000232790 001__ 232790
000232790 005__ 20181203024906.0
000232790 0247_ $$2doi$$a10.1126/scitranslmed.aan0401
000232790 022__ $$a1946-6234
000232790 02470 $$2ISI$$a000414654200004
000232790 037__ $$aARTICLE
000232790 245__ $$aMatrix-binding checkpoint immunotherapies enhance antitumor efficacy and reduce adverse events
000232790 260__ $$bAmer Assoc Advancement Science$$c2017$$aWashington
000232790 269__ $$a2017
000232790 300__ $$a14
000232790 336__ $$aJournal Articles
000232790 520__ $$aImmune checkpoint blockade exhibits considerable antitumor activity, but previous studies have reported instances of severe treatment-related adverse events. We sought to explore local immune checkpoint blockade, with an antibody (Ab) form that would be retained intra-or peritumorally, limiting systemic exposure. To accomplish this, we conjugated the checkpoint blockade Abs to an extracellular matrix (ECM)-super-affinity peptide derived from placenta growth factor-2 (PlGF-(2123-144)). We show enhanced tissue retention and lower Ab concentrations in blood plasma after PlGF-(2123-144) conjugation, reducing systemic side effects such as the risk of autoimmune diabetes. Peritumoral injections of PlGF-(2123-144)-anti-CTLA4 (cytotoxic T lymphocyte antigen 4) and PlGF-(2123-144)-anti-PD-L1 (programmed death ligand 1) Abs delayed tumor growth and prolonged survival compared to the unmodified Abs in genetically engineered murine tumor models of melanoma and breast cancer. The PlGF-(2123-144)-Abs increased tumor-infiltrating activated CD8(+) and CD4(+) T cells, resulting in a delay of distant tumor growth as well. This simple and translatable approach of engineered ECM-binding Abs may present a viable and safer approach in checkpoint blockade.
000232790 700__ $$uUniv Chicago, Inst Mol Engn, Chicago, IL 60637 USA$$aIshihara, Jun
000232790 700__ $$uUniv Chicago, Inst Mol Engn, Chicago, IL 60637 USA$$aFukunaga, Kazuto
000232790 700__ $$uUniv Chicago, Inst Mol Engn, Chicago, IL 60637 USA$$aIshihara, Ako
000232790 700__ $$uEcole Polytech Fed Lausanne, Inst Bioengn, CH-1015 Lausanne, Switzerland$$aLarsson, Hans M.
000232790 700__ $$uUniv Chicago, Inst Mol Engn, Chicago, IL 60637 USA$$aPotin, Lambert
000232790 700__ $$uUniv Chicago, Inst Mol Engn, Chicago, IL 60637 USA$$aHosseinchi, Peyman
000232790 700__ $$uEcole Polytech Fed Lausanne, Inst Bioengn, CH-1015 Lausanne, Switzerland$$aGalliverti, Gabriele
000232790 700__ $$0242992$$g160091$$uUniv Chicago, Inst Mol Engn, Chicago, IL 60637 USA$$aSwartz, Melody A.
000232790 700__ $$uUniv Chicago, Inst Mol Engn, Chicago, IL 60637 USA$$aHubbell, Jeffrey A.$$g141360$$0240350
000232790 773__ $$j9$$tScience Translational Medicine$$k415$$qeaan0401
000232790 909C0 $$0252196$$pLMRP$$xU11032
000232790 909C0 $$xU11747$$0252115$$pLLCB
000232790 909CO $$particle$$ooai:infoscience.tind.io:232790
000232790 937__ $$aEPFL-ARTICLE-232790
000232790 973__ $$rREVIEWED$$sPUBLISHED$$aEPFL
000232790 980__ $$aARTICLE