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Selection of a Nuclease-Resistant RNA Aptamer Targeting CD19

SIMPLE SUMMARY: Haematological malignancies show a constantly growing incidence, accounting for 6.5% of new cancer cases worldwide. Among them, B-cell neoplasms often show resistance to conventional chemotherapy that is also associated with numerous adverse effects. Therefore, in order for the treat...

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Detalles Bibliográficos
Autores principales: Esposito, Carla L., Van Roosbroeck, Katrien, Santamaria, Gianluca, Rotoli, Deborah, Sandomenico, Annamaria, Wierda, William G., Ferrajoli, Alessandra, Ruvo, Menotti, Calin, George A., de Franciscis, Vittorio, Catuogno, Silvia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533794/
https://www.ncbi.nlm.nih.gov/pubmed/34680368
http://dx.doi.org/10.3390/cancers13205220
Descripción
Sumario:SIMPLE SUMMARY: Haematological malignancies show a constantly growing incidence, accounting for 6.5% of new cancer cases worldwide. Among them, B-cell neoplasms often show resistance to conventional chemotherapy that is also associated with numerous adverse effects. Therefore, in order for the treatment outcome to be improved, the development of new safe and effective targeted therapeutic approaches represents a main challenge. In this regard, nucleic acid aptamers are very attractive molecules. Indeed, they show high affinity and specificity for their target, increased tumour penetration, and low toxicity. Recently, CD19 has emerged as a key surface marker of malignant B cells, suitable for the development of new compounds for malignant B-cell targeting. Here, we isolated an RNA aptamer targeting the human CD19 antigen on malignant B cells that was able to rapidly internalise into target cells. Therefore, it represents a useful carrier for secondary reagents and a promising tool for the development of new safe and effective targeted therapies for B-cell malignancy treatment. ABSTRACT: The transmembrane glycoprotein cluster of differentiation 19 (CD19) is a B cell–specific surface marker, expressed on the majority of neoplastic B cells, and has recently emerged as a very attractive biomarker and therapeutic target for B-cell malignancies. The development of safe and effective ligands for CD19 has become an important need for the development of targeted conventional and immunotherapies. In this regard, aptamers represent a very interesting class of molecules. Additionally referred to as ‘chemical antibodies’, they show many advantages as therapeutics, including low toxicity and immunogenicity. Here, we isolated a nuclease-resistant RNA aptamer binding to the human CD19 glycoprotein. In order to develop an aptamer also useful as a carrier for secondary reagents, we adopted a cell-based SELEX (Systematic Evolution of Ligands by EXponential Enrichment) protocol adapted to isolate aptamers able to internalise upon binding to their cell surface target. We describe a 2′-fluoro pyrimidine modified aptamer, named B85.T2, which specifically binds to CD19 and shows an exquisite stability in human serum. The aptamer showed an estimated dissociation constant (K(D)) of 49.9 ± 13 nM on purified human recombinant CD19 (rhCD19) glycoprotein, a good binding activity on human B-cell chronic lymphocytic leukaemia cells expressing CD19, and also an effective and rapid cell internalisation, thus representing a promising molecule for CD19 targeting, as well as for the development of new B-cell malignancy-targeted therapies.