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Structurally-defined αMHC-II nanobody-drug conjugates: Therapeutic and imaging platforms for B-cell lymphoma
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Published Date:
Jan 14 2016
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Publisher's site:
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Source:Angew Chem Int Ed Engl. 55(7):2416-2420.
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[PDF-1.06 MB]
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Alternative Title:Angew Chem Int Ed Engl
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Description:Antibody-drug conjugates (ADCs) of defined structure hold great promise for cancer therapies, but further advances are constrained by the complex structures of full-sized antibodies. Camelid-derived single-domain antibody fragments (VHHs or nanobodies) offer a possible solution to this challenge by providing expedited target screening and validation through switching between imaging and therapeutic activities. We used a nanobody (VHH7) specific for murine MHC-II and rendered "sortase-ready" for the introduction of oligoglycine-modified cytotoxic payloads or NIR fluorophores. The VHH7 conjugates outcompeted commercial monoclonal antibodies (mAbs) for internalization and exhibited high specificity and cytotoxicity against A20 murine B-cell lymphoma. Non-invasive NIR imaging with a VHH7-fluorophore conjugate showed rapid tumor targeting on both localized and metastatic lymphoma models. Subsequent treatment with the nanobody-drug conjugate efficiently controlled tumor growth and metastasis without obvious systemic toxicity.
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Subject:
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Pubmed ID:26840214
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Pubmed Central ID:PMC4820396
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