A scDb-based trivalent bispecific antibody for T-cell-mediated killing of HER3-expressing cancer cells

Abstract HER3 is a member of the EGF receptor family and elevated expression is associated with cancer progression and therapy resistance. HER3-specific T-cell engagers might be a suitable treatment option to circumvent the limited efficacy observed for HER3-blocking antibodies in clinical trials. I...

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Autores principales:	Nadine Aschmoneit, Sophia Steinlein, Lennart Kühl, Oliver Seifert, Roland E. Kontermann
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d989d218664f4b1999818ee6967f204d
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spelling	oai:doaj.org-article:d989d218664f4b1999818ee6967f204d2021-12-02T18:34:06ZA scDb-based trivalent bispecific antibody for T-cell-mediated killing of HER3-expressing cancer cells10.1038/s41598-021-93351-02045-2322https://doaj.org/article/d989d218664f4b1999818ee6967f204d2021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-93351-0https://doaj.org/toc/2045-2322Abstract HER3 is a member of the EGF receptor family and elevated expression is associated with cancer progression and therapy resistance. HER3-specific T-cell engagers might be a suitable treatment option to circumvent the limited efficacy observed for HER3-blocking antibodies in clinical trials. In this study, we developed bispecific antibodies for T-cell retargeting to HER3-expressing tumor cells, utilizing either a single-chain diabody format (scDb) with one binding site for HER3 and one for CD3 on T-cells or a trivalent bispecific scDb-scFv fusion protein exhibiting an additional binding site for HER3. The scDb-scFv showed increased binding to HER3-expressing cancer cell lines compared to the scDb and consequently more effective T-cell activation and T-cell proliferation. Furthermore, the bivalent binding mode of the scDb-scFv for HER3 translated into more potent T-cell mediated cancer cell killing, and allowed to discriminate between moderate and low HER3-expressing target cells. Thus, our study demonstrated the applicability of HER3 for T-cell retargeting with bispecific antibodies, even at moderate expression levels, and the increased potency of an avidity-mediated specificity gain, potentially resulting in a wider safety window of bispecific T-cell engaging antibodies targeting HER3.Nadine AschmoneitSophia SteinleinLennart KühlOliver SeifertRoland E. KontermannNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nadine Aschmoneit Sophia Steinlein Lennart Kühl Oliver Seifert Roland E. Kontermann A scDb-based trivalent bispecific antibody for T-cell-mediated killing of HER3-expressing cancer cells
description	Abstract HER3 is a member of the EGF receptor family and elevated expression is associated with cancer progression and therapy resistance. HER3-specific T-cell engagers might be a suitable treatment option to circumvent the limited efficacy observed for HER3-blocking antibodies in clinical trials. In this study, we developed bispecific antibodies for T-cell retargeting to HER3-expressing tumor cells, utilizing either a single-chain diabody format (scDb) with one binding site for HER3 and one for CD3 on T-cells or a trivalent bispecific scDb-scFv fusion protein exhibiting an additional binding site for HER3. The scDb-scFv showed increased binding to HER3-expressing cancer cell lines compared to the scDb and consequently more effective T-cell activation and T-cell proliferation. Furthermore, the bivalent binding mode of the scDb-scFv for HER3 translated into more potent T-cell mediated cancer cell killing, and allowed to discriminate between moderate and low HER3-expressing target cells. Thus, our study demonstrated the applicability of HER3 for T-cell retargeting with bispecific antibodies, even at moderate expression levels, and the increased potency of an avidity-mediated specificity gain, potentially resulting in a wider safety window of bispecific T-cell engaging antibodies targeting HER3.
format	article
author	Nadine Aschmoneit Sophia Steinlein Lennart Kühl Oliver Seifert Roland E. Kontermann
author_facet	Nadine Aschmoneit Sophia Steinlein Lennart Kühl Oliver Seifert Roland E. Kontermann
author_sort	Nadine Aschmoneit
title	A scDb-based trivalent bispecific antibody for T-cell-mediated killing of HER3-expressing cancer cells
title_short	A scDb-based trivalent bispecific antibody for T-cell-mediated killing of HER3-expressing cancer cells
title_full	A scDb-based trivalent bispecific antibody for T-cell-mediated killing of HER3-expressing cancer cells
title_fullStr	A scDb-based trivalent bispecific antibody for T-cell-mediated killing of HER3-expressing cancer cells
title_full_unstemmed	A scDb-based trivalent bispecific antibody for T-cell-mediated killing of HER3-expressing cancer cells
title_sort	scdb-based trivalent bispecific antibody for t-cell-mediated killing of her3-expressing cancer cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/d989d218664f4b1999818ee6967f204d
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A scDb-based trivalent bispecific antibody for T-cell-mediated killing of HER3-expressing cancer cells

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