Abstract 4553: A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint

Abstract

Abstract PD-L1-blocking antibodies produce significant clinical benefit in selected cancer patients by reactivating functionally-impaired anticancer T cells. However, their efficacy is potentially reduced by ‘on-target/off-tumor' binding to PD-L1 widely expressed on normal cells. This lack of tumor selectivity potentially induces a generalized activation of all antigen-experienced T cells as is evidenced by frequent autoimmune-related adverse events during and after treatment. To address these issues, we constructed a tetravalent bispecific antibody (bsAb), designated PD-L1xEGFR, to direct PD-L1-blockade to EGFR-expressing cancer cells and thus reactivate anticancer T cells more selectively. The IC50 of PD-L1xEGFR for binding to EGFR+ cancer cells was ~140 fold lower compared to an analogous PD-L1-blocking bsAb of irrelevant target antigen specificity (PD-L1xMock). Importantly, treatment with PD-L1xEGFR selectively enhanced activation status, INF-γ production, and activity of anti-CD3xanti-EpCAM-redirected T cells in presence of EGFR+/EpCAM+, but not EGFR-/EpCAM+ carcinoma cells. Similarly, capacity of PD-L1xEGFR to promote proliferation and IFN-γ production by CMVpp65-specific CD8+ effector T cells was enhanced in the presence of EGFR+/CMVpp65+ 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 tumor-bearing mice 111In-PD-L1xEGFR showed a significantly higher tumor uptake compared to 111In-PD-L1xMock. In conclusion, PD-L1xEGFR blocks the PD-1/PD-L1 immune checkpoint in an EGFR-directed manner, which promotes a more 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. Citation Format: Iris Koopmans, Douwe F. Samplonius, Robert J. van Ginkel, Peter J. Wierstra, Sandra Heskamp, Edwin Bremer, Wijnand Helfrich. A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4553.