Structurally-defined αMHC-II nanobody-drug conjugates: Therapeutic and imaging platforms for B-cell lymphoma

Details

• Alternative Title:
  Angew Chem Int Ed Engl
• Personal Author:
  Fang, Tao ; Duarte, Joao N. ; Ling, Jingjing ; Li, Zeyang ; Guzman, Jonathan S. ; Ploegh, Hidde L.
• 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.
• Keywords:
  Animals Antibody–drug Conjugates Antineoplastic Agents Cancer Cell Line, Tumor Histocompatibility Antigens Class II Humans Lymphoma, B-Cell Mice Nanobody Single-Domain Antibodies Sortase

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• Source:
  Angew Chem Int Ed Engl. 55(7):2416-2420
• Pubmed ID:
  26840214
• Pubmed Central ID:
  PMC4820396
• Document Type:
  Journal Article
• Funding:
  DP1 GM106409/GM/NIGMS NIH HHSUnited States/ ; P30 CA014051/CA/NCI NIH HHSUnited States/ ; DP1 GM106409/DP/NCCDPHP CDC HHSUnited States/ ; R01 AI087879/AI/NIAID NIH HHSUnited States/ ; R01AI087879/AI/NIAID NIH HHSUnited States/
• Volume:
  55
• Issue:
  7
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:9055ea9f6b63070d103a849d2e68462b73d8fc05a875a91418d0fe77a949c8e8
• Download URL:
  https://stacks.cdc.gov/view/cdc/39653/cdc_39653_DS1.pdf
• File Type:
  [PDF - 1.06 MB ]