title: Structurally Defined αMHC-II Nanobody-Drug Conjugates: A Therapeutic and Imaging System for B-Cell Lymphoma.
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.
authors: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA, 02142, USA.
authors: Tao
authors: T
authors: Fang
authors: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA, 02142, USA.
authors: Joao N
authors: JN
authors: Duarte
authors: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA, 02142, USA.|Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
authors: Jingjing
authors: J
authors: Ling
authors: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA, 02142, USA.|Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
authors: Zeyang
authors: Z
authors: Li
authors: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA, 02142, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
authors: Jonathan S
authors: JS
authors: Guzman
authors: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA, 02142, USA. ploegh@wi.mit.edu.|Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. ploegh@wi.mit.edu.
authors: Hidde L
authors: HL
authors: Ploegh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D000949:Histocompatibility Antigens Class II / Q000737:chemistry*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000473:pathology / Q000628:therapy*; D051379:Mice; D061905:Single-Domain Antibodies
chemical_list: D000970:Antineoplastic Agents; D000949:Histocompatibility Antigens Class II; D061905:Single-Domain Antibodies
keywords: antibody-drug conjugates; antitumor agents; imaging agents; nanobodies; sortase