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Structurally Defined αMHC‐II Nanobody–Drug Conjugates: A Therapeutic and Imaging System for B‐Cell Lymphoma
Author(s) -
Fang Tao,
Duarte Joao N.,
Ling Jingjing,
Li Zeyang,
Guzman Jonathan S.,
Ploegh Hidde L.
Publication year - 2016
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201509432
Subject(s) - conjugate , antibody drug conjugate , antibody , monoclonal antibody , immunotoxin , internalization , cancer research , lymphoma , cytotoxicity , chemistry , biology , immunology , cell , biochemistry , mathematical analysis , mathematics , in vitro
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.