Contact person: Menotti Ruvo, menotti.ruvo
unina.itActors: Annamaria Sandomenico, annamaria.sandomenico
gmail.com, Menotti Ruvo, menotti.ruvounina.it, Human serum albumin (HSA), is the natural ligand carrier most abundant(40 mg/mL) and with the longest half-life in the blood (19 days). It is showinga remarkable promise as a carrier for anti-cancer as well as other smallmolecule therapeutic agents which can be loaded through covalent attachment orby non covalent interactions on dedicated binding sites. HSA is indeed able to(i) prolong the circulation half-life of drugs that would be otherwise rapidly filteredoff through the kidneys and, (ii) to promote drug accumulation within tumors.
The selective andoriented decoration of NP-HSA with targeting agents (TAs) like antibodies,antibody fragments, antibody surrogates, peptides and aptamers that more specificallybind to tumor markers, introduces molecular cues that drive and accumulate drug-loadedNPs on biomarker-overexpressing tissues, thus representing a relevant advancementto the existing technologies. NP-HSA decorated with multiple Fabs or bioactivepeptides against multiple biomarkers have been also developed in order toincrease the specificity and the possibility to target different tissues. In ourtechnology the molecular cues are attached in an oriented manner to NPs througha linker anchored to the free thiols of cysteine 34 of albumin. The linkerbears reactive amines or glutamines that are joined to the TAs using a microbialtransglutaminase (MTG, [
1-3
]) making the immobilizationhighly selective, oriented and controllable in terms of extent of surfacemodification. NP-HSAs loaded with cytotoxic drugs, labelled with fluorophoresand surface modified with the TAs, represent the next generation of antibodydrug conjugates (ADC) that have the potential to satisfy broad medical needs inoncology and other relevant diseases
*
. We haveso far realized NP-HSA-Fab conjugates using anti-Her2
[4],
anti-Cripto-1
[5]
and anti-Nodal Fabs
[6, 7]
and NP-HSA-peptide derivatives using peptidesthat bind VEGFR1
[8-10].
[1]
Caporale A, Selis F, Sandomenico A, Jotti GS, Tonon G, Ruvo M. The LQSP
tetrapeptide is a new highly efficient substrate of microbial transglutaminase
for the site-specific derivatization of peptides and proteins. Biotechnol J. 2015 Jan;10(1):154-61.
[2] Caporale A, Monti A, Selis F, Sandomenico A, Tonon G, Ruvo M, Doti N. A comparative analysis of catalytic activity and stability of microbial transglutaminase in controlled denaturing conditions. J Biotechnol. 2019 Aug 20;302:48-57.
[3] Doti N, Caporale A, Monti A, Sandomenico A, Selis F, Ruvo M. A recent update on the use of microbial transglutaminase for the generation of biotherapeutics. World J Microbiol Biotechnol, 2020, 36, (4), 53.
[4] Selis F, Sandomenico A, 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. Generation and testing of engineered multimeric Fabs of trastuzumab. Int J Biol Macromol. 2020 Dec 1;164:4516-4531.
[5] 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 neutralizing effects in vitro. Biochimie. 2019 Mar;158:246-256.
[6] Strizzi L, Sandomenico A, Margaryan NV, Focà A, Sanguigno L, Bodenstine TM, Chandler GS, Reed DW, Gilgur A, Seftor EA, Seftor RE, Khalkhali-Ellis Z, Leonardi A, Ruvo M, Hendrix MJ. Effects of a novel Nodal-targeting monoclonal antibody in melanoma. Oncotarget. 2015 Oct 27;6(33):34071-86. doi: 10.18632/oncotarget.6049.
[7] Focà A, Sanguigno L, Focà G, Strizzi L, Iannitti R, Palumbo R, Hendrix MJ, Leonardi A, Ruvo M, Sandomenico A. New Anti-Nodal Monoclonal Antibodies Targeting the Nodal Pre-Helix Loop Involved in Cripto-1 Binding. Int J Mol Sci. 2015 Sep 7;16(9):21342-62.
[8] Tarallo V, Iaccarino E, Cicatiello V, Sanna R, Ruvo M, De Falco S. Oral Delivery of a Tetrameric Tripeptide Inhibitor of VEGFR1 Suppresses Pathological Choroid Neovascularization. Int J Mol Sci. 2020 Jan 9;21(2):410. doi: 10.3390/ijms21020410. PMID: 31936463; PMCID: PMC7014271.
[9] Cicatiello V, Apicella I, Tudisco L, Tarallo V, Formisano L, Sandomenico A, Kim Y, Bastos-Carvalho A, Orlandi A, Ambati J, Ruvo M, Bianco R, De Falco S. Powerful anti-tumor and anti-angiogenic activity of a new anti-vascular endothelial growth factor receptor 1 peptide in colorectal cancer models. Oncotarget. 2015 Apr 30;6(12):10563-76. doi: 10.18632/oncotarget.3384.
[10] Ponticelli S, Marasco D, Tarallo V, Albuquerque RJ, Mitola S, Takeda A, Stassen JM, Presta M, Ambati J, Ruvo M, De Falco S. Modulation of angiogenesis by a tetrameric tripeptide that antagonizes vascular endothelial growth factor receptor 1. J Biol Chem. 2008 Dec 5;283(49):34250-9.
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