T-cell Activating Tribodies as a Novel Approach for Efficient Killing of ErbB2-positive Cancer Cells

Gennaro Riccio; Ana Rita Ricardo; Margherita Passariello; Kathy Saraiva; Valentina Rubino; Philip Cunnah; Nico Mertens; Claudia De Lorenzo

doi:10.1097/CJI.0000000000000248

T-cell Activating Tribodies as a Novel Approach for Efficient Killing of ErbB2-positive Cancer Cells

Gennaro Riccio, Ana Rita Ricardo, Margherita Passariello, Kathy Saraiva, Valentina Rubino, Philip Cunnah, Nico Mertens, Claudia De Lorenzo

Risultato della ricerca: Contributo su rivista › Articolo in rivista › peer review

Abstract

L'articolo affronta uno dei profili più problematici della c.d. "saga Taricco", ossia dell'insieme delle sentenze e ordinanze scaturite a seguito della prima sentenza della Corte di giustizia UE nel 2015, C-105/14, Ivo Taricco et al.: viene dapprima esposto l'approccio adottato dalla Corte Costituzionale italiana e quello della Corte di giustizia Ue, mettendo in evidenza la diversità di impostazione teorica e le ricadute pratiche di ciascun criterio di interpretazione del rapporto fra primato, diritti fondamentali della persona e controlimiti costituzionali. Infine viene indicata una possibile chiave di lettura intermedia che potrebbe evitare in futuro il riaccendersi di conflittualità su vicende analoghe.

Lingua originale	Inglese
pagine (da-a)	1-10
Numero di pagine	10
Rivista	Journal of Immunotherapy
Volume	42
Numero di pubblicazione	1
DOI	https://doi.org/10.1097/CJI.0000000000000248
Stato di pubblicazione	Pubblicato - 1 gen 2019
Pubblicato esternamente	Sì

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10.1097/CJI.0000000000000248

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title = "T-cell Activating Tribodies as a Novel Approach for Efficient Killing of ErbB2-positive Cancer Cells",

abstract = "The Tyrosine Kinase Receptor ErbB2 (HER2) when overexpressed in breast cancer (BC) is associated with poor prognosis. The monoclonal antibody Trastuzumab has become a standard treatment of ErbB2+BC. The antibody treatment has limited efficacy, often meets resistance and induces cardiotoxicity. T-cell recruiting bispecific antibody derivatives (TRBA) offer a more effective alternative to standard antibody therapy. We evaluated a panel of TRBAs targeting 3 different epitopes on the ErbB2 receptor either in a bivalent targeting tribody structure or as a monovalent scFv-fusion (BiTE format) for binding, cytotoxicity on Trastuzumab-resistant cell lines, and induction of cardiotoxicity. All three TRBAs bind with high affinity to the ErbB2 extracellular domain and a large panel of ErbB2-positive tumor cells. Tribodies had an increased in vitro cytotoxic potency as compared to BiTEs. It is interesting to note that, Tribodies targeting the epitopes on ErbB2 receptor domains I and II bind and activate lysis of mammary and gastric tumor cells more efficiently than a Tribody targeting the Trastuzumab epitope on domain IV. The first 2 are also active on Trastuzumab-resistant cancer cells lacking or masking the epitope recognized by Trastuzumab. None of the Tribodies studied showed significant toxicity on human cardiomyocytes. Altogether these results make these novel anti-ErbB2 bispecific Tribodies candidates for therapeutic development for treating ErbB2-positive Trastuzumab-resistant cancer patients.",

keywords = "ErbB2/HER2, T-cell engager, cancer, immunotherapy, tribody",

author = "Gennaro Riccio and Ricardo, {Ana Rita} and Margherita Passariello and Kathy Saraiva and Valentina Rubino and Philip Cunnah and Nico Mertens and {De Lorenzo}, Claudia",

year = "2019",

month = jan,

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doi = "10.1097/CJI.0000000000000248",

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AU - Riccio, Gennaro

AU - Ricardo, Ana Rita

AU - Passariello, Margherita

AU - Saraiva, Kathy

AU - Rubino, Valentina

AU - Cunnah, Philip

AU - Mertens, Nico

AU - De Lorenzo, Claudia

PY - 2019/1/1

Y1 - 2019/1/1

N2 - The Tyrosine Kinase Receptor ErbB2 (HER2) when overexpressed in breast cancer (BC) is associated with poor prognosis. The monoclonal antibody Trastuzumab has become a standard treatment of ErbB2+BC. The antibody treatment has limited efficacy, often meets resistance and induces cardiotoxicity. T-cell recruiting bispecific antibody derivatives (TRBA) offer a more effective alternative to standard antibody therapy. We evaluated a panel of TRBAs targeting 3 different epitopes on the ErbB2 receptor either in a bivalent targeting tribody structure or as a monovalent scFv-fusion (BiTE format) for binding, cytotoxicity on Trastuzumab-resistant cell lines, and induction of cardiotoxicity. All three TRBAs bind with high affinity to the ErbB2 extracellular domain and a large panel of ErbB2-positive tumor cells. Tribodies had an increased in vitro cytotoxic potency as compared to BiTEs. It is interesting to note that, Tribodies targeting the epitopes on ErbB2 receptor domains I and II bind and activate lysis of mammary and gastric tumor cells more efficiently than a Tribody targeting the Trastuzumab epitope on domain IV. The first 2 are also active on Trastuzumab-resistant cancer cells lacking or masking the epitope recognized by Trastuzumab. None of the Tribodies studied showed significant toxicity on human cardiomyocytes. Altogether these results make these novel anti-ErbB2 bispecific Tribodies candidates for therapeutic development for treating ErbB2-positive Trastuzumab-resistant cancer patients.

AB - The Tyrosine Kinase Receptor ErbB2 (HER2) when overexpressed in breast cancer (BC) is associated with poor prognosis. The monoclonal antibody Trastuzumab has become a standard treatment of ErbB2+BC. The antibody treatment has limited efficacy, often meets resistance and induces cardiotoxicity. T-cell recruiting bispecific antibody derivatives (TRBA) offer a more effective alternative to standard antibody therapy. We evaluated a panel of TRBAs targeting 3 different epitopes on the ErbB2 receptor either in a bivalent targeting tribody structure or as a monovalent scFv-fusion (BiTE format) for binding, cytotoxicity on Trastuzumab-resistant cell lines, and induction of cardiotoxicity. All three TRBAs bind with high affinity to the ErbB2 extracellular domain and a large panel of ErbB2-positive tumor cells. Tribodies had an increased in vitro cytotoxic potency as compared to BiTEs. It is interesting to note that, Tribodies targeting the epitopes on ErbB2 receptor domains I and II bind and activate lysis of mammary and gastric tumor cells more efficiently than a Tribody targeting the Trastuzumab epitope on domain IV. The first 2 are also active on Trastuzumab-resistant cancer cells lacking or masking the epitope recognized by Trastuzumab. None of the Tribodies studied showed significant toxicity on human cardiomyocytes. Altogether these results make these novel anti-ErbB2 bispecific Tribodies candidates for therapeutic development for treating ErbB2-positive Trastuzumab-resistant cancer patients.

KW - ErbB2/HER2

KW - T-cell engager

KW - cancer

KW - immunotherapy

KW - tribody

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DO - 10.1097/CJI.0000000000000248

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JO - Journal of Immunotherapy

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T-cell Activating Tribodies as a Novel Approach for Efficient Killing of ErbB2-positive Cancer Cells

Abstract

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