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Crystal structure of NRP2 in complex with aNRP2-10 Fab fragment
Structural highlights
FunctionNRP2_HUMAN High affinity receptor for semaphorins 3C, 3F, VEGF-165 and VEGF-145 isoforms of VEGF, and the PLGF-2 isoform of PGF. Publication Abstract from PubMedAlthough blocking the binding of vascular endothelial growth factor (VEGF) to neuropilin-2 (NRP2) on tumor cells is a potential strategy to treat aggressive carcinomas, a lack of effective reagents that can be used clinically has hampered this potential therapy. Here, we describe the generation of a fully humanized, high-affinity monoclonal antibody (aNRP2-10) that specifically inhibits the binding of VEGF to NRP2, conferring antitumor activity without causing toxicity. Using triple-negative breast cancer as a model, we demonstrated that aNRP2-10 could be used to isolate cancer stem cells (CSCs) from heterogeneous tumor populations and inhibit CSC function and epithelial-to-mesenchymal transition. aNRP2-10 sensitized cell lines, organoids, and xenografts to chemotherapy and inhibited metastasis by promoting the differentiation of CSCs to a state that is more responsive to chemotherapy and less prone to metastasis. These data provide justification for the initiation of clinical trials designed to improve the response of patients with aggressive tumors to chemotherapy using this monoclonal antibody. Inhibition of VEGF binding to neuropilin-2 enhances chemosensitivity and inhibits metastasis in triple-negative breast cancer.,Xu Z, Goel HL, Burkart C, Burman L, Chong YE, Barber AG, Geng Y, Zhai L, Wang M, Kumar A, Menefee A, Polizzi C, Eide L, Rauch K, Rahman J, Hamel K, Fogassy Z, Klopp-Savino S, Paz S, Zhang M, Cubitt A, Nangle LA, Mercurio AM Sci Transl Med. 2023 May 3;15(694):eadf1128. doi: 10.1126/scitranslmed.adf1128. , Epub 2023 May 3. PMID:37134152[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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