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In silico analysis of STX2a-PE15-P4A8 chimeric protein as a novel immunotoxin for cancer therapy

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Abstract

Today, the targeted therapies like the use of immunotoxins are increased which targeted specific antigens or receptors on the surface of tumor cells. Fibroblast growth factor-inducible 14 (Fn14) is a cytokine receptor which involves several intercellular signaling pathways and can be highly expressed in the surface of cancer cells. Since the cleavage of enzymatic domain of Pseudomonas exotoxin A (PE) occurs in one step by furin protease, we fused enzymatic subunit of Shiga-like toxin type 2a (Stx2a) with domain II and a portion of Ib of PE to increase the toxicity of Stx. Then, we genetically fused the Fv fragment of an anti-Fn14 monoclonal antibody (P4A8) to STX2a-PE15 and evaluated the STX2a-PE15-P4A8 chimeric protein as a new immunotoxin candidate. In silico analysis showed that the STX2a-PE15-P4A8 is a stable chimeric protein with high affinity to the Fn14 receptor. Despite, the STX2a-PE15-P4A8 can be bind to the B cell receptor, but it has been weakly presented by major histocompatibility complex molecules II (MHC-II). So, it may have a little immunogenicity. On the basis of our in-silico studies we predict that STX2a-PE15-P4A8 can be a good candidate for cancer immunotherapy.

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Data availability

All data analyzed during this study are included in this article.

Abbreviations

Stx:

Shiga toxin

Stx2a:

Shiga-like toxin type 2a

PE:

Pseudomonas exotoxin A

MHC-II:

Major histocompatibility complex molecules II

Fn14:

Fibroblast growth factor-inducible 14

ScFv:

Single chain fragment variable

VH:

Heavy chain variable domain

VL:

Light chain variable domain

E.coli :

Escherichia coli

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Funding

This study is part of a research project with Grant No. 29903 that supported by Tehran University of Medical Sciences & Health Services.

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Authors and Affiliations

  1. Division of Microbiology, Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

    Maryam Keshtvarz & Masoumeh Douraghi

  2. Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran

    Jafar Salimian

  3. Applied Microbiology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Vanak Sq. Molasadra St., P.O. Box 19395-5487, Tehran, Iran

    Jafar Amani

  4. Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Science, Tehran, Iran

    Ehsan Rezaie

Authors
  1. Maryam Keshtvarz
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  2. Jafar Salimian
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  3. Jafar Amani
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  4. Masoumeh Douraghi
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  5. Ehsan Rezaie
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Contributions

MK, JA, and JF designed the chimeric protein for the article. MK, ER and JA assessed the chimeric protein through various bioinformatic softwares and drafted the early version of the manuscript. MD and JF evaluated and discussed the software and the results. MD, ER and JF provided comments on the manuscript and contributed to editing of the manuscript. MD received the grant for the current study. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jafar Amani or Masoumeh Douraghi.

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Keshtvarz, M., Salimian, J., Amani, J. et al. In silico analysis of STX2a-PE15-P4A8 chimeric protein as a novel immunotoxin for cancer therapy. In Silico Pharmacol. 9, 19 (2021). https://doi.org/10.1007/s40203-021-00079-w

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