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Arming Filamentous Bacteriophage, a Nature-Made Nanoparticle, for New Vaccine and Immunotherapeutic Strategies

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Arming Filamentous Bacteriophage, a Nature-Made Nanoparticle, for New Vaccine and Immunotherapeutic Strategies pharmaceutics Review Arming Filamentous Bacteriophage, a Nature-Made Nanoparticle, for New Vaccine and Immunotherapeutic Strategies Rossella Sartorius 1 , Luciana D’Apice 1,* , Antonella Prisco 2 and Piergiuseppe De Berardinis 1 1 Institute of Biochemistry and Cell Biology (IBBC), 80131 CNR Naples, Italy 2 Institute of Genetics and Biophysics “A. Buzzati-Traverso” (IGB), 80131 CNR Naples, Italy * Correspondence: [email protected]; Tel.: +39-081-613-2584 Received: 26 June 2019; Accepted: 22 August 2019; Published: 1 September 2019 Abstract: The pharmaceutical use of bacteriophages as safe and inexpensive therapeutic tools is collecting renewed interest. The use of lytic phages to fight antibiotic-resistant bacterial strains is pursued in academic and industrial projects and is the object of several clinical trials. On the other hand, filamentous bacteriophages used for the phage display technology can also have diagnostic and therapeutic applications. Filamentous bacteriophages are nature-made nanoparticles useful for their size, the capability to enter blood vessels, and the capacity of high-density antigen expression. In the last decades, our laboratory focused its efforts in the study of antigen delivery strategies based on the filamentous bacteriophage ‘fd’, able to trigger all arms of the immune response, with particular emphasis on the ability of the MHC class I restricted antigenic determinants displayed on phages to induce strong and protective cytotoxic responses. We showed that fd bacteriophages, engineered to target mouse dendritic cells (DCs), activate innate and adaptive responses without the need of exogenous adjuvants, and more recently, we described the display of immunologically active lipids. In this review, we will provide an overview of the reported applications of the bacteriophage carriers and describe the advantages of exploiting this technology for delivery strategies. Keywords: filamentous bacteriophage; vaccine; nanoparticle; targeting; phage display; antigen delivery 1. Introduction Bacteriophages only infect and multiply with their specific host and currently, as bacterial resistance to antibiotics becomes widespread, the therapeutic use of bacteriophages is back on the agenda [1]. Recently, on the basis of successful treatments in five people with phage cocktails under a U.S. food and drug administration (FDA) process designed for emergencies, the University of California, San Diego (UCSD) is launching the Center for Innovative Phage Applications and Therapeutics (IPATH) to refine phage treatment and perform phage trials focused on patients with a single, known bacterial infection and without withholding other potentially beneficial treatments, including antibiotics [2]. In this context, an efficacious clinical treatment of Mycobacterium abscessus infection in a 15 years-old cystic fibrosis patient using a cocktail of three genetically engineered phages was recently reported [3], re-launching the use of bacteriophages as nanopharmaceuticals against antibiotic-resistant bacteria. Besides the use of lytic phages as antibacterials, which has been extensively reviewed elsewhere [2], a collection of evidence was obtained in recent years on the potential translational usage of filamentous bacteriophages. Filamentous phages are single-strand DNA virions belonging to the Inoviridae family; phages f1, fd, and M13 are a sub-group of rod-like shaped Inoviruses with a repeated and ordered capsid Pharmaceutics 2019, 11, 437; doi:10.3390/pharmaceutics11090437 www.mdpi.com/journal/pharmaceutics Pharmaceutics 2019, 11, x FOR PEER REVIEW 2 of 22 Filamentous phages are single-strand DNA virions belonging to the Inoviridae family; phages Pharmaceuticsf1, fd, and 2019M13, 11 are, 437 a sub-group of rod-like shaped Inoviruses with a repeated and ordered capsid2 of 22 structure. They are closely related species, sharing almost the same genome (with only about 1–2% of difference) that infect and replicate in Escherichia coli bacterial cells and which are often structure. They are closely related species, sharing almost the same genome (with only about 1–2% of collectively referred to as Ff phages. difference) that infect and replicate in Escherichia coli bacterial cells and which are often collectively Their peculiar proteic structure, together with the flexibility of the DNA genome and the referred to as Ff phages. easiness of purification has fostered their application in the phage display technology, with Their peculiar proteic structure, together with the flexibility of the DNA genome and the easiness of particular attention to the production of therapeutic antibodies first, and then as antigen delivery purificationsystem for the has development fostered their of application new vaccine in theformulations phage display [4,5] technology,. with particular attention to the production of therapeutic antibodies first, and then as antigen delivery system for the development Although practically every filamentous bacteriophage coat protein can be used to display offoreign new vaccineamino acidic formulations sequences, [4,5 ].the pVIII protein is the most used for the expression of exogenous peptidesAlthough in high practically copy number. every filamentous The pIII bacteriophageprotein, instead coat, proteinhas been can successfully be used to display used for foreign the aminoexpression acidic of sequences, up to five thecopies pVIII per protein virion is of the the most receptor used-ligand for the and expression single-chain of exogenous antibody peptides fragment in high(scFv copy) [6] ( number.Figure 1) The. pIII protein, instead, has been successfully used for the expression of up to five copies per virion of the receptor-ligand and single-chain antibody fragment (scFv) [6] (Figure1). Figure 1. Schematic image of a filamentous bacteriophage nanoparticle engineered for the expression ofFigure a short 1. antigenicSchematic peptide image asof a fusionfilamentous with N-terminus bacteriophage of the nanoparticle pVIII protein engineered and a single-chain for the expression antibody fragmentof a short (scFv) antigenic for thepeptide targeting, as a asfusion a fusion with with N-terminus the N-terminus of the pVII of theI protein pIII protein. and a Thesingle circular-chain single-strandantibody fragment DNA rich(scFv in) CpGfor the motifs targeting, can be as recognized a fusion w byith PPR the andN-terminus acts as an ofadjuvant. the pIII protein. The circular single-strand DNA rich in CpG motifs can be recognized by PPR and acts as an adjuvant. The foreign sequence expression is highly stable since the (poly)peptides of interest are genetically fusedThe to phage foreign proteins sequence and notexpress linkedion by is chemical highly bonds.stable since Small the peptides (poly)peptides can be easily of expressedinterest are on allgenetically copies of fused the pVIII to phage major proteins coat protein, and whereasnot linked for by the chemical expression bonds. of longer Small sequences peptides (14–20can be aminoeasily acids),expressed such on as all immunologically copies of the relevantpVIII major peptides, coat itprotein, is often whereas necessary for to the construct expression hybrid of phages,longer whichsequences express (14– recombinant20 amino acids copies), such of the as pVIII immunological interspersedly with relevant wild-type peptides, copies, it is in often order necessary to guarantee to aconstruct high expression hybrid phages, of the exogenous which express sequence recombinant without a copiesffecting of the the stability pVIII interspersed of the phage with lattice. wild Due-type to thecopies, highly-symmetrical in order to guarantee and repeated a high structure, expression Ff phagesof the areexog suitableenous forsequence the high-density without affecting exposure the of onestability or more of the epitopes phage onlattice. the coat Due surface. to the high Overallly-symmetric phage nanoparticlesal and repeated are made structure of highly, Ff phages organized are monomerssuitable for represented the high-density mainly exposure by the pVIII of proteinone or more (5.5 kDa), epitopes an alpha-helix on the coat closely surface. packed Overall to compose phage ananoparticles right-handed are helical mad latexe of highly with a organized rod-like structure. monomers represented mainly by the pVIII protein (5.5 kDa),Combining an alpha-helix a relatively closely packed simple to surface compose structure a right- withhanded a particulate helical latex nature with a and rod with-like structure. adjuvant properties,Combining filamentous a relatively phages simple represent surface ideal structure nanoparticles with a comparedparticulate to nature other carriers.and with Drugs adjuvant can beproperties, easily conjugated filamentous to thephages phage represent surface ideal by chemical nanoparticles modification compared of aminoto other and carriers. carboxyl Drugs groups can exposedbe easily in conjugate the aminod terminusto the phage of the surface pVIIIprotein. by chemical Furthermore, modification the filamentous of amino and phages carboxyl are extremely groups tolerantexposed to in variations the amino in theterminus size of theirof the genome, pVIII pro whichtein. makes Furthermore, them versatile the filamentous for engineering phages through are theextremely phage displaytolerant technique, to variations allowing in thethe successfulsize of their expression genome, of Bwhich and T (CD4makes+ andthem CD8 versatile+) epitopes for onengineering the phage through nanoparticles, the phage and between display
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