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

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.

SUBMITTER: Liu L

PROVIDER: S-EPMC9499378 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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

Liu Longchao L Chen Jiahui J Bae Joonbeom J Li Huiyu H Sun Zhichen Z Moore Casey C Hsu Eric E Han Chuanhui C Qiao Jian J Fu Yang-Xin YX

Nature biomedical engineering 20211101 11

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 ...[more]

PMID: 34725504

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Project description:BackgroundAntibodies and derivative drugs targeting immune checkpoints have been approved for the treatment of several malignancies, but there are fewer responses in patients with pancreatic cancer. Here, we designed a nanobody molecule with bi-targeting on PD-L1 and CXCR4, as both targets are overexpressed in many cancer cells and play important roles in tumorigenesis. We characterized the biochemical and anti-tumour activities of the bispecific nanobodies in vitro and in vivo.MethodsA nanobody molecule was designed and constructed. The nanobody sequences targeting PD-L1 and CXCR4 were linked by the (G4S)3 flexible peptide to construct the anti-PD-L1/CXCR4 bispecific nanobody. The bispecific nanobody was expressed in E. coli cells and purified by affinity chromatography. The purified nanobody was biochemically characterized by mass spectrometry, Western blotting and flow cytometry to confirm the molecule and its association with both PD-L1 and CXCR4. The biological function of the nanobody and its anti-tumour effects were examined by an in vitro tumour cell-killing assay and in vivo tumour inhibition in mouse xenograft models.ResultsA novel anti-PD-L1/CXCR4 bispecific nanobody was designed, constructed and characterized. The molecule specifically bound to two targets on the surface of human cancer cells and inhibited CXCL12-induced Jurkat cell migration. The bispecific nanobody increased the level of IFN-γ secreted by T-cell activation. The cytotoxicity of human peripheral blood mononuclear cells (hPBMCs) against pancreatic cancer cells was enhanced by the molecule in combination with IL-2. In a human pancreatic cancer xenograft model, the anti-PD-L1/CXCR4 nanobody markedly inhibited tumour growth and was superior to the combo-treatment by anti-PD-L1 nanobody and anti-CXCR4 nanobody or treatment with atezolizumab as a positive control. Immunofluorescence and immunohistochemical staining of xenograft tumours showed that the anti-tumour effects were associated with the inhibition of angiogenesis and the infiltration of immune cells.ConclusionThese results clearly revealed that the anti-PD-L1/CXCR4 bispecific nanobody exerted anti-tumour efficacy in vitro and inhibited tumour growth in vivo. This agent can be further developed as a therapeutic reagent to treat human pancreatic cancer by simultaneously blocking two critical targets.

Project description:BackgroundAlthough immune checkpoint inhibitors have been a breakthrough in clinical oncology, these therapies fail to produce durable responses in a significant fraction of patients. This lack of long-term efficacy may be due to a poor pre-existing network linking innate and adaptive immunity. Here, we present an antisense oligonucleotide (ASO)-based strategy that dually targets toll-like receptor 9 (TLR9) and programmed cell death ligand 1 (PD-L1), aiming to overcome resistance to anti-PD-L1 monoclonal therapy.MethodsWe designed a high-affinity immunomodulatory IM-TLR9:PD-L1-ASO antisense oligonucleotide (hereafter, IM-T9P1-ASO) targeting mouse PD-L1 messenger RNA and activating TLR9. Then, we performed in vitro and in vivo studies to validate the IM-T9P1-ASO activity, efficacy, and biological effects in tumors and draining lymph nodes. We also performed intravital imaging to study IM-T9P1-ASO pharmacokinetics in the tumor.ResultsIM-T9P1-ASO therapy, unlike PD-L1 antibody therapy, results in durable antitumor responses in multiple mouse cancer models. Mechanistically, IM-T9P1-ASO activates a state of tumor-associated dendritic cells (DCs), referred to here as DC3s, which have potent antitumor potential but express the PD-L1 checkpoint. IM-T9P1-ASO has two roles: it triggers the expansion of DC3s by engaging with TLR9 and downregulates PD-L1, thereby unleashing the antitumor functions of DC3s. This dual action leads to tumor rejection by T cells. The antitumor efficacy of IM-T9P1-ASO depends on the antitumor cytokine interleukin-12 (IL-12), produced by DC3s, and Batf3, a transcription factor required for DC development.ConclusionsBy simultaneously targeting TLR9 and PD-L1, IM-T9P1-ASO amplifies antitumor responses via DC activation, leading to sustained therapeutic efficacy in mice. By highlighting differences and similarities between mouse and human DCs, this study could serve to develop similar therapeutic strategies for patients with cancer.

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

Publications

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

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