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Structurally Defined αMHC‐II Nanobody–Drug Conjugates: A Therapeutic and Imaging System for B‐Cell Lymphoma |
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| Authors: | Dr Tao Fang Dr Joao N Duarte Jingjing Ling Zeyang Li Jonathan S Guzman Prof Dr Hidde L Ploegh |
| Institution: | 1. Whitehead Institute for Biomedical Research, Cambridge, MA, USA;2. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA;3. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA |
| Abstract: | 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. |
| Keywords: | sortase antibody– drug conjugates antitumor agents imaging agents nanobodies |