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A fusion protein of IFN and anti-PD-L1 antibody and its application

A PD-L1, fusion protein technology, applied in the fields of genetic engineering and biomedical medicine, can solve the problems of reducing the treatment effect, patient side effects, etc., to achieve the effect of enhancing the response and increasing the targeting effect

Active Publication Date: 2021-08-27
泉州向日葵生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the widespread expression of IFNAR receptors in normal tissues, high doses of type I interferon can induce severe side effects in patients, including flu-like symptoms (fever, headache, etc.), vomiting, leukopenia, anemia, thrombocytopenia and other symptoms
In addition, type I interferon can upregulate the expression of the immunosuppressive molecule PD-L1, which in turn suppresses the antitumor immune response and reduces the therapeutic effect

Method used

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  • A fusion protein of IFN and anti-PD-L1 antibody and its application
  • A fusion protein of IFN and anti-PD-L1 antibody and its application
  • A fusion protein of IFN and anti-PD-L1 antibody and its application

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preparation example Construction

[0075] During the preparation of the heterodimer, different type I interferons were also used to prepare the second polypeptide mIFNb-Fc (encoding nucleic acid as shown in SEQ ID NO.7), hIFNα2-Fc (encoding nucleic acid as shown in SEQ ID NO.7) NO.8), hIFNb-Fc (encoding nucleic acid as shown in SEQ ID NO.9), mIFNγ-Fc (encoding nucleic acid as shown in SEQ ID NO.10), the resulting heterodimers all have relatively Good inhibitory effect on tumor cell proliferation; among the above-mentioned heterodimer fusion proteins, IFNα-Fc has a better effect; and the heterodimer fusion protein composed of mIFNα4-Fc and Anti-PD-L1 has the best effect Excellent, the relevant detailed comparison data are not shown here.

[0076] Homologous dimer: The mouse IFN-α4 C-terminus is connected to the N-terminal of ScFv(PD-L1)-Fc to obtain the first polypeptide and the second polypeptide of the homologous dimer fusion protein (SEQ ID NO. 3). Its nucleotide sequence (SEQ ID NO.6) was cloned into the p...

Embodiment 1

[0091] Example 1: Topical administration of type I IFN overcomes tumor resistance to PD-1 / PD-L1 blockade therapy

[0092] A recent study showed that the clinical response of patients treated with immune checkpoint blockade correlated with T cell activation status and tumor burden. Consistent with this, the present invention found that anti-PD-L1 antibody was effective in small A20 tumors (3 ) showed effective tumor control ( figure 1 a). On the contrary, when the tumor becomes larger (>100mm 3 ), the antitumor effect decreased significantly ( figure 1 b). Advanced tumors may have developed multiple mechanisms to suppress antitumor immune responses. Indeed, when comparing T cell activation in small and large tumors, it was observed that PD-L1 blockade induced robust T cell activation in small tumors, whereas the same treatment had limited effects on T cells in advanced tumors ( figure 1c), The data suggest that insufficient T cell activation may be the reason advanced t...

Embodiment 2

[0095] Example 2: Construction of IFN-anti-PD-L1 fusion protein for specific delivery of IFN to tumor tissue

[0096] Most patients are unable to implement the local application of interferon to the tumor. Furthermore, systemic delivery of type I IFNs often has limited antitumor activity and severe side effects. Targeting antibodies with cytokines has proven to be an effective strategy for the local delivery of immune modulatory molecules. However, identifying tumor-specific molecules for therapeutic targeting is quite difficult. PD-L1 has been reported to be highly expressed in tumor tissues. Recent studies have shown that anti-PD-L1 antibodies specifically accumulate in PD-L1-positive tumor tissues. Moreover, in addition to their antitumor functions, IFNs strongly induce PD-L1 expression, thereby suppressing T cell responses to tumors. In order to overcome this counteracting effect and realize mutual promotion of immune (re)activation in TME, the present invention propos...

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Abstract

The present invention relates to an IFN-anti-PD-L1 fusion protein, a pharmaceutical composition and a kit containing the fusion protein, and an application of the fusion protein in tumor treatment. The fusion protein of the present invention can simultaneously target PD‑L1 and IFN receptors, and the activation of IFN signals in the tumor microenvironment can enhance PD‑1 / PD‑L1 therapy against tumors by inducing more powerful T cell activation; at the same time , anti-PD‑L1 antibody can be used to specifically deliver immunomodulatory molecules into tumor tissue; the fusion protein generates multiple feed-forward responses, which not only increase the targeting effect, reduce toxicity, but also enhance the response to IFN therapy, so that the anti-PD‑L1 Tumor effect is maximized.

Description

technical field [0001] The invention belongs to the technical fields of genetic engineering and biomedicine, and specifically relates to a fusion protein of IFN and an anti-PD-L1 antibody, a pharmaceutical composition and a kit containing the fusion protein, and the application of the fusion protein in the treatment of tumor diseases. Background technique [0002] Programmed cell death protein 1 (PD-1) is a key immune checkpoint molecule that inhibits TCR signaling activation of T cells, thereby attenuating the intensity and duration of immune responses. Its ligand PD-L1 is generally upregulated in tumor cells and becomes one of the mechanisms for tumors to escape immune response. PD-1 / PD-L1 blockade therapy (referred to as PD therapy) can induce a long-lasting immune response to tumor cells in various cancer patients. However, in practice, objective and effective immune responses have only been observed in a small proportion of patients undergoing PD therapy; in addition, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K19/00A61K39/395A61P35/00A61K48/00A61K38/21
CPCA61K38/21A61K38/212A61K39/39558A61P35/00C07K14/555C07K16/2827A61K48/00C07K2319/30A61K2300/00C07K2319/00C07K14/56A61K2039/505A61K2039/545C07K2317/76C07K2317/73A61K38/00A61K47/68A61K47/6849A61K38/215A61K38/217A61K39/3955C07K14/565C07K14/57C07K16/2818C07K2317/21C07K2317/24C07K2317/54C07K2317/55C07K2317/569C07K2317/622
Inventor 傅阳心梁永彭华
Owner 泉州向日葵生物科技有限公司
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