Monoclonal Antibodies and recombinant fragments for therapeutic and diagnostic applications
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Monoclonal Antibodies and recombinant fragments for therapeutic and diagnostic applications
Research areas: Molecules of immunologic interest, 

Keywords: Monoclonal antibody, Recombinant Fragment, Fab, scFv, ADC, Antibody humanization, CART

Contact person: Annamaria Sandomenico, annamaria.sandomenicogmail.com

Actors: Annamaria Sandomenico, annamaria.sandomenicogmail.com, Menotti Ruvo, menotti.ruvounina.it, Nunzianna Doti, nunzia.dotigmail.com,

Description:
MonoclonalAntibodies (mAb) are biomolecules with high specificity and affinity and in principle can be raised against any antigen [1]. Antibodies are made of structural modules that can be isolated from the original molecule or recombinantly produced to obtain new functional formats with tailored biochemical, biophysical and functional properties. The modular nature of immunoglobulins is continuously exploited to engineer“customized” therapeutics with pharmacologic properties optimized for specific diagnostic and therapeutic applications. Half-life, biodistribution, valency, affinity, avidity, tissue penetration and bioactivity can each be controlled by selecting and combining appropriate modular domains with defined structural features, allowing a tight control over both safety and efficacy of antibody products. Antibodies fragments in several new formats are routinely investigated to increase their specificity and therapeutic efficacy and to achieve site-specific functionalizations with reporters and other payloads to generate innovative diagnostic reagents and Antibody Drug Conjugates (ADC) [2, 3].

In the last decade, we have developed mAbs against several protein targets [4-12] including tumours biomarkers and therapeutic targets for several diseases like Cripto-1, Nodal, theE2 protein of HCV, Ape1 and PRAME. In the last years, we have also set up a bacterial expression platform for generating ad hoc engineered recombinant Fabs and scFv fragments [13] that bear reactive sites for their site-specific modification and multimerization using Microbial Transglutaminaseenzyme (MTG) [14,15]. The platform has been validated using the anti-Her2monoclonal antibody trastuzumab obtaining multimeric recombinant variants of the trastuzumab Fab and scFv. Bispecific humanized Fab2 with affinities similar or superior to the full-lenght antibodies have been also obtained using anti-Cripto-1 and anti Nodal Fabs. Site-specific labelling with dyes/fluorophores or cytotoxic payloads are similarly achieved by direct functionalization or decorating 100 nm nanoparticles made of human albumin loaded with cytotoxic agents, thus obtaining highly innovative 2 nd generation ADCs. Biochemical and biophysical studies of scFv fragments against relevant therapeutic targets are also underway to support the design of CART systems.



Selected papers:

[1] Sivaccumar J, Sandomenico A, Vitagliano L, Ruvo M.Monoclonal antibodies: A prospective and retrospective view.
 Curr Med Chem. 2020 Feb 19. doi: 10.2174/0929867327666200219142231.  

[2] Selis F, Focà G, Sandomenico A, Marra C, Di MauroC, Saccani Jotti G, Scaramuzza S, Politano A, Sanna R, Ruvo M, Tonon G.Pegylated Trastuzumab Fragments Acquire an Increased in Vivo Stability but Showa Largely Reduced Affinity for the Target Antigen

Int J Mol Sci. 2016 Apr 1;17(4):491. doi:10.3390/ijms17040491.  

[3] Sandomenico A, Sivaccumar JP, Ruvo M. Evolution ofEscherichia coli Expression System in Producing Antibody Recombinant Fragments.Int J Mol Sci. 2020 Aug 31;21(17):6324. doi: 10.3390/ijms21176324.  

[4] Focà G, Iaccarino E, Focà A, Sanguigno L,Untiveros G, Cuevas-Nunez M, Strizzi L, Leonardi A, Ruvo M, Sandomenico A.Development of conformational antibodies targeting Cripto-1 with neutralizingeffects in vitro.  Biochimie. 2019Mar;158:246-256. doi: 10.1016/j.biochi.2019.01.016. Epub 2019 Jan 28.  

[5] Canassa-DeLeo T, Campo VL, Rodrigues LC, MarchioriMF, Fuzo C, Brigido MM, Sandomenico A, Ruvo M, Maranhão AQ, Dias-Baruffi M.Multifaceted antibodies development against synthetic α-dystroglycan mucinglycopeptide as promising tools for dystroglycanopathies diagnostic. GlycoconjJ. 2020 Feb;37(1):77-93. doi: 10.1007/s10719-019-09893-z. Epub 2019 Dec 10.  

[6] Calvanese L, Focà A, Sandomenico A, Focà G,Caporale A, Doti N, Iaccarino E, Leonardi A, D'Auria G, Ruvo M, Falcigno L.Structural insights into the interaction of a monoclonal antibody and Nodalpeptides by STD-NMR spectroscopy. Bioorg Med Chem. 2017 Dec15;25(24):6589-6596. doi: 10.1016/j.bmc.2017.10.036. Epub 2017 Oct 28.  

[7] Sandomenico A, Focà A, Sanguigno L, Caporale A,Focà G, Pignalosa A, Corvino G, Caragnano A, Beltrami AP, Antoniali G, Tell G,Leonardi A, Ruvo M. Monoclonal antibodies against pools of mono- andpolyacetylated peptides selectively recognize acetylated lysines within thecontext of the original antigen. MAbs. 2016 Nov/Dec;8(8):1575-1589. doi:10.1080/19420862.2016.1225643. Epub 2016 Aug 25.  

[8] Sandomenico A, Leonardi A, Berisio R, Sanguigno L,Focà G, Focà A, Ruggiero A, Doti N, Muscariello L, Barone D, Farina C, OwsiankaA, Vitagliano L, Patel AH, Ruvo M. Generation and Characterization ofMonoclonal Antibodies against a Cyclic Variant of Hepatitis C Virus E2 Epitope412-422. J Virol. 2016 Jan 27;90(7):3745-59. doi: 10.1128/JVI.02397-15

[9] Strizzi L, Sandomenico A, Margaryan NV, Focà A,Sanguigno L, Bodenstine TM, Chandler GS, Reed DW, Gilgur A, Seftor EA, SeftorRE, Khalkhali-Ellis Z, Leonardi A, Ruvo M, Hendrix MJ. Effects of a novelNodal-targeting monoclonal antibody in melanoma. Oncotarget. 2015 Oct27;6(33):34071-86. doi: 10.18632/oncotarget.6049.

  [10] Focà A, Sanguigno L, Focà G, Strizzi L, IannittiR, Palumbo R, Hendrix MJ, Leonardi A, Ruvo M, Sandomenico A. New Anti-NodalMonoclonal Antibodies Targeting the Nodal Pre-Helix Loop Involved in Cripto-1Binding. Int J Mol Sci. 2015 Sep 7;16(9):21342-62. doi: 10.3390/ijms160921342.  

[11] Sandomenico A, Ruvo M. Targeting Nodal andCripto-1: Perspectives Inside Dual Potential Theranostic CancerBiomarkers.  Curr Med Chem.2019;26(11):1994-2050. doi: 10.2174/0929867325666180912104707.

[12]  Sivaccumar JP, Leonardi A, Iaccarino E, Corvino G, Sanguigno L, Chambery A, Russo R, Valletta M, Latino D, Capasso D, Doti N, Ruvo M,   Sandomenico A . Devolopment of a New Highly Selective Monoclonal Antibody against Preferentially Expressed Antigen in Melanoma (PRAME) and identification of the Target Epitope by Bio_Layer Interferometry Int J Mol Sci. 2021 Mar 20;22(6):3166. doi: 10.3390/ijms22063166.

  [ 13]Selis F, SandomenicoA, Cantile M, Sanna R, Calvanese L, Falcigno L, Dell'Omo P, Esperti A,De Falco S, Focà A, Caporale A, Iaccarino E, Truppo E, Scaramuzza S, Tonon G,Ruvo M. Generationand testing of engineered multimeric Fabs of trastuzumab. Int J Biol Macromol.2020 Dec 1;164:4516-4531. doi: 10.1016/j.ijbiomac.2020.09.050. Epub 2020

[ 14 ] Caporale A, Selis F, Sandomenico A, Jotti GS,Tonon G, Ruvo M. The LQSP tetrapeptide is a new highly efficient substrate ofmicrobial transglutaminase for the site-specific derivatization of peptides andproteins.  Biotechnol J. 2015Jan;10(1):154-61. doi: 10.1002/biot.201400466. Epub 2014 Dec 16.  

[15] Doti N, Caporale A, Monti A, Sandomenico A, SelisF, Ruvo M. A recent update on the use of microbial transglutaminase for thegeneration of biotherapeutics. World J Microbiol Biotechnol, 2020, 36, (4), 53.

Monoclonal Antibodies and recombinant fragments for therapeutic and diagnostic applications
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Last modified by Annamaria Sandomenico on Thursday 08 April 2021, 7:13:02
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