Development of nanobodies targeting hepatocellular carcinoma and application of nanobody-based CAR-T technology
Abstract Background Chimeric antigen receptor T (CAR-T) cell therapy, as an emerging anti-tumor treatment, has garnered extensive attention in the study of targeted therapy of multiple tumor-associated antigens in hepatocellular carcinoma (HCC). However, the suppressive microenvironment and individu...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-04-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-024-05159-x |
| _version_ | 1797209107275448320 |
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| author | Keming Lin Baijin Xia Xuemei Wang Xin He Mo Zhou Yingtong Lin Yidan Qiao Rong Li Qier Chen Yuzhuang Li Jinzhu Feng Tao Chen Cancan Chen Xinyu Li Hui Zhang Lijuan Lu Bingfeng Liu Xu Zhang |
| author_facet | Keming Lin Baijin Xia Xuemei Wang Xin He Mo Zhou Yingtong Lin Yidan Qiao Rong Li Qier Chen Yuzhuang Li Jinzhu Feng Tao Chen Cancan Chen Xinyu Li Hui Zhang Lijuan Lu Bingfeng Liu Xu Zhang |
| author_sort | Keming Lin |
| collection | DOAJ |
| description | Abstract Background Chimeric antigen receptor T (CAR-T) cell therapy, as an emerging anti-tumor treatment, has garnered extensive attention in the study of targeted therapy of multiple tumor-associated antigens in hepatocellular carcinoma (HCC). However, the suppressive microenvironment and individual heterogeneity results in downregulation of these antigens in certain patients’ cancer cells. Therefore, optimizing CAR-T cell therapy for HCC is imperative. Methods In this study, we administered FGFR4-ferritin (FGFR4-HPF) nanoparticles to the alpaca and constructed a phage library of nanobodies (Nbs) derived from alpaca, following which we screened for Nbs targeting FGFR4. Then, we conducted the functional validation of Nbs. Furthermore, we developed Nb-derived CAR-T cells and evaluated their anti-tumor ability against HCC through in vitro and in vivo validation. Results Our findings demonstrated that we successfully obtained high specificity and high affinity Nbs targeting FGFR4 after screening. And the specificity of Nbs targeting FGFR4 was markedly superior to their binding to other members of the FGFR family proteins. Furthermore, the Nb-derived CAR-T cells, targeting FGFR4, exhibited significantly enhanced anti-tumor efficacy in both experiments when in vitro and in vivo. Conclusions In summary, the results of this study suggest that the CAR-T cells derived from high specificity and high affinity Nbs, targeting FGFR4, exhibited significantly enhanced anti-tumor efficacy in vitro and in vivo. This is an exploration of FGFR4 in the field of Nb-derived CAR-T cell therapy for HCC, holding promise for enhancing safety and effectiveness in the clinical treatment of HCC in the future. |
| first_indexed | 2024-04-24T09:49:26Z |
| format | Article |
| id | doaj.art-ecc7adc80b2848708c3915de61119331 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-24T09:49:26Z |
| publishDate | 2024-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-ecc7adc80b2848708c3915de611193312024-04-14T11:27:46ZengBMCJournal of Translational Medicine1479-58762024-04-0122111510.1186/s12967-024-05159-xDevelopment of nanobodies targeting hepatocellular carcinoma and application of nanobody-based CAR-T technologyKeming Lin0Baijin Xia1Xuemei Wang2Xin He3Mo Zhou4Yingtong Lin5Yidan Qiao6Rong Li7Qier Chen8Yuzhuang Li9Jinzhu Feng10Tao Chen11Cancan Chen12Xinyu Li13Hui Zhang14Lijuan Lu15Bingfeng Liu16Xu Zhang17Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen UniversityInstitute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen UniversityInstitute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen UniversityInstitute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen UniversityInstitute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen UniversityInstitute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen UniversityInstitute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen UniversityInstitute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen UniversityInstitute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen UniversityInstitute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen UniversityInstitute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen UniversityInstitute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Pathology, The First Affiliated Hospital, Sun Yat-sen UniversityShenzhen Key Laboratory of Systems Medicine for Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-sen UniversityInstitute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Medical Oncology, The Third Affiliated Hospital of Sun Yat-sen UniversityInstitute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen UniversityInstitute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen UniversityAbstract Background Chimeric antigen receptor T (CAR-T) cell therapy, as an emerging anti-tumor treatment, has garnered extensive attention in the study of targeted therapy of multiple tumor-associated antigens in hepatocellular carcinoma (HCC). However, the suppressive microenvironment and individual heterogeneity results in downregulation of these antigens in certain patients’ cancer cells. Therefore, optimizing CAR-T cell therapy for HCC is imperative. Methods In this study, we administered FGFR4-ferritin (FGFR4-HPF) nanoparticles to the alpaca and constructed a phage library of nanobodies (Nbs) derived from alpaca, following which we screened for Nbs targeting FGFR4. Then, we conducted the functional validation of Nbs. Furthermore, we developed Nb-derived CAR-T cells and evaluated their anti-tumor ability against HCC through in vitro and in vivo validation. Results Our findings demonstrated that we successfully obtained high specificity and high affinity Nbs targeting FGFR4 after screening. And the specificity of Nbs targeting FGFR4 was markedly superior to their binding to other members of the FGFR family proteins. Furthermore, the Nb-derived CAR-T cells, targeting FGFR4, exhibited significantly enhanced anti-tumor efficacy in both experiments when in vitro and in vivo. Conclusions In summary, the results of this study suggest that the CAR-T cells derived from high specificity and high affinity Nbs, targeting FGFR4, exhibited significantly enhanced anti-tumor efficacy in vitro and in vivo. This is an exploration of FGFR4 in the field of Nb-derived CAR-T cell therapy for HCC, holding promise for enhancing safety and effectiveness in the clinical treatment of HCC in the future.https://doi.org/10.1186/s12967-024-05159-xHCCNanoparticleNanobodyPhage displayNb-derived CAR-T cell therapy |
| spellingShingle | Keming Lin Baijin Xia Xuemei Wang Xin He Mo Zhou Yingtong Lin Yidan Qiao Rong Li Qier Chen Yuzhuang Li Jinzhu Feng Tao Chen Cancan Chen Xinyu Li Hui Zhang Lijuan Lu Bingfeng Liu Xu Zhang Development of nanobodies targeting hepatocellular carcinoma and application of nanobody-based CAR-T technology Journal of Translational Medicine HCC Nanoparticle Nanobody Phage display Nb-derived CAR-T cell therapy |
| title | Development of nanobodies targeting hepatocellular carcinoma and application of nanobody-based CAR-T technology |
| title_full | Development of nanobodies targeting hepatocellular carcinoma and application of nanobody-based CAR-T technology |
| title_fullStr | Development of nanobodies targeting hepatocellular carcinoma and application of nanobody-based CAR-T technology |
| title_full_unstemmed | Development of nanobodies targeting hepatocellular carcinoma and application of nanobody-based CAR-T technology |
| title_short | Development of nanobodies targeting hepatocellular carcinoma and application of nanobody-based CAR-T technology |
| title_sort | development of nanobodies targeting hepatocellular carcinoma and application of nanobody based car t technology |
| topic | HCC Nanoparticle Nanobody Phage display Nb-derived CAR-T cell therapy |
| url | https://doi.org/10.1186/s12967-024-05159-x |
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