{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Koopmans I"],"funding":["Netherlands Organisation for scientific research","Dutch Cancer Society","KWF Kankerbestrijding"],"pagination":["e1466016"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6136863"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["7(8)"],"pubmed_abstract":["PD-L1-blocking antibodies produce significant clinical benefit in selected cancer patients by reactivating functionally-impaired antigen-experienced anticancer T cells. However, the efficacy of current PD-L1-blocking antibodies is potentially reduced by 'on-target/off-tumor' binding to PD-L1 widely expressed on normal cells. This lack of tumor selectivity may induce a generalized activation of all antigen-experienced T cells which may explain the frequent occurrence of autoimmune-related adverse events during and after treatment. To address these issues, we constructed a bispecific antibody (bsAb), designated PD-L1xEGFR, to direct PD-L1-blockade to EGFR-expressing cancer cells and to more selectively reactivate anticancer T cells. Indeed, the IC50 of PD-L1xEGFR for blocking PD-L1 on EGFR<sup>+</sup> cancer cells was ∼140 fold lower compared to that of the analogous PD-L1-blocking bsAb PD-L1xMock with irrelevant target antigen specificity. Importantly, activation status, IFN-γ production, and oncolytic activity of anti-CD3xanti-EpCAM-redirected T cells was enhanced when cocultured with EGFR-expressing carcinoma cells. Similarly, the capacity of PD-L1xEGFR to promote proliferation and IFN-γ production by CMVpp65-directed CD8<sup>+</sup> effector T cells was enhanced when cocultured with EGFR-expressing CMVpp65-transfected cancer cells. In contrast, the clinically-used PD-L1-blocking antibody MEDI4736 (durvalumab) promoted T cell activation indiscriminate of EGFR expression on cancer cells. Additionally, in mice xenografted with EGFR-expressing cancer cells <sup>111</sup>In-PD-L1xEGFR showed a significantly higher tumor uptake compared to <sup>111</sup>In-PD-L1xMock. In conclusion, PD-L1xEGFR blocks the PD-1/PD-L1 immune checkpoint in an EGFR-directed manner, thereby promoting the selective reactivation of anticancer T cells. This novel targeted approach may be useful to enhance efficacy and safety of PD-1/PD-L1 checkpoint blockade in EGFR-overexpressing malignancies."],"journal":["Oncoimmunology"],"pubmed_title":["A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint."],"pmcid":["PMC6136863"],"funding_grant_id":["RUG2014-6986","RUG2012-5541","RUG2013-6209","NWO 91617039"],"pubmed_authors":["Koopmans I","Heskamp S","Wierstra PJ","van Ginkel RJ","Bremer E","Samplonius DF","Helfrich W","Hendriks D"],"additional_accession":[]},"is_claimable":false,"name":"A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint.","description":"PD-L1-blocking antibodies produce significant clinical benefit in selected cancer patients by reactivating functionally-impaired antigen-experienced anticancer T cells. However, the efficacy of current PD-L1-blocking antibodies is potentially reduced by 'on-target/off-tumor' binding to PD-L1 widely expressed on normal cells. This lack of tumor selectivity may induce a generalized activation of all antigen-experienced T cells which may explain the frequent occurrence of autoimmune-related adverse events during and after treatment. To address these issues, we constructed a bispecific antibody (bsAb), designated PD-L1xEGFR, to direct PD-L1-blockade to EGFR-expressing cancer cells and to more selectively reactivate anticancer T cells. Indeed, the IC50 of PD-L1xEGFR for blocking PD-L1 on EGFR<sup>+</sup> cancer cells was ∼140 fold lower compared to that of the analogous PD-L1-blocking bsAb PD-L1xMock with irrelevant target antigen specificity. Importantly, activation status, IFN-γ production, and oncolytic activity of anti-CD3xanti-EpCAM-redirected T cells was enhanced when cocultured with EGFR-expressing carcinoma cells. Similarly, the capacity of PD-L1xEGFR to promote proliferation and IFN-γ production by CMVpp65-directed CD8<sup>+</sup> effector T cells was enhanced when cocultured with EGFR-expressing CMVpp65-transfected cancer cells. In contrast, the clinically-used PD-L1-blocking antibody MEDI4736 (durvalumab) promoted T cell activation indiscriminate of EGFR expression on cancer cells. Additionally, in mice xenografted with EGFR-expressing cancer cells <sup>111</sup>In-PD-L1xEGFR showed a significantly higher tumor uptake compared to <sup>111</sup>In-PD-L1xMock. In conclusion, PD-L1xEGFR blocks the PD-1/PD-L1 immune checkpoint in an EGFR-directed manner, thereby promoting the selective reactivation of anticancer T cells. This novel targeted approach may be useful to enhance efficacy and safety of PD-1/PD-L1 checkpoint blockade in EGFR-overexpressing malignancies.","dates":{"release":"2018-01-01T00:00:00Z","publication":"2018","modification":"2026-06-13T04:02:30.511Z","creation":"2019-03-26T23:56:24Z"},"accession":"S-EPMC6136863","cross_references":{"pubmed":["30221065"],"doi":["10.1080/2162402X.2018.1466016"]}}