Related Experiment Video
Updated: Jul 7, 2025
Analyzing Tumor and Tissue Distribution of Target Antigen Specific Therapeutic Antibody
Published on: May 16, 2020
Generation and Characterization of SORT1-Targeted Antibody-Drug Conjugate for the Treatment of SORT1-Positive Breast
Weiliang Zhuang1,2, Wei Zhang2, Liping Xie2
1Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
Abstract:
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.
Insights
New antibody-drug conjugates targeting Sortilin-1 (SORT1) show promise for advanced breast cancer treatment. These SORT1-targeted ADCs demonstrate potent anti-tumor activity and offer a potential new therapeutic option for patients resistant to current treatments.
Area of Science:
- Oncology
- Immunotherapy
- Drug Development
Background:
- Advanced breast tumors remain challenging to treat due to antigen heterogeneity and drug resistance.
- Existing antibody-drug conjugates (ADCs) offer improved outcomes but face limitations.
- Novel therapeutic targets are needed to overcome current treatment challenges in breast cancer.
Purpose of the Study:
- To evaluate Sortilin-1 (SORT1) as a potential target for antibody-drug conjugates (ADCs) in breast cancer treatment.
- To generate and characterize novel SORT1-targeted ADCs.
- To compare the efficacy and safety of different ADC constructs.
Main Methods:
- Generation of a humanized antibody (8D302) with high affinity for SORT1.
- Conjugation of 8D302 with cytotoxic payloads MMAE and DXd to create ADCs 8D302-MMAE and 8D302-DXd.
- In vitro and in vivo evaluation of ADC cytotoxicity, bystander killing, anti-tumor activity, safety, and pharmacokinetics.
Main Results:
- Both 8D302-MMAE and 8D302-DXd exhibited potent cytotoxicity against SORT1-positive breast cancer cells and induced bystander killing.
- 8D302-MMAE demonstrated superior in vitro and in vivo anti-tumor activity compared to 8D302-DXd.
- 8D302-DXd presented a more favorable safety and pharmacokinetic profile than 8D302-MMAE.
- SORT1 showed faster internalization and lysosomal trafficking, with higher turnover than HER2.
- 8D302-DXd outperformed trastuzumab-DXd (a HER2-targeted ADC) in cell cytotoxicity and tumor suppression.
Conclusions:
- Sortilin-1 (SORT1) is a promising target for antibody-drug conjugate development in breast cancer.
- SORT1-targeted ADCs, particularly 8D302-DXd, show significant potential for treating SORT1-positive breast tumors.
- The high turnover of SORT1 may enhance the efficacy of SORT1-targeted ADCs, offering a new therapeutic strategy.
More Related Videos
14:20Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
11:02Genetic Encoding of a Non-Canonical Amino Acid for the Generation of Antibody-Drug Conjugates Through a Fast Bioorthogonal Reaction
Published on: September 14, 2018
