EGFRvⅢ-targeted immunotoxin combined with temozolomide and bispecific antibody for the eradication of established glioblastoma

EGFRvⅢ is an established target for immunotherapy of glioblastoma (GBM). Current study aims to explore the efficacy of EGFRvⅢ-targeted immunotoxin combined with temozolomide (TMZ) or T cell-engaged bispecific antibody for the treatment of GBM. We generated three rabbit monoclonal antibodies (R1, R2,...
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Gespeichert in:

Autor*in:	Le Huang [verfasserIn] Huixia He [verfasserIn] Ke Wang [verfasserIn] Xuqian Ma [verfasserIn] Xin Chen [verfasserIn] Wenxin Chen [verfasserIn] Xuan Wang [verfasserIn] Xiaobing Jiang [verfasserIn] Mingqian Feng [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	EGFRvⅢ Glioblastoma Temozolomide Immunotoxin Bispecific antibody

Übergeordnetes Werk:	In: Biomedicine & Pharmacotherapy - Elsevier, 2021, 155(2022), Seite 113659-
Übergeordnetes Werk:	volume:155 ; year:2022 ; pages:113659-

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1016/j.biopha.2022.113659

Katalog-ID:	DOAJ02111451X

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allfields	10.1016/j.biopha.2022.113659 doi (DE-627)DOAJ02111451X (DE-599)DOAJbe87eedc176d49429131834f1984ec64 DE-627 ger DE-627 rakwb eng RM1-950 Le Huang verfasserin aut EGFRvⅢ-targeted immunotoxin combined with temozolomide and bispecific antibody for the eradication of established glioblastoma 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier EGFRvⅢ is an established target for immunotherapy of glioblastoma (GBM). Current study aims to explore the efficacy of EGFRvⅢ-targeted immunotoxin combined with temozolomide (TMZ) or T cell-engaged bispecific antibody for the treatment of GBM. We generated three rabbit monoclonal antibodies (R1, R2, and R6) that specifically bound to EGFRvⅢ, but not EGFR, with high affinity. Immunotoxins were made by fusing the scFv of these antibodies with engineered Pseudomonas exotoxin PE24. The in vitro cytotoxicity and specificity of the immunotoxins was rigorously validated by EGFRvⅢ and EGFR-expressed cell lines. The in vivo efficacy of immunotoxin monotherapy and in combination with TMZ or EGFRvⅢ-targeted bispecific antibody was evaluated in orthotopic and subcutaneous xenograft mouse models. EGFRvⅢ immunotoxins potently killed U87, U251 and GL261 cells that were forcefully expressing EGFRvⅢ, with IC50 values bellow 1.2 ng/ml. In a subcutaneous model, multiple intratumoral injections of immunotoxin at a dose of 2 mg/kg resulted in complete tumor regression in 3/5 of mice. In a C57BL/6 orthotopic glioblastoma model transplanted with GL261 cells that expressed a mouse version of EGFRvⅢ, two injections of 10 micrograms of immunotoxin in the lateral ventricles significantly improved the survival, with 2/5 mice being completely cured. Furthermore, in a subcutaneous xenograft model transplanted with EGFRvⅢ-expressed U87 cells, a single intratumoral injection of immuntoxin followed by i.v. injections of TMZ or EGFRvⅢ-targeted bispecific antibody achieved complete regression in mice. Taken together, EGFRvⅢ immunotoxin combined with TMZ or T cell-engaged bispecific antibody offers promise for curative treatment of GBM. EGFRvⅢ Glioblastoma Temozolomide Immunotoxin Bispecific antibody Therapeutics. Pharmacology Huixia He verfasserin aut Ke Wang verfasserin aut Xuqian Ma verfasserin aut Xin Chen verfasserin aut Wenxin Chen verfasserin aut Xuan Wang verfasserin aut Xiaobing Jiang verfasserin aut Mingqian Feng verfasserin aut In Biomedicine & Pharmacotherapy Elsevier, 2021 155(2022), Seite 113659- (DE-627)306717565 (DE-600)1501510-5 19506007 nnns volume:155 year:2022 pages:113659- https://doi.org/10.1016/j.biopha.2022.113659 kostenfrei https://doaj.org/article/be87eedc176d49429131834f1984ec64 kostenfrei http://www.sciencedirect.com/science/article/pii/S0753332222010484 kostenfrei https://doaj.org/toc/0753-3322 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2008 GBV_ILN_2014 GBV_ILN_2025 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2064 GBV_ILN_2106 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 155 2022 113659-
spelling	10.1016/j.biopha.2022.113659 doi (DE-627)DOAJ02111451X (DE-599)DOAJbe87eedc176d49429131834f1984ec64 DE-627 ger DE-627 rakwb eng RM1-950 Le Huang verfasserin aut EGFRvⅢ-targeted immunotoxin combined with temozolomide and bispecific antibody for the eradication of established glioblastoma 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier EGFRvⅢ is an established target for immunotherapy of glioblastoma (GBM). Current study aims to explore the efficacy of EGFRvⅢ-targeted immunotoxin combined with temozolomide (TMZ) or T cell-engaged bispecific antibody for the treatment of GBM. We generated three rabbit monoclonal antibodies (R1, R2, and R6) that specifically bound to EGFRvⅢ, but not EGFR, with high affinity. Immunotoxins were made by fusing the scFv of these antibodies with engineered Pseudomonas exotoxin PE24. The in vitro cytotoxicity and specificity of the immunotoxins was rigorously validated by EGFRvⅢ and EGFR-expressed cell lines. The in vivo efficacy of immunotoxin monotherapy and in combination with TMZ or EGFRvⅢ-targeted bispecific antibody was evaluated in orthotopic and subcutaneous xenograft mouse models. EGFRvⅢ immunotoxins potently killed U87, U251 and GL261 cells that were forcefully expressing EGFRvⅢ, with IC50 values bellow 1.2 ng/ml. In a subcutaneous model, multiple intratumoral injections of immunotoxin at a dose of 2 mg/kg resulted in complete tumor regression in 3/5 of mice. In a C57BL/6 orthotopic glioblastoma model transplanted with GL261 cells that expressed a mouse version of EGFRvⅢ, two injections of 10 micrograms of immunotoxin in the lateral ventricles significantly improved the survival, with 2/5 mice being completely cured. Furthermore, in a subcutaneous xenograft model transplanted with EGFRvⅢ-expressed U87 cells, a single intratumoral injection of immuntoxin followed by i.v. injections of TMZ or EGFRvⅢ-targeted bispecific antibody achieved complete regression in mice. Taken together, EGFRvⅢ immunotoxin combined with TMZ or T cell-engaged bispecific antibody offers promise for curative treatment of GBM. EGFRvⅢ Glioblastoma Temozolomide Immunotoxin Bispecific antibody Therapeutics. Pharmacology Huixia He verfasserin aut Ke Wang verfasserin aut Xuqian Ma verfasserin aut Xin Chen verfasserin aut Wenxin Chen verfasserin aut Xuan Wang verfasserin aut Xiaobing Jiang verfasserin aut Mingqian Feng verfasserin aut In Biomedicine & Pharmacotherapy Elsevier, 2021 155(2022), Seite 113659- (DE-627)306717565 (DE-600)1501510-5 19506007 nnns volume:155 year:2022 pages:113659- https://doi.org/10.1016/j.biopha.2022.113659 kostenfrei https://doaj.org/article/be87eedc176d49429131834f1984ec64 kostenfrei http://www.sciencedirect.com/science/article/pii/S0753332222010484 kostenfrei https://doaj.org/toc/0753-3322 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2008 GBV_ILN_2014 GBV_ILN_2025 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2064 GBV_ILN_2106 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 155 2022 113659-
allfields_unstemmed	10.1016/j.biopha.2022.113659 doi (DE-627)DOAJ02111451X (DE-599)DOAJbe87eedc176d49429131834f1984ec64 DE-627 ger DE-627 rakwb eng RM1-950 Le Huang verfasserin aut EGFRvⅢ-targeted immunotoxin combined with temozolomide and bispecific antibody for the eradication of established glioblastoma 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier EGFRvⅢ is an established target for immunotherapy of glioblastoma (GBM). Current study aims to explore the efficacy of EGFRvⅢ-targeted immunotoxin combined with temozolomide (TMZ) or T cell-engaged bispecific antibody for the treatment of GBM. We generated three rabbit monoclonal antibodies (R1, R2, and R6) that specifically bound to EGFRvⅢ, but not EGFR, with high affinity. Immunotoxins were made by fusing the scFv of these antibodies with engineered Pseudomonas exotoxin PE24. The in vitro cytotoxicity and specificity of the immunotoxins was rigorously validated by EGFRvⅢ and EGFR-expressed cell lines. The in vivo efficacy of immunotoxin monotherapy and in combination with TMZ or EGFRvⅢ-targeted bispecific antibody was evaluated in orthotopic and subcutaneous xenograft mouse models. EGFRvⅢ immunotoxins potently killed U87, U251 and GL261 cells that were forcefully expressing EGFRvⅢ, with IC50 values bellow 1.2 ng/ml. In a subcutaneous model, multiple intratumoral injections of immunotoxin at a dose of 2 mg/kg resulted in complete tumor regression in 3/5 of mice. In a C57BL/6 orthotopic glioblastoma model transplanted with GL261 cells that expressed a mouse version of EGFRvⅢ, two injections of 10 micrograms of immunotoxin in the lateral ventricles significantly improved the survival, with 2/5 mice being completely cured. Furthermore, in a subcutaneous xenograft model transplanted with EGFRvⅢ-expressed U87 cells, a single intratumoral injection of immuntoxin followed by i.v. injections of TMZ or EGFRvⅢ-targeted bispecific antibody achieved complete regression in mice. Taken together, EGFRvⅢ immunotoxin combined with TMZ or T cell-engaged bispecific antibody offers promise for curative treatment of GBM. EGFRvⅢ Glioblastoma Temozolomide Immunotoxin Bispecific antibody Therapeutics. Pharmacology Huixia He verfasserin aut Ke Wang verfasserin aut Xuqian Ma verfasserin aut Xin Chen verfasserin aut Wenxin Chen verfasserin aut Xuan Wang verfasserin aut Xiaobing Jiang verfasserin aut Mingqian Feng verfasserin aut In Biomedicine & Pharmacotherapy Elsevier, 2021 155(2022), Seite 113659- (DE-627)306717565 (DE-600)1501510-5 19506007 nnns volume:155 year:2022 pages:113659- https://doi.org/10.1016/j.biopha.2022.113659 kostenfrei https://doaj.org/article/be87eedc176d49429131834f1984ec64 kostenfrei http://www.sciencedirect.com/science/article/pii/S0753332222010484 kostenfrei https://doaj.org/toc/0753-3322 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2008 GBV_ILN_2014 GBV_ILN_2025 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2064 GBV_ILN_2106 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 155 2022 113659-
allfieldsGer	10.1016/j.biopha.2022.113659 doi (DE-627)DOAJ02111451X (DE-599)DOAJbe87eedc176d49429131834f1984ec64 DE-627 ger DE-627 rakwb eng RM1-950 Le Huang verfasserin aut EGFRvⅢ-targeted immunotoxin combined with temozolomide and bispecific antibody for the eradication of established glioblastoma 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier EGFRvⅢ is an established target for immunotherapy of glioblastoma (GBM). Current study aims to explore the efficacy of EGFRvⅢ-targeted immunotoxin combined with temozolomide (TMZ) or T cell-engaged bispecific antibody for the treatment of GBM. We generated three rabbit monoclonal antibodies (R1, R2, and R6) that specifically bound to EGFRvⅢ, but not EGFR, with high affinity. Immunotoxins were made by fusing the scFv of these antibodies with engineered Pseudomonas exotoxin PE24. The in vitro cytotoxicity and specificity of the immunotoxins was rigorously validated by EGFRvⅢ and EGFR-expressed cell lines. The in vivo efficacy of immunotoxin monotherapy and in combination with TMZ or EGFRvⅢ-targeted bispecific antibody was evaluated in orthotopic and subcutaneous xenograft mouse models. EGFRvⅢ immunotoxins potently killed U87, U251 and GL261 cells that were forcefully expressing EGFRvⅢ, with IC50 values bellow 1.2 ng/ml. In a subcutaneous model, multiple intratumoral injections of immunotoxin at a dose of 2 mg/kg resulted in complete tumor regression in 3/5 of mice. In a C57BL/6 orthotopic glioblastoma model transplanted with GL261 cells that expressed a mouse version of EGFRvⅢ, two injections of 10 micrograms of immunotoxin in the lateral ventricles significantly improved the survival, with 2/5 mice being completely cured. Furthermore, in a subcutaneous xenograft model transplanted with EGFRvⅢ-expressed U87 cells, a single intratumoral injection of immuntoxin followed by i.v. injections of TMZ or EGFRvⅢ-targeted bispecific antibody achieved complete regression in mice. Taken together, EGFRvⅢ immunotoxin combined with TMZ or T cell-engaged bispecific antibody offers promise for curative treatment of GBM. EGFRvⅢ Glioblastoma Temozolomide Immunotoxin Bispecific antibody Therapeutics. Pharmacology Huixia He verfasserin aut Ke Wang verfasserin aut Xuqian Ma verfasserin aut Xin Chen verfasserin aut Wenxin Chen verfasserin aut Xuan Wang verfasserin aut Xiaobing Jiang verfasserin aut Mingqian Feng verfasserin aut In Biomedicine & Pharmacotherapy Elsevier, 2021 155(2022), Seite 113659- (DE-627)306717565 (DE-600)1501510-5 19506007 nnns volume:155 year:2022 pages:113659- https://doi.org/10.1016/j.biopha.2022.113659 kostenfrei https://doaj.org/article/be87eedc176d49429131834f1984ec64 kostenfrei http://www.sciencedirect.com/science/article/pii/S0753332222010484 kostenfrei https://doaj.org/toc/0753-3322 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2008 GBV_ILN_2014 GBV_ILN_2025 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2064 GBV_ILN_2106 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 155 2022 113659-
allfieldsSound	10.1016/j.biopha.2022.113659 doi (DE-627)DOAJ02111451X (DE-599)DOAJbe87eedc176d49429131834f1984ec64 DE-627 ger DE-627 rakwb eng RM1-950 Le Huang verfasserin aut EGFRvⅢ-targeted immunotoxin combined with temozolomide and bispecific antibody for the eradication of established glioblastoma 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier EGFRvⅢ is an established target for immunotherapy of glioblastoma (GBM). Current study aims to explore the efficacy of EGFRvⅢ-targeted immunotoxin combined with temozolomide (TMZ) or T cell-engaged bispecific antibody for the treatment of GBM. We generated three rabbit monoclonal antibodies (R1, R2, and R6) that specifically bound to EGFRvⅢ, but not EGFR, with high affinity. Immunotoxins were made by fusing the scFv of these antibodies with engineered Pseudomonas exotoxin PE24. The in vitro cytotoxicity and specificity of the immunotoxins was rigorously validated by EGFRvⅢ and EGFR-expressed cell lines. The in vivo efficacy of immunotoxin monotherapy and in combination with TMZ or EGFRvⅢ-targeted bispecific antibody was evaluated in orthotopic and subcutaneous xenograft mouse models. EGFRvⅢ immunotoxins potently killed U87, U251 and GL261 cells that were forcefully expressing EGFRvⅢ, with IC50 values bellow 1.2 ng/ml. In a subcutaneous model, multiple intratumoral injections of immunotoxin at a dose of 2 mg/kg resulted in complete tumor regression in 3/5 of mice. In a C57BL/6 orthotopic glioblastoma model transplanted with GL261 cells that expressed a mouse version of EGFRvⅢ, two injections of 10 micrograms of immunotoxin in the lateral ventricles significantly improved the survival, with 2/5 mice being completely cured. Furthermore, in a subcutaneous xenograft model transplanted with EGFRvⅢ-expressed U87 cells, a single intratumoral injection of immuntoxin followed by i.v. injections of TMZ or EGFRvⅢ-targeted bispecific antibody achieved complete regression in mice. Taken together, EGFRvⅢ immunotoxin combined with TMZ or T cell-engaged bispecific antibody offers promise for curative treatment of GBM. EGFRvⅢ Glioblastoma Temozolomide Immunotoxin Bispecific antibody Therapeutics. Pharmacology Huixia He verfasserin aut Ke Wang verfasserin aut Xuqian Ma verfasserin aut Xin Chen verfasserin aut Wenxin Chen verfasserin aut Xuan Wang verfasserin aut Xiaobing Jiang verfasserin aut Mingqian Feng verfasserin aut In Biomedicine & Pharmacotherapy Elsevier, 2021 155(2022), Seite 113659- (DE-627)306717565 (DE-600)1501510-5 19506007 nnns volume:155 year:2022 pages:113659- https://doi.org/10.1016/j.biopha.2022.113659 kostenfrei https://doaj.org/article/be87eedc176d49429131834f1984ec64 kostenfrei http://www.sciencedirect.com/science/article/pii/S0753332222010484 kostenfrei https://doaj.org/toc/0753-3322 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2008 GBV_ILN_2014 GBV_ILN_2025 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2064 GBV_ILN_2106 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 155 2022 113659-
language	English
source	In Biomedicine & Pharmacotherapy 155(2022), Seite 113659- volume:155 year:2022 pages:113659-
sourceStr	In Biomedicine & Pharmacotherapy 155(2022), Seite 113659- volume:155 year:2022 pages:113659-
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	EGFRvⅢ Glioblastoma Temozolomide Immunotoxin Bispecific antibody Therapeutics. Pharmacology
isfreeaccess_bool	true
container_title	Biomedicine & Pharmacotherapy
authorswithroles_txt_mv	Le Huang @@aut@@ Huixia He @@aut@@ Ke Wang @@aut@@ Xuqian Ma @@aut@@ Xin Chen @@aut@@ Wenxin Chen @@aut@@ Xuan Wang @@aut@@ Xiaobing Jiang @@aut@@ Mingqian Feng @@aut@@
publishDateDaySort_date	2022-01-01T00:00:00Z
hierarchy_top_id	306717565
id	DOAJ02111451X
language_de	englisch
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callnumber-first	R - Medicine
author	Le Huang
spellingShingle	Le Huang misc RM1-950 misc EGFRvⅢ misc Glioblastoma misc Temozolomide misc Immunotoxin misc Bispecific antibody misc Therapeutics. Pharmacology EGFRvⅢ-targeted immunotoxin combined with temozolomide and bispecific antibody for the eradication of established glioblastoma
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topic_title	RM1-950 EGFRvⅢ-targeted immunotoxin combined with temozolomide and bispecific antibody for the eradication of established glioblastoma EGFRvⅢ Glioblastoma Temozolomide Immunotoxin Bispecific antibody
topic	misc RM1-950 misc EGFRvⅢ misc Glioblastoma misc Temozolomide misc Immunotoxin misc Bispecific antibody misc Therapeutics. Pharmacology
topic_unstemmed	misc RM1-950 misc EGFRvⅢ misc Glioblastoma misc Temozolomide misc Immunotoxin misc Bispecific antibody misc Therapeutics. Pharmacology
topic_browse	misc RM1-950 misc EGFRvⅢ misc Glioblastoma misc Temozolomide misc Immunotoxin misc Bispecific antibody misc Therapeutics. Pharmacology
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title	EGFRvⅢ-targeted immunotoxin combined with temozolomide and bispecific antibody for the eradication of established glioblastoma
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title_full	EGFRvⅢ-targeted immunotoxin combined with temozolomide and bispecific antibody for the eradication of established glioblastoma
author_sort	Le Huang
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author_browse	Le Huang Huixia He Ke Wang Xuqian Ma Xin Chen Wenxin Chen Xuan Wang Xiaobing Jiang Mingqian Feng
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doi_str_mv	10.1016/j.biopha.2022.113659
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title_sort	egfrvⅲ-targeted immunotoxin combined with temozolomide and bispecific antibody for the eradication of established glioblastoma
callnumber	RM1-950
title_auth	EGFRvⅢ-targeted immunotoxin combined with temozolomide and bispecific antibody for the eradication of established glioblastoma
abstract	EGFRvⅢ is an established target for immunotherapy of glioblastoma (GBM). Current study aims to explore the efficacy of EGFRvⅢ-targeted immunotoxin combined with temozolomide (TMZ) or T cell-engaged bispecific antibody for the treatment of GBM. We generated three rabbit monoclonal antibodies (R1, R2, and R6) that specifically bound to EGFRvⅢ, but not EGFR, with high affinity. Immunotoxins were made by fusing the scFv of these antibodies with engineered Pseudomonas exotoxin PE24. The in vitro cytotoxicity and specificity of the immunotoxins was rigorously validated by EGFRvⅢ and EGFR-expressed cell lines. The in vivo efficacy of immunotoxin monotherapy and in combination with TMZ or EGFRvⅢ-targeted bispecific antibody was evaluated in orthotopic and subcutaneous xenograft mouse models. EGFRvⅢ immunotoxins potently killed U87, U251 and GL261 cells that were forcefully expressing EGFRvⅢ, with IC50 values bellow 1.2 ng/ml. In a subcutaneous model, multiple intratumoral injections of immunotoxin at a dose of 2 mg/kg resulted in complete tumor regression in 3/5 of mice. In a C57BL/6 orthotopic glioblastoma model transplanted with GL261 cells that expressed a mouse version of EGFRvⅢ, two injections of 10 micrograms of immunotoxin in the lateral ventricles significantly improved the survival, with 2/5 mice being completely cured. Furthermore, in a subcutaneous xenograft model transplanted with EGFRvⅢ-expressed U87 cells, a single intratumoral injection of immuntoxin followed by i.v. injections of TMZ or EGFRvⅢ-targeted bispecific antibody achieved complete regression in mice. Taken together, EGFRvⅢ immunotoxin combined with TMZ or T cell-engaged bispecific antibody offers promise for curative treatment of GBM.
abstractGer	EGFRvⅢ is an established target for immunotherapy of glioblastoma (GBM). Current study aims to explore the efficacy of EGFRvⅢ-targeted immunotoxin combined with temozolomide (TMZ) or T cell-engaged bispecific antibody for the treatment of GBM. We generated three rabbit monoclonal antibodies (R1, R2, and R6) that specifically bound to EGFRvⅢ, but not EGFR, with high affinity. Immunotoxins were made by fusing the scFv of these antibodies with engineered Pseudomonas exotoxin PE24. The in vitro cytotoxicity and specificity of the immunotoxins was rigorously validated by EGFRvⅢ and EGFR-expressed cell lines. The in vivo efficacy of immunotoxin monotherapy and in combination with TMZ or EGFRvⅢ-targeted bispecific antibody was evaluated in orthotopic and subcutaneous xenograft mouse models. EGFRvⅢ immunotoxins potently killed U87, U251 and GL261 cells that were forcefully expressing EGFRvⅢ, with IC50 values bellow 1.2 ng/ml. In a subcutaneous model, multiple intratumoral injections of immunotoxin at a dose of 2 mg/kg resulted in complete tumor regression in 3/5 of mice. In a C57BL/6 orthotopic glioblastoma model transplanted with GL261 cells that expressed a mouse version of EGFRvⅢ, two injections of 10 micrograms of immunotoxin in the lateral ventricles significantly improved the survival, with 2/5 mice being completely cured. Furthermore, in a subcutaneous xenograft model transplanted with EGFRvⅢ-expressed U87 cells, a single intratumoral injection of immuntoxin followed by i.v. injections of TMZ or EGFRvⅢ-targeted bispecific antibody achieved complete regression in mice. Taken together, EGFRvⅢ immunotoxin combined with TMZ or T cell-engaged bispecific antibody offers promise for curative treatment of GBM.
abstract_unstemmed	EGFRvⅢ is an established target for immunotherapy of glioblastoma (GBM). Current study aims to explore the efficacy of EGFRvⅢ-targeted immunotoxin combined with temozolomide (TMZ) or T cell-engaged bispecific antibody for the treatment of GBM. We generated three rabbit monoclonal antibodies (R1, R2, and R6) that specifically bound to EGFRvⅢ, but not EGFR, with high affinity. Immunotoxins were made by fusing the scFv of these antibodies with engineered Pseudomonas exotoxin PE24. The in vitro cytotoxicity and specificity of the immunotoxins was rigorously validated by EGFRvⅢ and EGFR-expressed cell lines. The in vivo efficacy of immunotoxin monotherapy and in combination with TMZ or EGFRvⅢ-targeted bispecific antibody was evaluated in orthotopic and subcutaneous xenograft mouse models. EGFRvⅢ immunotoxins potently killed U87, U251 and GL261 cells that were forcefully expressing EGFRvⅢ, with IC50 values bellow 1.2 ng/ml. In a subcutaneous model, multiple intratumoral injections of immunotoxin at a dose of 2 mg/kg resulted in complete tumor regression in 3/5 of mice. In a C57BL/6 orthotopic glioblastoma model transplanted with GL261 cells that expressed a mouse version of EGFRvⅢ, two injections of 10 micrograms of immunotoxin in the lateral ventricles significantly improved the survival, with 2/5 mice being completely cured. Furthermore, in a subcutaneous xenograft model transplanted with EGFRvⅢ-expressed U87 cells, a single intratumoral injection of immuntoxin followed by i.v. injections of TMZ or EGFRvⅢ-targeted bispecific antibody achieved complete regression in mice. Taken together, EGFRvⅢ immunotoxin combined with TMZ or T cell-engaged bispecific antibody offers promise for curative treatment of GBM.
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title_short	EGFRvⅢ-targeted immunotoxin combined with temozolomide and bispecific antibody for the eradication of established glioblastoma
url	https://doi.org/10.1016/j.biopha.2022.113659 https://doaj.org/article/be87eedc176d49429131834f1984ec64 http://www.sciencedirect.com/science/article/pii/S0753332222010484 https://doaj.org/toc/0753-3322
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EGFRvⅢ-targeted immunotoxin combined with temozolomide and bispecific antibody for the eradication of established glioblastoma

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