Koopmans et al. created PD-L1xEGFR – an IgG1, tetravalent bispecific antibody – and demonstrated in vitro that it targets PD-L1+EGFR+ tumor cells, inhibits tumor cell proliferation, selectively and effectively blocks the PD-1 axis upon concurrent EGFR binding, and enhances the cytotoxic functionality of antigen-experienced T cells. In vivo, PD-L1xEGFR exhibited higher tumor uptake and accumulation than PD-L1xMock antibody. These results suggest that PD-L1xEGFR has the potential to reduce on-target/off-tumor binding that is observed with current PD-L1 antibodies.
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(+) cancer cells was approximately 140 fold lower compared to that of the analogous PD-L1-blocking bsAb PD-L1xMock with irrelevant target antigen specificity. Importantly, activation status, IFN-gamma 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-gamma production by CMVpp65-directed CD8(+) 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 (111)In-PD-L1xEGFR showed a significantly higher tumor uptake compared to (111)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.
Author Info: (1) University of Groningen, University Medical Center Groningen (UMCG), Department of Surgery, Laboratory for Translational Surgical Oncology, Groningen, The Netherlands. (2) Univ
Author Info: (1) University of Groningen, University Medical Center Groningen (UMCG), Department of Surgery, Laboratory for Translational Surgical Oncology, Groningen, The Netherlands. (2) University of Groningen, University Medical Center Groningen (UMCG), Department of Surgery, Laboratory for Translational Surgical Oncology, Groningen, The Netherlands. (3) University of Groningen, University Medical Center Groningen (UMCG), Department of Surgery, Laboratory for Translational Surgical Oncology, Groningen, The Netherlands. (4) University of Groningen, University Medical Center Groningen (UMCG), Department of Surgery, Laboratory for Translational Surgical Oncology, Groningen, The Netherlands. (5) Radboud University Medical Center, Department of Radiology and Nuclear Medicine, Nijmegen, The Netherlands. (6) Radboud University Medical Center, Department of Radiology and Nuclear Medicine, Nijmegen, The Netherlands. (7) University of Groningen, UMCG, Department of Hematology, Section Immunohematology, Groningen, The Netherlands. (8) University of Groningen, University Medical Center Groningen (UMCG), Department of Surgery, Laboratory for Translational Surgical Oncology, Groningen, The Netherlands.
