Rejuvenation of tumour-specific T cells through bispecific antibodies targeting PD-L1 on dendritic cells

L Liu, J Chen, J Bae, H Li, Z Sun, C Moore… - Nature biomedical …, 2021 - nature.com
L Liu, J Chen, J Bae, H Li, Z Sun, C Moore, E Hsu, C Han, J Qiao, YX Fu
Nature biomedical engineering, 2021nature.com
Bispecific T-cell engagers (BiTEs) preferentially targeting tumour-associated antigens and
stimulating CD3-mediated signalling are being used in patients to treat acute B-cell
lymphoblastic leukemia. However, the potency of BiTEs in solid tumours is limited by their
short half-life and their severe toxicity at relevant therapeutic doses. Here we report the
design and in vivo performance of a bispecific antibody that simultaneously targets the
murine T-cell co-receptor CD3ε and the murine immune checkpoint programmed-death …
Abstract
Bispecific T-cell engagers (BiTEs) preferentially targeting tumour-associated antigens and stimulating CD3-mediated signalling are being used in patients to treat acute B-cell lymphoblastic leukemia. However, the potency of BiTEs in solid tumours is limited by their short half-life and their severe toxicity at relevant therapeutic doses. Here we report the design and in vivo performance of a bispecific antibody that simultaneously targets the murine T-cell co-receptor CD3ε and the murine immune checkpoint programmed-death ligand 1 (PD-L1). In multiple syngeneic tumour models, the bispecific antibody generated higher antitumour immune responses than conventional BiTEs targeting tumour-associated antigens and CD3ε. We found that the durable antigen-specific T-cell responses resulted from the rejuvenation of CD8 T cells, owing to the blockade of PD-L1 on dendritic cells (but not on tumour cells) and co-stimulation by B7-1&2 (a peripheral membrane protein on dendritic cells). Bispecific T-cell engagers targeting dendritic cells rather than tumour cells may represent a general means of T-cell rejuvenation for durable cancer immunotherapy.
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