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Proteinaceous heterodimer and use thereof

A heterodimer, protein technology, applied in the direction of animal/human protein, immunoglobulin, anti-enzyme immunoglobulin, etc., can solve the problem that the yield of heterodimer protein cannot be further improved, and cannot be controlled or eliminated very effectively. Protein homodimers and other issues have achieved significant anti-tumor activity, long in vivo half-life, and high expression yield.

Pending Publication Date: 2020-01-21
DINGFU BIOTARGET
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, even with the "knothole" modification, it is still not very effective to control or eliminate the formation of protein homodimers, and the yield of heterodimeric proteins is difficult to further improve

Method used

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  • Proteinaceous heterodimer and use thereof
  • Proteinaceous heterodimer and use thereof
  • Proteinaceous heterodimer and use thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0405] Method for preparing protein heterodimer or protein mixture

[0406] In another aspect, the present application provides a method for producing a protein heterodimer or a protein mixture comprising a protein heterodimer, the method comprising (i) culturing the host of the present application under conditions that affect the expression of the protein heterodimer Cells, and (ii) harvesting of expressed protein heterodimers or protein mixtures containing expressed protein heterodimers (such as the protein mixtures of the present application).

[0407] In some embodiments, the method of producing protein heterodimers comprises the following steps:

[0408] (1) Provide a first member of a heterodimer, wherein the first member includes a light chain and a heavy chain, and the heavy chain includes a first Fc region, wherein the light chain and the heavy chain are complexed to form a binding specificity for tumor antigens The targeting part;

[0409] (2) Provide a second member of th...

Embodiment approach

[0417] 1. A protein heterodimer comprising a first member and a second member, the second member being different from the first member, wherein: the first member comprises a light chain and a heavy chain, and the heavy The chain includes a first Fc region, and the light chain is complexed with the heavy chain to form a targeting moiety exhibiting binding specificity to tumor antigens; the second member includes a polypeptide that includes a second Fc region Fusion immunomodulator; the first member and the second member associate through the complexation of the first Fc region and the second Fc region to form the heterodimer; the first The Fc region includes a first modification and / or the second Fc region includes a second modification, wherein the first modification and / or the second modification are more effective in promoting all the holes than the hole modification including the node modification and the hole modification. The heterodimerization between the first member and...

Embodiment 1

[0529] Example 1: Modification and preparation of polypeptide

[0530] 1.1 Determine the amino acid modification in the Fc region

[0531] The amino acid residues of the CH3-CH3 domain interface of human IgG1 were determined. Wild-type human IgG1 contains a first heavy chain (chain A) and a second heavy chain (chain B). The respective interface amino acids of chain A and chain B are shown in Table 1 below. The positions of amino acids are determined according to the EU index of KABAT numbering:

[0532]

[0533]

[0534] Table 1. CH3-CH3 interface residues in the Fc region of wild-type human IgG1 antibody (PDB number 1DN2)

[0535] Then, amino acid modifications (such as amino acid substitutions) are made to interface residues to obtain the following modification groups (as shown in Table 2 below, refer to KH knuckle hole modification). In this application, chain A is also referred to as Fc9 or the first Fc region , Chain B is also called Fc6 or the second Fc region:

[0536]

[0537]...

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Abstract

Provided are proteinaceous heterodimers, pharmaceutical compositions, medicaments and / or kits comprising the proteinaceous heterodimers, methods for producing the proteinaceous heterodimers, and usesthereof.

Description

Background technique [0001] Although the immune response against tumor antigens (Disis et al. (1997) J. Clin. Oncol. 15:3363-3367) can be detected, the malignant cells that cause the disease usually cannot cause the immune response that causes rejection. Studies have shown that the immunogenicity of tumor cells can be enhanced by introducing immunomodulatory molecules (such as cytokines and costimulatory molecules) into cells. However, the eradication of residual cancer cells may require the targeting of widespread micrometastatic tumor deposits, which cannot be directly used for gene transfer. In addition, the expression and stability of the introduced immunomodulatory molecules are often far from satisfactory. Immunomodulators (such as cytokines) produced by immune system cells can directly or indirectly activate adaptive immune response cells and play an important role in eliciting protective anti-tumor immunity. The innate immune system can be triggered by bacterial produc...

Claims

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Application Information

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IPC IPC(8): C07K16/46C07K19/00C12N15/13A61K39/395A61P35/00
CPCA61P35/00C07K14/5428C07K14/55C07K14/56C07K14/565C07K14/57C07K2319/00C07K2319/70C07K16/00C07K16/2863C07K16/303C07K16/3092C07K16/32C07K16/40A61K2039/505C07K2317/22C07K2317/526C07K2317/569C07K2317/622C07K2317/64C07K2317/732C07K2317/92C07K2319/30C07K16/22C07K16/30C07K16/46C07K2317/52
Inventor 徐霆栾彦彭建建付凯赵猛汪皛皛
Owner DINGFU BIOTARGET
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