PAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer

Abstract High-grade serous ovarian cancers (HGSOC) represent the most common subtype of ovarian malignancies. Due to the frequency of late-stage diagnosis and high rates of recurrence following standard of care treatments, novel therapies are needed to promote durable responses. We investigated the...

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Autores principales:	Emily Lee, Sarah Szvetecz, Ryan Polli, Angelo Grauel, Jayson Chen, Joyce Judge, Smita Jaiswal, Rie Maeda, Stephanie Schwartz, Bernd Voedisch, Mateusz Piksa, Chietara Japutra, Lingheswar Sadhasivam, Yiqin Wang, Ana Carrion, Sinan Isim, Jinsheng Liang, Thomas Nicholson, Hong Lei, Qing Fang, Michelle Steinkrauss, Dana Walker, Joel Wagner, Viviana Cremasco, Hui Qin Wang, Giorgio G. Galli, Brian Granda, Keith Mansfield, Quincey Simmons, Andrew Anh Nguyen, Nicole Vincent Jordan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/43b3a91fdd2f4465a835393a7f3b1b6b
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spelling	oai:doaj.org-article:43b3a91fdd2f4465a835393a7f3b1b6b2021-12-02T17:03:50ZPAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer10.1038/s41598-021-93992-12045-2322https://doaj.org/article/43b3a91fdd2f4465a835393a7f3b1b6b2021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-93992-1https://doaj.org/toc/2045-2322Abstract High-grade serous ovarian cancers (HGSOC) represent the most common subtype of ovarian malignancies. Due to the frequency of late-stage diagnosis and high rates of recurrence following standard of care treatments, novel therapies are needed to promote durable responses. We investigated the anti-tumor activity of CD3 T cell engaging bispecific antibodies (TCBs) directed against the PAX8 lineage-driven HGSOC tumor antigen LYPD1 and demonstrated that anti-LYPD1 TCBs induce T cell activation and promote in vivo tumor growth inhibition in LYPD1-expressing HGSOC. To selectively target LYPD1-expressing tumor cells with high expression while sparing cells with low expression, we coupled bivalent low-affinity anti-LYPD1 antigen-binding fragments (Fabs) with the anti-CD3 scFv. In contrast to the monovalent anti-LYPD1 high-affinity TCB (VHP354), the bivalent low-affinity anti-LYPD1 TCB (QZC131) demonstrated antigen density-dependent selectivity and showed tolerability in cynomolgus monkeys at the maximum dose tested of 3 mg/kg. Collectively, these data demonstrate that bivalent TCBs directed against LYPD1 have compelling efficacy and safety profiles to support its use as a treatment for high-grade serous ovarian cancers.Emily LeeSarah SzveteczRyan PolliAngelo GrauelJayson ChenJoyce JudgeSmita JaiswalRie MaedaStephanie SchwartzBernd VoedischMateusz PiksaChietara JaputraLingheswar SadhasivamYiqin WangAna CarrionSinan IsimJinsheng LiangThomas NicholsonHong LeiQing FangMichelle SteinkraussDana WalkerJoel WagnerViviana CremascoHui Qin WangGiorgio G. GalliBrian GrandaKeith MansfieldQuincey SimmonsAndrew Anh NguyenNicole Vincent JordanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Emily Lee Sarah Szvetecz Ryan Polli Angelo Grauel Jayson Chen Joyce Judge Smita Jaiswal Rie Maeda Stephanie Schwartz Bernd Voedisch Mateusz Piksa Chietara Japutra Lingheswar Sadhasivam Yiqin Wang Ana Carrion Sinan Isim Jinsheng Liang Thomas Nicholson Hong Lei Qing Fang Michelle Steinkrauss Dana Walker Joel Wagner Viviana Cremasco Hui Qin Wang Giorgio G. Galli Brian Granda Keith Mansfield Quincey Simmons Andrew Anh Nguyen Nicole Vincent Jordan PAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer
description	Abstract High-grade serous ovarian cancers (HGSOC) represent the most common subtype of ovarian malignancies. Due to the frequency of late-stage diagnosis and high rates of recurrence following standard of care treatments, novel therapies are needed to promote durable responses. We investigated the anti-tumor activity of CD3 T cell engaging bispecific antibodies (TCBs) directed against the PAX8 lineage-driven HGSOC tumor antigen LYPD1 and demonstrated that anti-LYPD1 TCBs induce T cell activation and promote in vivo tumor growth inhibition in LYPD1-expressing HGSOC. To selectively target LYPD1-expressing tumor cells with high expression while sparing cells with low expression, we coupled bivalent low-affinity anti-LYPD1 antigen-binding fragments (Fabs) with the anti-CD3 scFv. In contrast to the monovalent anti-LYPD1 high-affinity TCB (VHP354), the bivalent low-affinity anti-LYPD1 TCB (QZC131) demonstrated antigen density-dependent selectivity and showed tolerability in cynomolgus monkeys at the maximum dose tested of 3 mg/kg. Collectively, these data demonstrate that bivalent TCBs directed against LYPD1 have compelling efficacy and safety profiles to support its use as a treatment for high-grade serous ovarian cancers.
format	article
author	Emily Lee Sarah Szvetecz Ryan Polli Angelo Grauel Jayson Chen Joyce Judge Smita Jaiswal Rie Maeda Stephanie Schwartz Bernd Voedisch Mateusz Piksa Chietara Japutra Lingheswar Sadhasivam Yiqin Wang Ana Carrion Sinan Isim Jinsheng Liang Thomas Nicholson Hong Lei Qing Fang Michelle Steinkrauss Dana Walker Joel Wagner Viviana Cremasco Hui Qin Wang Giorgio G. Galli Brian Granda Keith Mansfield Quincey Simmons Andrew Anh Nguyen Nicole Vincent Jordan
author_facet	Emily Lee Sarah Szvetecz Ryan Polli Angelo Grauel Jayson Chen Joyce Judge Smita Jaiswal Rie Maeda Stephanie Schwartz Bernd Voedisch Mateusz Piksa Chietara Japutra Lingheswar Sadhasivam Yiqin Wang Ana Carrion Sinan Isim Jinsheng Liang Thomas Nicholson Hong Lei Qing Fang Michelle Steinkrauss Dana Walker Joel Wagner Viviana Cremasco Hui Qin Wang Giorgio G. Galli Brian Granda Keith Mansfield Quincey Simmons Andrew Anh Nguyen Nicole Vincent Jordan
author_sort	Emily Lee
title	PAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer
title_short	PAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer
title_full	PAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer
title_fullStr	PAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer
title_full_unstemmed	PAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer
title_sort	pax8 lineage-driven t cell engaging antibody for the treatment of high-grade serous ovarian cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/43b3a91fdd2f4465a835393a7f3b1b6b
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PAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer

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