A Targeted Catalytic Nanobody (T-CAN) with Asparaginolytic Activity

<i>E. coli</i> L-asparaginase is an amidohydrolase (EC 3.5.1.1) which has been successfully used for the treatment of Acute Lymphoblastic Leukemia for over 50 years. Despite its efficacy, its side effects, and especially its intrinsic immunogenicity, hamper its usage in a significant sub...

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Autores principales:	Maristella Maggi, Greta Pessino, Isabella Guardamagna, Leonardo Lonati, Cristina Pulimeno, Claudia Scotti
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	L-asparaginase acute lymphoblastic leukaemia antibody-drug conjugates CD19 catalytic nanobody Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/0aec481af2694847a11eac4671973910
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spelling	oai:doaj.org-article:0aec481af2694847a11eac46719739102021-11-25T17:01:56ZA Targeted Catalytic Nanobody (T-CAN) with Asparaginolytic Activity10.3390/cancers132256372072-6694https://doaj.org/article/0aec481af2694847a11eac46719739102021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/22/5637https://doaj.org/toc/2072-6694<i>E. coli</i> L-asparaginase is an amidohydrolase (EC 3.5.1.1) which has been successfully used for the treatment of Acute Lymphoblastic Leukemia for over 50 years. Despite its efficacy, its side effects, and especially its intrinsic immunogenicity, hamper its usage in a significant subset of cases, thus limiting therapeutic options. Innovative solutions to improve on these drawbacks have been attempted, but none of them have been truly successful so far. In this work, we fully replaced the enzyme scaffold, generating an active, miniaturized form of L-asparaginase by protein engineering of a camel single domain antibody, a class of antibodies known to have a limited immunogenicity in humans. We then targeted it onto tumor cells by an antibody scFv fragment directed onto the CD19 B-cell surface receptor expressed on ALL cells. We named this new type of nanobody-based antibody-drug conjugate “Targeted Catalytic Nanobody” (T-CAN). The new molecule retains the catalytic activity and the binding capability of the original modules and successfully targets CD19 expressing cells in vitro. Thanks to its theoretically reduced immunogenic potential compared to the original molecule, the T-CAN can represent a novel approach to tackle current limitations in L-asparaginase usage.Maristella MaggiGreta PessinoIsabella GuardamagnaLeonardo LonatiCristina PulimenoClaudia ScottiMDPI AGarticleL-asparaginaseacute lymphoblastic leukaemiaantibody-drug conjugatesCD19catalytic nanobodyNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5637, p 5637 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	L-asparaginase acute lymphoblastic leukaemia antibody-drug conjugates CD19 catalytic nanobody Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	L-asparaginase acute lymphoblastic leukaemia antibody-drug conjugates CD19 catalytic nanobody Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Maristella Maggi Greta Pessino Isabella Guardamagna Leonardo Lonati Cristina Pulimeno Claudia Scotti A Targeted Catalytic Nanobody (T-CAN) with Asparaginolytic Activity
description	<i>E. coli</i> L-asparaginase is an amidohydrolase (EC 3.5.1.1) which has been successfully used for the treatment of Acute Lymphoblastic Leukemia for over 50 years. Despite its efficacy, its side effects, and especially its intrinsic immunogenicity, hamper its usage in a significant subset of cases, thus limiting therapeutic options. Innovative solutions to improve on these drawbacks have been attempted, but none of them have been truly successful so far. In this work, we fully replaced the enzyme scaffold, generating an active, miniaturized form of L-asparaginase by protein engineering of a camel single domain antibody, a class of antibodies known to have a limited immunogenicity in humans. We then targeted it onto tumor cells by an antibody scFv fragment directed onto the CD19 B-cell surface receptor expressed on ALL cells. We named this new type of nanobody-based antibody-drug conjugate “Targeted Catalytic Nanobody” (T-CAN). The new molecule retains the catalytic activity and the binding capability of the original modules and successfully targets CD19 expressing cells in vitro. Thanks to its theoretically reduced immunogenic potential compared to the original molecule, the T-CAN can represent a novel approach to tackle current limitations in L-asparaginase usage.
format	article
author	Maristella Maggi Greta Pessino Isabella Guardamagna Leonardo Lonati Cristina Pulimeno Claudia Scotti
author_facet	Maristella Maggi Greta Pessino Isabella Guardamagna Leonardo Lonati Cristina Pulimeno Claudia Scotti
author_sort	Maristella Maggi
title	A Targeted Catalytic Nanobody (T-CAN) with Asparaginolytic Activity
title_short	A Targeted Catalytic Nanobody (T-CAN) with Asparaginolytic Activity
title_full	A Targeted Catalytic Nanobody (T-CAN) with Asparaginolytic Activity
title_fullStr	A Targeted Catalytic Nanobody (T-CAN) with Asparaginolytic Activity
title_full_unstemmed	A Targeted Catalytic Nanobody (T-CAN) with Asparaginolytic Activity
title_sort	targeted catalytic nanobody (t-can) with asparaginolytic activity
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/0aec481af2694847a11eac4671973910
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A Targeted Catalytic Nanobody (T-CAN) with Asparaginolytic Activity

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