Human interleukin 2-polyethylene glycol conjugate and application thereof

Abstract

The invention provides a human interleukin 2-polyethylene glycol conjugate and application thereof. The human interleukin 2-polyethylene glycol conjugate provided by the invention comprises recombinant human interleukin 2 containing at least one non-natural amino acid and PEG coupled to the at least one non-natural amino acid, the non-natural amino acid is a carbonyl terminal group-containing compound with a structure as shown in a formula (I) or an enantiomer thereof, and PEG is coupled to the at least one non-natural amino acid by forming an oxime bond between the carbonyl end group and PEG containing a hydroxylamine end group. The human interleukin 2-polyethylene glycol conjugate provided by the invention can be singly used or combined with other anti-tumor drugs, and is used for treating diseases such as solid tumors and hematologic tumors.

Description

technical field [0001] The invention relates to the field of biopharmaceuticals, in particular to a human interleukin 2-polyethylene glycol conjugate and an 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 T cells (including CD4 + and CD8 + T cells) growth, proliferation, differentiation, 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 IL-2 by Morgan et al. in 1976, it has been widely used clinically. In 19...

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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

Fusion expression can only realize the modification of the fusion molecule at the N-terminus or C-terminus of the target protein, and cannot optimize the modification site

[0009] 3. Partial site-directed mutation combined with fusion expression of IL-2 does not show special advantages in practical application

[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.

However, this coupling method and chemical modification method need to introduce a relatively expensive alkyne structure, and an acceptable drug-antibody coupling ratio can only be obtained when the equivalent is used, which increases the corresponding production cost and process. The process is also more complex and the process conditions are harsh

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