Generation and Characterization of SORT1-Targeted Antibody–Drug Conjugate for the Treatment of SORT1-Positive Breast Tumor
Antibody–drug conjugates (ADCs) have greatly improved the outcomes of advanced breast tumors. However, the treatment of breast tumors with existing ADCs is still hindered by many issues, such as tumor antigen heterogeneity and drug resistance. Therefore, ADCs against new targets would provide option...
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MDPI AG
2023-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/24/17631 |
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| author | Weiliang Zhuang Wei Zhang Liping Xie Lei Wang Yuan Li Ziyu Wang Ao Zhang Haitao Qiu Jun Feng Baohong Zhang Youjia Hu |
| author_facet | Weiliang Zhuang Wei Zhang Liping Xie Lei Wang Yuan Li Ziyu Wang Ao Zhang Haitao Qiu Jun Feng Baohong Zhang Youjia Hu |
| author_sort | Weiliang Zhuang |
| collection | DOAJ |
| description | Antibody–drug conjugates (ADCs) have greatly improved the outcomes of advanced breast tumors. However, the treatment of breast tumors with existing ADCs is still hindered by many issues, such as tumor antigen heterogeneity and drug resistance. Therefore, ADCs against new targets would provide options for the treatment of these challenges. Sortilin-1 (SORT1) may be a promising target for ADC as it is upregulated in breast cancer. To evaluate the possibility of SORT1 as an ADC target, a humanized antibody_8D302 with high affinity against SORT1 was generated. Additionally, 8D302 was conjugated with MMAE and DXd to generate two ADCs_8D302-MMAE and 8D302-DXd, respectively. Both 8D302-MMAE and 8D302-DXd showed effective cytotoxicity against SORT1 positive breast tumor cell lines and induced bystander killing. Consequently, 8D302-MMAE showed relatively better anti-tumor activity than 8D302-DXd both in vitro and in vivo, but 8D302-DXd had superior safety profile and pharmacokinetics profile over 8D302-MMAE. Furthermore, SORT1 induced faster internalization and lysosomal trafficking of antibodies and had a higher turnover compared with HER2. Also, 8D302-DXd exhibited superior cell cytotoxicity and tumor suppression over trastuzumab-DXd, a HER2-targeted ADC. We hypothesize that the high turnover of SORT1 enables SORT1-targeted ADC to be a powerful agent for the treatment of SORT1-positive breast tumor. |
| first_indexed | 2024-03-08T20:40:26Z |
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| id | doaj.art-02a80cef279548d88178f8e2f3a28af0 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-08T20:40:26Z |
| publishDate | 2023-12-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-02a80cef279548d88178f8e2f3a28af02023-12-22T14:15:25ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-12-0124241763110.3390/ijms242417631Generation and Characterization of SORT1-Targeted Antibody–Drug Conjugate for the Treatment of SORT1-Positive Breast TumorWeiliang Zhuang0Wei Zhang1Liping Xie2Lei Wang3Yuan Li4Ziyu Wang5Ao Zhang6Haitao Qiu7Jun Feng8Baohong Zhang9Youjia Hu10Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, ChinaChina State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, ChinaChina State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, ChinaEngineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, ChinaChina State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, ChinaChina State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, ChinaChina State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, ChinaChina State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, ChinaChina State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, ChinaEngineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, ChinaChina State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, ChinaAntibody–drug conjugates (ADCs) have greatly improved the outcomes of advanced breast tumors. However, the treatment of breast tumors with existing ADCs is still hindered by many issues, such as tumor antigen heterogeneity and drug resistance. Therefore, ADCs against new targets would provide options for the treatment of these challenges. Sortilin-1 (SORT1) may be a promising target for ADC as it is upregulated in breast cancer. To evaluate the possibility of SORT1 as an ADC target, a humanized antibody_8D302 with high affinity against SORT1 was generated. Additionally, 8D302 was conjugated with MMAE and DXd to generate two ADCs_8D302-MMAE and 8D302-DXd, respectively. Both 8D302-MMAE and 8D302-DXd showed effective cytotoxicity against SORT1 positive breast tumor cell lines and induced bystander killing. Consequently, 8D302-MMAE showed relatively better anti-tumor activity than 8D302-DXd both in vitro and in vivo, but 8D302-DXd had superior safety profile and pharmacokinetics profile over 8D302-MMAE. Furthermore, SORT1 induced faster internalization and lysosomal trafficking of antibodies and had a higher turnover compared with HER2. Also, 8D302-DXd exhibited superior cell cytotoxicity and tumor suppression over trastuzumab-DXd, a HER2-targeted ADC. We hypothesize that the high turnover of SORT1 enables SORT1-targeted ADC to be a powerful agent for the treatment of SORT1-positive breast tumor.https://www.mdpi.com/1422-0067/24/24/17631SORT1ADCMMAEDXdinternalizationbreast cancer |
| spellingShingle | Weiliang Zhuang Wei Zhang Liping Xie Lei Wang Yuan Li Ziyu Wang Ao Zhang Haitao Qiu Jun Feng Baohong Zhang Youjia Hu Generation and Characterization of SORT1-Targeted Antibody–Drug Conjugate for the Treatment of SORT1-Positive Breast Tumor International Journal of Molecular Sciences SORT1 ADC MMAE DXd internalization breast cancer |
| title | Generation and Characterization of SORT1-Targeted Antibody–Drug Conjugate for the Treatment of SORT1-Positive Breast Tumor |
| title_full | Generation and Characterization of SORT1-Targeted Antibody–Drug Conjugate for the Treatment of SORT1-Positive Breast Tumor |
| title_fullStr | Generation and Characterization of SORT1-Targeted Antibody–Drug Conjugate for the Treatment of SORT1-Positive Breast Tumor |
| title_full_unstemmed | Generation and Characterization of SORT1-Targeted Antibody–Drug Conjugate for the Treatment of SORT1-Positive Breast Tumor |
| title_short | Generation and Characterization of SORT1-Targeted Antibody–Drug Conjugate for the Treatment of SORT1-Positive Breast Tumor |
| title_sort | generation and characterization of sort1 targeted antibody drug conjugate for the treatment of sort1 positive breast tumor |
| topic | SORT1 ADC MMAE DXd internalization breast cancer |
| url | https://www.mdpi.com/1422-0067/24/24/17631 |
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