Abstract
ABSTRACTPD-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 ∼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+ 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 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, 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.
Highlights
Immune checkpoint protein programmed death-ligand 1 (PDL1) normally serves to dampen adoptive immune responses in a timely and localized manner in order to prevent collateral damage and autoimmunity by limiting antigen-experienced PD-1C/ CD8C T cells to proliferate, produce cytokine and attack cells.[1]
PD-L1xEGFR dose-dependent bound to A431 cells, whereas PD-L1xMock only showed minimal binding to A431 cells (Fig. 1B)
Since epidermal growth factor receptor (EGFR) expression levels on cancer cells typically strongly exceed those of PD-L1, we reason that binding of bsAb PD-L1xEGFR to EGFRC cancer cells is usually dominated by its capacity to target EGFR
Summary
Immune checkpoint protein programmed death-ligand 1 (PDL1) normally serves to dampen adoptive immune responses in a timely and localized manner in order to prevent collateral damage and autoimmunity by limiting antigen-experienced PD-1C/ CD8C T cells to proliferate, produce cytokine and attack cells.[1]. PD-L1blocking antibodies, such as atezolizumab, avelumab, and durvalumab, showed prominent clinical activity in patients with advanced stage melanoma[8,9,10] and non-small-cell lung carcinoma (NSCLC).[11,12] the efficacy of current conventional monospecific PD-L1-blocking antibodies is potentially hampered due to on-target/off-tumor binding to numerous normal cell types that express PD-L1 In this respect, binding to PD-L1-expressing cells in blood or other tissue may prevent antibody extravasation and accumulation at the site of the tumor.[13,14] lack of tumor-selectivity appears to result in generalized activation of antigen-experienced T cells, including functionally silenced autoreactive T cells. The latter aspect is evidenced by the frequent occurrence of severe autoimmune-related adverse events during and after treatment with PD-L1-blocking antibodies
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