal ischemia. F1000Res. 2014; 3:131. PMC: 4215751. DOI: 10.12688/f1000research.4219.2. View