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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Pubmed ID:26840214
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Pubmed Central ID:PMC4820396
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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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Funding:DP1 GM106409/GM/NIGMS NIH HHS/United States
R01 AI087879/AI/NIAID NIH HHS/United States
DP1 GM106409/DP/NCCDPHP CDC HHS/United States
R01AI087879/AI/NIAID NIH HHS/United States
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