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Antibody Generation Using Cancer-Derived Small Extracellular Vesicles (sEVs): A Platform for Targeted Cancer Therapy
Maryam Firouzi1, Changsun Kang1, Xiaoyu Ren1
1Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Campus, Oklahoma City, OK, 73117, USA.
Abstract:
Despite advances in tumor-targeting therapies, drug delivery efficiency to solid tumors remains low in most preclinical studies, highlighting the need for more effective targeting ligands. A novel method is developed to generate tumor-targeting monoclonal antibodies (mAbs) using cancer-derived small extracellular vesicles (sEVs), which inherit the structural and functional features of their parent cells. sEVs isolated from human ovarian carcinoma cell lines (OVCAR-8) are injected into mice to elicit an immune response. Hybridoma technology is used to generate mAbs, which are screened for either high specificity or cytotoxicity toward OVCAR-8 cells. Two lead mAbs are individually decorated onto paclitaxel-loaded CD8⁺ T cell-derived sEVs (antibody-functionalized TSEV/P; AB-TSEV/P), and the resulting formulations are evaluated in OVCAR-8 tumor-bearing mice. Both AB-TSEV/P formulations significantly reduce tumor growth without affecting body weight. Biodistribution studies using IR780-loaded AB-TSEV reveal enhanced tumor accumulation compared to non-targeted controls. RNA sequencing and spatial transcriptomics show that antibody-decorated sEVs induce transcriptional changes associated with immune activation and tumor suppression. This antibody generation strategy enables cancer cell-specific targeting and supports its application in targeted cancer therapy and personalized oncology.
Insights
Researchers developed a new method using cancer-derived extracellular vesicles to create targeted antibodies for ovarian cancer therapy. This approach enhances drug delivery and reduces tumor growth by activating the immune system.
Area of Science:
- Oncology
- Immunology
- Nanotechnology
Background:
- Drug delivery to solid tumors faces challenges, limiting the efficacy of targeted therapies.
- Effective targeting ligands are crucial for improving preclinical and clinical cancer treatment outcomes.
- Small extracellular vesicles (sEVs) can inherit features from parent cancer cells, offering potential for drug delivery.
Purpose of the Study:
- To develop a novel method for generating tumor-targeting monoclonal antibodies (mAbs) using cancer-derived small extracellular vesicles (sEVs).
- To evaluate the efficacy of antibody-functionalized sEVs loaded with paclitaxel in reducing ovarian carcinoma tumor growth.
- To investigate the biodistribution and immune-modulating effects of these targeted sEVs.
Main Methods:
- Generating mAbs by immunizing mice with ovarian cancer cell-derived sEVs and employing hybridoma technology.
- Decorating paclitaxel-loaded CD8+ T cell-derived sEVs (TSEV/P) with selected mAbs to create antibody-functionalized TSEV/P (AB-TSEV/P).
- Assessing tumor growth, body weight, biodistribution (using IR780 labeling), RNA sequencing, and spatial transcriptomics in OVCAR-8 tumor-bearing mice.
Main Results:
- Both AB-TSEV/P formulations significantly inhibited tumor growth in OVCAR-8 bearing mice without causing weight loss.
- Biodistribution studies showed enhanced accumulation of antibody-decorated sEVs in tumors compared to non-targeted controls.
- Transcriptomic analysis revealed that antibody-decorated sEVs induced immune activation and tumor suppression signatures.
Conclusions:
- The novel antibody generation strategy utilizing cancer-derived sEVs enables specific cancer cell targeting.
- Antibody-functionalized sEVs demonstrate potential as an effective platform for targeted cancer therapy.
- This approach supports applications in personalized oncology and advanced targeted cancer treatments.
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