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Targeted Delivery of miR-34a via Anti-CD47 Antibody Conjugates for Enhanced Cancer Immunotherapy in Triple Negative
Youngri Ryu1, Eun Hye Kim1, Hochung Jang1
1Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
Abstract:
Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks estrogen receptor, progesterone receptor, and HER2 expression, which limits the efficacy of targeted therapies. MicroRNA-34a-5p (miR-34a), a tumor-suppressor miRNA known for regulating oncogenic pathways, initially appeared promising as a therapeutic avenue. However, the clinical translation of miR-34a has been hindered by challenges such as poor stability, inefficient cytoplasmic delivery, and immune-related toxicities, as evidenced by the failure of MRX34 in trials. To address these limitations, this study developes a novel antibody-oligonucleotide conjugate (AOC) platform anti-CD47-miR-34a conjugate (aCD47-C-miR34a). The aCD47-C-miR34a system combines the anti-CD47 antibodies with miR-34a using a bioreducible linker, ensuring targeted cytoplasmic delivery via CD47-mediated endocytosis and endosomal escape. CD47, an immune checkpoint protein overexpressed in TNBC, facilitates immune evasion, making it an attractive therapeutic target. In preclinical TNBC models, aCD47-C-miR34a successfully restored miR-34a's tumor-suppressive functions by downregulating oncogenic pathways including PD-L1, while modulating the tumor microenvironment. This dual mechanism promoted macrophage phagocytosis, enhanced CD8+ T-cell activation, and induced apoptosis, resulting in significant tumor inhibition without systemic toxicity. These findings demonstrate the transformative potential of aCD47-C-miR34a in overcoming TNBC's oncogenic and immune-evasive mechanisms, paving the way for innovative treatments in TNBC and other heterogeneous, aggressive cancers.
Insights
A new antibody-oligonucleotide conjugate (aCD47-C-miR34a) delivers tumor-suppressing microRNA-34a-5p (miR-34a) to triple-negative breast cancer (TNBC) cells. This approach overcomes delivery challenges and inhibits aggressive TNBC growth by modulating the tumor microenvironment.
Area of Science:
- Oncology
- Molecular Biology
- Immunotherapy
Background:
- Triple-negative breast cancer (TNBC) is aggressive, lacking targeted therapy options.
- MicroRNA-34a-5p (miR-34a) shows tumor-suppressive potential but faces clinical delivery hurdles.
- CD47 is overexpressed in TNBC, contributing to immune evasion and serving as a therapeutic target.
Purpose of the Study:
- To develop a novel antibody-oligonucleotide conjugate (AOC) for targeted delivery of miR-34a to TNBC.
- To evaluate the efficacy of the anti-CD47-miR-34a conjugate (aCD47-C-miR34a) in preclinical TNBC models.
- To investigate the dual mechanism of action of aCD47-C-miR34a in restoring tumor suppression and modulating the immune microenvironment.
Main Methods:
- Design and synthesis of an antibody-oligonucleotide conjugate (aCD47-C-miR34a) linking anti-CD47 antibodies to miR-34a via a bioreducible linker.
- Utilizing CD47-mediated endocytosis for targeted delivery and endosomal escape of miR-34a into TNBC cells.
- Assessing the conjugate's effects on oncogenic pathways (e.g., PD-L1), tumor microenvironment modulation (macrophage phagocytosis, T-cell activation), and tumor growth in preclinical TNBC models.
Main Results:
- The aCD47-C-miR34a conjugate successfully delivered miR-34a to TNBC cells, restoring its tumor-suppressive functions.
- Downregulation of oncogenic pathways, including PD-L1, and modulation of the tumor microenvironment were observed.
- Enhanced macrophage phagocytosis, CD8+ T-cell activation, and significant tumor inhibition were achieved with no systemic toxicity.
Conclusions:
- The novel aCD47-C-miR34a conjugate effectively overcomes TNBC's oncogenic and immune-evasive characteristics.
- This AOC platform demonstrates significant potential for treating aggressive TNBC and other challenging cancers.
- Targeted delivery of therapeutic miRNAs via AOCs represents a promising strategy for cancer therapy.
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