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

Fang, Tao; Duarte, Joao N.; Ling, Jingjing; Li, Zeyang; Guzman, Jonathan S.; Ploegh, Hidde L.

doi:10.1002/anie.201509432

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

Published Date:

Jan 14 2016

Publisher's site:

http://dx.doi.org/10.1002/anie.201509432 New Site Icon

Source:

Angew Chem Int Ed Engl. 55(7):2416-2420.

[PDF - 1.06 MB]

Details:

Personal Authors:

Fang, Tao ; Duarte, Joao N. ; Ling, Jingjing ; Li, Zeyang ; Guzman, Jonathan S. ; ... More ▼

Keywords:

[+]

Pubmed ID:

26840214

Pubmed Central ID:

PMC4820396

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.

Document Type:

Journal Article

Collection(s):

CDC Public Access

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

Supporting Files:

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