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IL-10/FC fusion proteins useful as enhancers for immunotherapy

A technology of fusion protein and immunotherapy, applied in immunoglobulin, peptide/protein components, animal/human protein, etc.

Pending Publication Date: 2022-07-08
ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE (EPFL)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, a facile and safe in vivo metabolic intervention that can be combined with ACT to eradicate solid tumors and induce durable therapy is still lacking

Method used

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  • IL-10/FC fusion proteins useful as enhancers for immunotherapy
  • IL-10/FC fusion proteins useful as enhancers for immunotherapy
  • IL-10/FC fusion proteins useful as enhancers for immunotherapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0121] Example 1: Preparation of Fc fusion protein IL-10 / Fc of the present invention

[0122] For recombinant human IL-10 and IgG1 Fc fusion protein (IL-10 / Fc of SEQ ID NO: 4) ( figure 1 a) processed to cross-react with mouse IL-10 receptor or human IL-10 receptor (IL-10R) via the IL-10 domain of the IL-10 / Fc fusion protein (Qiao et al., 2019, Cancer Cell 35, 901–915.e4). Therefore, the IL-10 / Fc fusion protein can act on both mouse and human CD8+ T cells.

[0123] IL-10 / Fc fusion proteins were obtained by using a gene carrying an IL-10 / Fc fusion gene (as previously described in Guo et al., 2012, or in Zheng et al., 1997, J. Immunol., 158, 4507–4513 or in Commercial mammalian expression vectors such as pcDNA3.1 or pSectag2A described in Steele et al., 1995, J. Immunol., 154, 5590–5600) were expressed from HEK293 free style cells and then harvested by centrifugation after 7 days in culture containing Culture supernatant of IL-10 / Fc.

[0124] The IL-10 / Fc fusion protein was f...

Embodiment 2

[0125] Example 2: The role of fusion protein IL-10 / Fc of the present invention in IL-10-mediated metabolic reprogramming

[0126]In a co-culture system of B16F10 mouse melanoma cells and activated Pmel CD8+ T cells recognizing gp100 cognate antigens, the basal and maximal oxygen consumption rate (OCR) of CD8+ T cells were determined using the fusion protein IL-10 / Fc of the present invention. Both increased after treatment, while the extracellular acidification rate (ECAR) remained unchanged ( figure 2 a-c). The ratio of OCR to EACR was significantly increased in CD8+ T cells treated with IL-10 / Fc ( figure 2 d), which indicates that IL-10 signaling actively promotes T cell oxidative phosphorylation (OXPHOS). Consequently, T cell counts and cytotoxicity are greatly enhanced ( figure 2 e and figure 2 f). Importantly, this metabolic reprogramming effect was not observed in CD8+ T cells without antigen stimulation ( figure 2 d), which suggests that IL-10-mediated metabol...

Embodiment 3

[0129] Example 3: In vivo anti-tumor effect of the fusion protein of the present invention

[0130] Enhancement of OXPHOS or inhibition of glycolytic metabolism in CD8+ T cells by various agents promoted CD8+ T cell proliferation, memory development and antitumor function in the TME (Zhang et al., 2017, Cancer Cell 32, 377–391.e9; Chowdhury et al., 2018, Cancer Immunol. Res. 6, 1375-1387; Sukumar et al., 2013, 123, 4479-4488). Based on the observed metabolic regulation effect of the Fc fusion protein of the present invention on CD8+ T cells, in order to improve the efficacy of T cell adoptive immunotherapy on solid tumors, whether IL-10 / Fc can achieve in vivo metabolic intervention of CD8+ T cells Were studied.

[0131] To overcome T cell depletion in the TME, the in vivo antitumor effects of IL-10 / Fc together with TCR transgenic CD8+ T cells (Pmel CD8+ T cells or OTI CD8+ T cells) or ACT of HER2 CAR-T cells were shown in several studies. tumor models such as B16F10 (low imm...

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Abstract

The present invention relates to novel agents useful in anti-cancer therapies, such as anti-cancer adoptive T cell transfer (ACT) immunotherapies or immune checkpoint blocking therapies, and related compositions, uses, and methods thereof.

Description

[0001] Field of Invention [0002] The present invention relates generally to the field of anticancer therapy, and in particular to adjuvants useful in anticancer immunotherapy, such as adoptive T cell transfer (ACT) immunotherapy and immune checkpoint blockade. Background technique [0003] Adoptive T cell transfer (ACT) immunotherapy has recently produced excellent clinical results. Unlike traditional chemotherapy and radiation, immunotherapy activates the host immune system to attack malignancies and may offer long-term protection against recurrence with less toxicity than traditional chemotherapy and radiation. In adoptive CD8+ T cell therapy, a large number of tumor-specific T cells are derived from the patient and infused back into the patient after ex vivo expansion (Jiang et al., 2019, Cancer Lett., 10;462:23-32; Levine et al. ., 2017 Cell Therapy. Mol. Ther.-Methods Clin. Dev. 4, 92–101). T cells can be expanded from naturally induced tumor-specific CD8+ T cells iso...

Claims

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Application Information

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IPC IPC(8): A61K38/20A61K47/55A61K47/65A61K47/68A61P35/00C07K14/54
CPCA61K38/2066A61K47/55A61K47/65A61K47/6813A61P35/00C07K14/5428A61K39/4644A61K39/464406A61K39/4632A61K2239/57A61K2239/38A61K39/4631A61K39/4611A61K39/464492C07K2319/30C07K2317/52A61K35/17A61K38/1774A61K45/06
Inventor 郭雨刚唐力谢虞清
Owner ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE (EPFL)
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