Structurally Defined aMHC-II Nanobody-Drug Conjugates: A Therapeutic and Imaging System for B-Cell Lymphoma

被引：75

作者：

Fang, Tao ^{[1
]}

Duarte, Joao N. ^{[1
]}

Ling, Jingjing ^{[1
,3
]}

Li, Zeyang ^{[1
,3
]}

Guzman, Jonathan S. ^{[1
,2
]}

Ploegh, Hidde L. ^{[1
,2
]}

机构：

[1] Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA

[2] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[3] MIT, Dept Chem, 77 Massachusetts Ave, Cambridge, MA 02139 USA

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2016年 / 55卷 / 07期

关键词：

sortase; antibody-drug conjugates; antitumor agents; imaging agents; nanobodies; ANTIBODY-FRAGMENT; CD20; EXPRESSION; LIGATION;

D O I：

10.1002/anie.201509432

中图分类号：

O6 [化学];

学科分类号：

070301 [无机化学];

摘要：

Antibody-drug conjugates (ADCs) of defined structure hold great promise for cancer therapies, but further advances are constrained by the complex structures of fullsized 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.

引用

页码：2416 / 2420

页数：5

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