Skip to main content

Advertisement

SpringerLink
Log in

A Precisely Designed Immunotoxin Against VCAM1 Consisting of a Humanized Antibody Variable Domain Fused to Granzyme: An In Silico Approach

  • Published:
International Journal of Peptide Research and Therapeutics Aims and scope Submit manuscript

Abstract

Atherosclerosis is a complex disease related to cardiovascular disorders and is one of the most considerable causes of mortality worldwide. It has been shown that the immune system plays a pivotal role in generating atherosclerosis plaques. The atherosclerosis plaques form via activation of endothelial cells by recruiting adhesion molecules such as VCAM1. Therefore, VCAM1 could be considered as a suitable target to design immune-therapeutics. In this regard, we have lunched an in silico approach to design an immunotoxin against VCAM1. The structure of an anti-VCAM1 antibody was predicted using homology modeling software. The structure of the predicted chains were linked by (Gly4Ser)3 linker. Then, using various modeling software the structure of the GrB was linked to the antibody structure via an adaptor sequence. The final structure was energy minimized, evaluated for accuracy and characterized for its biological properties. Our results indicated that the employed structure prediction method has successfully managed to model the immunotoxin structure. Moreover, our results indicated that the designed immunotoxin is capable of VCAM1 interaction with proper orientation involving its C–D loop. In conclusion it should be pointed out that, the employed in silico approach could pave the way for precise and accurate design of immune-therapeutic agents against cancer. Using this approach we have designed an immunotoxin capable of VCAM1 targeting in a proper orientation and following cancer cell destruction by the toxin domain of the molecule.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Ahmad ZA, Yeap SK, Ali AM, Ho WY, Alitheen NBM, Hamid M (2012) scFv antibody: principles and clinical application. Clin Dev Immunol. https://doi.org/10.1155/2012/980250

    Article  PubMed  PubMed Central  Google Scholar 

  • Akbari B, Farajnia S, Ahdi Khosroshahi S, Safari F, Yousefi M, Dariushnejad H, Rahbarnia L (2017) Immunotoxins in cancer therapy: review update. Int Rev Immunol 36(4):207–219

    Article  CAS  PubMed  Google Scholar 

  • Antignani A, FitzGerald D (2013) Immunotoxins: the role of the toxin. Toxins 5(8):1486–1502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barquera S, Pedroza-Tobías A, Medina C, Hernández-Barrera L, Bibbins-Domingo K, Lozano R, Moran AE (2015) Global overview of the epidemiology of atherosclerotic cardiovascular disease. Arch Med Res 46(5):328–338

    Article  PubMed  Google Scholar 

  • Brown RA, Shantsila E, Varma C, Lip GY (2017) Current understanding of atherogenesis. Am J Med 130(3):268–282

    Article  CAS  PubMed  Google Scholar 

  • Chung J, Lee JE, Ryu EK, Lee S (2007) Vcam-1 specific monoclonal antibody. Hanwha Chemical Corp, Seoul

    Google Scholar 

  • Cook-Mills JM, Marchese ME, Abdala-Valencia H (2011) Vascular cell adhesion molecule-1 expression and signaling during disease: regulation by reactive oxygen species and antioxidants. Antioxid Redox Signal 15(6):1607–1638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Marco A (2009) Strategies for successful recombinant expression of disulfide bond-dependent proteins in Escherichia coli. Microb Cell Fact 8(1):26

    Article  PubMed  PubMed Central  Google Scholar 

  • Gimbrone MA Jr, García-Cardeña G (2013) Vascular endothelium, hemodynamics, and the pathobiology of atherosclerosis. Cardiovasc Pathol 22(1):9–15

    Article  CAS  PubMed  Google Scholar 

  • Hehmann-Titt G, Schiffer S, Berges N, Melmer G, Barth S (2013) Improving the therapeutic potential of human granzyme B for targeted cancer therapy. Antibodies 2(1):19–49

    Article  CAS  Google Scholar 

  • Hiebert PR, Boivin WA, Zhao H, McManus BM, Granville DJ (2013) Perforin and granzyme B have separate and distinct roles during atherosclerotic plaque development in apolipoprotein E knockout mice. PLoS ONE 8(10):e78939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hurtubise J, McLellan K, Durr K, Onasanya O, Nwabuko D, Ndisang JF (2016) The different facets of dyslipidemia and hypertension in atherosclerosis. Curr Atheroscler Rep 18(12):82

    Article  PubMed  Google Scholar 

  • Jahangiri A, Amani J, Halabian R (2018a) In silico analyses of staphylococcal enterotoxin B as a DNA vaccine for cancer therapy. Int J Pept Res Ther 24(1):131–142

    Article  CAS  Google Scholar 

  • Jahangiri A, Rasooli I, Owlia P, Fooladi AAI, Salimian J (2018b) Highly conserved exposed immunogenic peptides of Omp34 against Acinetobacter baumannii: an innovative approach. J Microbiol Methods 144:79–85

    Article  CAS  PubMed  Google Scholar 

  • Jahangiri A, Rasooli I, Owlia P, Fooladi AAI, Salimian J (2018c) An integrative in silico approach to the structure of Omp33–36 in Acinetobacter baumannii. Comput Biol Chem 72:77–86

    Article  CAS  PubMed  Google Scholar 

  • Karim-Silva S, de Moura J, Noiray M, Minozzo JC, Aubrey N, Alvarenga LM, Billiald P (2016) Generation of recombinant antibody fragments with toxin-neutralizing potential in loxoscelism. Immunol Lett 176:90–96

    Article  CAS  PubMed  Google Scholar 

  • Khalili S, Rasaee M, Bamdad T (2017a) 3D structure of DKK1 indicates its involvement in both canonical and non-canonical Wnt pathways. Mol Biol 51(1):155–166

    Article  CAS  Google Scholar 

  • Khalili S, Rasaee MJ, Mousavi SL, Amani J, Jahangiri A, Borna H (2017b) In silico prediction and in vitro verification of a novel multi-epitope antigen for HBV detection. Mol Genet Microbiol Virol 32(4):230–240

    Article  Google Scholar 

  • Khalili S, Zakeri A, Hashemi ZS, Masoumikarimi M, Manesh MRR, Shariatifar N, Sani MJ (2017c) Structural analyses of the interactions between the thyme active ingredients and human serum albumin. Turk J Biochem 42(4):459–467

    CAS  Google Scholar 

  • Khalili S, Rasaee MJ, Bamdad T, Mard-Soltani M, Ghalehni MA, Jahangiri A, Pouriayevali MH, Aghasadeghi MR, Malaei F (2018) A novel molecular design for a hybrid phage-DNA construct against DKK1. Mol Biotechnol 60(11):833–842

    Article  CAS  PubMed  Google Scholar 

  • Kreitman RJ (2003) Immunotoxins for targeted cancer therapy. In: Lorberboum-Galski H, Lazarovici P (eds) Chimeric toxins. CRC Press, Boca Raton, pp 219–237

    Google Scholar 

  • Madhumathi J, Devilakshmi S, Sridevi S, Verma RS (2016) Immunotoxin therapy for hematologic malignancies: where are we heading?. Drug Discov Today 21(2):325–332

    Article  CAS  PubMed  Google Scholar 

  • Mard-Soltani M, Rasaee MJ, Khalili S, Sheikhi A, Hedayati M, Ghaderi-Zefrehi H, Alasvand M (2018) The effect of differentially designed fusion proteins to elicit efficient anti-human thyroid stimulating hormone immune responses. Iran J Allergy Asthma Immunol 17(2):158–170

    PubMed  Google Scholar 

  • McLaren JE, Michael DR, Ashlin TG, Ramji DP (2011) Cytokines, macrophage lipid metabolism and foam cells: implications for cardiovascular disease therapy. Progr Lipid Res 50(4):331–347

    Article  CAS  Google Scholar 

  • Mohammadpour H, Du W, O’Neill R, Khalili S, Qiu J, Repasky EA, McCarthy PL, Cao X (2018) Host-derived serine protease inhibitor 6 provides Granzyme B—independent protection of intestinal epithelial cells in murine graft-versus-host disease. Biol Blood Marrow Transplant 24(12):2397–2408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mosconi C, Arantes DAC, Goncalves AS, Alencar RCG, Oliveira JC, Silva TA, Mendonca EF, Batista AC (2017) Immunohistochemical investigations on the expression of programmed cell death ligand 1, human leukocyte antigens G and E, and granzyme B in intraoral mucoepidermoid carcinoma. Arch Oral Biol 83:55–62

    Article  CAS  PubMed  Google Scholar 

  • Nandy A, Basak SC (2016) A brief review of computer-assisted approaches to rational design of peptide vaccines. Int J Mol Sci 17(5):666

    Article  PubMed Central  Google Scholar 

  • Saito Y, Kondo H, Hojo Y (2011) Granzyme B as a novel factor involved in cardiovascular diseases. J Cardiol 57(2):141–147

    Article  PubMed  Google Scholar 

  • Sirskyj D, Diaz-Mitoma F, Golshani A, Kumar A, Azizi A (2011) Innovative bioinformatic approaches for developing peptide-based vaccines against hypervariable viruses. Immunol Cell Biol 89(1):81–89

    Article  CAS  PubMed  Google Scholar 

  • Tabas I, García-Cardeña G, Owens GK (2015) Recent insights into the cellular biology of atherosclerosis. J Cell Biol 209(1):13–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Todorovska A, Roovers RC, Dolezal O, Kortt AA, Hoogenboom HR, Hudson PJ (2001) Design and application of diabodies, triabodies and tetrabodies for cancer targeting. J Immunol Methods 248(1–2):47–66

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank Baqiyatallah University of Medical Sciences for supporting the conduct of this research.

Author information

Authors and Affiliations

  1. Applied Microbiology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Molla Sadra str., Tehran, POBOX: 19395-5487, Iran

    Mahmoud Ganji & Jafar Amani

  2. Department of Biology Sciences, Shahid Rajaee Teacher Training University, Tehran, Iran

    Saeed Khalili

  3. Department of Clinical Biochemistry, Faculty of Medical Sciences, Dezful University of Medical Sciences, Dezful, Iran

    Maysam Mard-Soltani

  4. Department of Research and Production of Poultry Viral Vaccine, Razi Vaccine and Serum Research Institute, Agricultural Research Education and Extension Organization (AREEO), Karaj, Iran

    Bahman Khalesi

  5. Cellular and Molecular Biology Research Center, Student Research Committee, School of Medicine, Babol University of Medical Sciences, Babol, Iran

    Ahmad Karkhah

Authors
  1. Mahmoud Ganji
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Saeed Khalili
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maysam Mard-Soltani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bahman Khalesi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ahmad Karkhah
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jafar Amani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jafar Amani.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 2217 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ganji, M., Khalili, S., Mard-Soltani, M. et al. A Precisely Designed Immunotoxin Against VCAM1 Consisting of a Humanized Antibody Variable Domain Fused to Granzyme: An In Silico Approach. Int J Pept Res Ther 26, 129–137 (2020). https://doi.org/10.1007/s10989-019-09822-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10989-019-09822-6

Keywords

Search

Navigation