Human interleukin 2-polyethylene glycol conjugate as well as preparation method and application thereof

Abstract

The invention discloses a human interleukin 2-polyethylene glycol conjugate as well as a preparation method and an application thereof. The human interleukin 2-polyethylene glycol conjugate comprisesrecombinant human interleukin 2 of at least one non-natural amino acid and PEG coupled to the at least one non-natural amino acid, the position of the at least one non-natural amino acid is selected from one or more sites of L36, M39, L40, M46, P47, L63, L66, E67, L70 and A73 corresponding to SEQ ID NO: 2, wherein the recombinant human interleukin 2 is a protein as shown in SEQ ID NO: 3 or a functional active fragment thereof. The human interleukin 2-polyethylene glycol conjugate provided by the invention can be used as a single drug or combined with an anti-tumor drug, and is used for treating solid tumors or blood tumors.

Description

technical field [0001] The invention belongs to the field of biopharmaceuticals, and relates to a human interleukin 2-polyethylene glycol conjugate and a preparation method and application thereof. Background technique [0002] Interleukin-2 (Interleukin 2, IL-2, often referred to as Interleukin 2) is an important immune regulatory factor produced by activated type I helper T lymphocytes (Th1), once known as T cell growth factor, Its main biological function is to promote the growth, proliferation and differentiation of T cells (including CD4+ and CD8+ T cells) in dual ways of stimulation and anti-apoptosis, and promote the further secretion of cytokines. In addition, interleukin 2 also stimulates the proliferation of NK cells, enhances NK killing activity and produces cytokines, induces the production of LAK cells; promotes the proliferation of B cells and secretes antibodies; Important role (Gaffena S.L., Cytokine 28:109e123, 2004). [0003] Since the first discovery of ...

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Problems solved by technology

[0007] 1. Simple amino acid site-directed mutation can reduce the binding ability to IL-2Rα, or enhance the binding ability to IL-2Rβ or IL-2Rγ, but it cannot effectively prolong the half-life of the molecule, and the mutant product is prone to immunogenic reactions in vivo , it is easy to reduce the biological activity of the product and cause a greater risk of toxicity

[0008] 2. Although simple fusion expression (such as fusion with Fc or HSA) or IL-2 modification can prolong the half-life of the molecule, it has no obvious advantage in actual use compared with unmodified IL-2

[0009] 3. Site-directed mutagenesis combined with fusion expression of IL-2 does not show special advantages in practical applications

[0010] 4. Conventional non-site-specific coupling of PEGylated IL-2 does not show special advantages in practical applications. PEGylated IL-2 that comprehensively weakens the binding ability of IL-2Rα has achieved staged success, but the non-site-specific coupling process The characteristics make it difficult to control the production process and quality, the molecular structure is complicated, and the mechanism of action is complicated.

[0018] However, for in vivo applications, the presence of transition metals (copper salts) is toxic to both bacteria and human cells

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