Simultaneous targeting of primary tumor, draining lymph node, and distant metastases through high endothelial
Liwei Jiang1, Sungwook Jung1, Jing Zhao1
1Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Abstract:
Cancer patients with malignant involvement of tumor-draining lymph nodes (TDLNs) and distant metastases have the poorest prognosis. A drug delivery platform that targets the primary tumor, TDLNs, and metastatic niches simultaneously, remains to be developed. Here, we generated a novel monoclonal antibody (MHA112) against peripheral node addressin (PNAd), a family of glycoproteins expressed on high endothelial venules (HEVs), which are present constitutively in the lymph nodes (LNs) and formed ectopically in the tumor stroma. MHA112 was endocytosed by PNAd-expressing cells, where it passed through the lysosomes. MHA112 conjugated antineoplastic drug Paclitaxel (Taxol) (MHA112-Taxol) delivered Taxol effectively to the HEV-containing tumors, TDLNs, and metastatic lesions. MHA112-Taxol treatment significantly reduced primary tumor size as well as metastatic lesions in a number of mouse and human tumor xenografts tested. These data, for the first time, indicate that human metastatic lesions contain HEVs and provide a platform that permits simultaneous targeted delivery of antineoplastic drugs to the three key sites of primary tumor, TDLNs, and metastases.
Insights
A new antibody (MHA112) targets cancer by delivering Paclitaxel (Taxol) to primary tumors, tumor-draining lymph nodes (TDLNs), and metastases. This approach effectively shrinks tumors and reduces metastatic spread in preclinical models.
Area of Science:
- Oncology
- Immunology
- Drug Delivery
Background:
- Malignant involvement of tumor-draining lymph nodes (TDLNs) and distant metastases significantly worsens cancer patient prognosis.
- Current therapeutic strategies lack platforms for simultaneous targeting of primary tumors, TDLNs, and metastatic sites.
Purpose of the Study:
- To develop a novel drug delivery platform for simultaneous targeting of primary tumors, TDLNs, and metastatic lesions.
- To evaluate the efficacy of a monoclonal antibody (MHA112) conjugated with Paclitaxel (MHA112-Taxol) against cancer progression.
Main Methods:
- Generated a monoclonal antibody (MHA112) targeting peripheral node addressin (PNAd) expressed on high endothelial venules (HEVs).
- Conjugated MHA112 with Paclitaxel (Taxol) to create MHA112-Taxol for targeted drug delivery.
- Assessed MHA112-Taxol efficacy in reducing primary tumor size and metastatic lesions in mouse and human tumor xenografts.
Main Results:
- MHA112 effectively targeted and was endocytosed by PNAd-expressing cells.
- MHA112-Taxol demonstrated effective delivery of Paclitaxel to HEV-containing tumors, TDLNs, and metastatic lesions.
- Significant reduction in primary tumor size and metastatic lesions was observed following MHA112-Taxol treatment.
Conclusions:
- Human metastatic lesions contain high endothelial venules (HEVs).
- MHA112-Taxol provides a novel platform for simultaneous targeted delivery of antineoplastic drugs to primary tumors, TDLNs, and metastases.
- This strategy holds promise for improving outcomes in patients with advanced cancer.
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