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Anti-CCR8*CTLA-4 bispecific antibody and application thereof

A bispecific antibody, CTLA-4 technology, applied in the field of tumor immunology, can solve the problems of difficult antibody affinity, lack of CCR8 monoclonal antibody, and difficult tissue penetration

Inactive Publication Date: 2020-02-25
普米斯生物技术(苏州)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the molecular mass of traditional monoclonal antibody (150kD) is too large to penetrate tissue, resulting in a low effective concentration in the tumor area and insufficient therapeutic effect; traditional antibodies are highly immunogenic, and engineered antibodies are difficult to reach original affinity
In addition, many factors such as the long development cycle of fully humanized traditional antibodies, high production costs, and insufficient stability limit their clinical application and popularity.
[0006] However, there is currently a lack of satisfactory monoclonal antibodies against CCR8 (especially nanobodies) in the art.

Method used

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  • Anti-CCR8*CTLA-4 bispecific antibody and application thereof
  • Anti-CCR8*CTLA-4 bispecific antibody and application thereof
  • Anti-CCR8*CTLA-4 bispecific antibody and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0196] Example 1: Expression and purification of human CCR8 protein

[0197] The nucleotide sequence of human CCR8 was synthesized in a commercially available vector, and the prepared plasmid was evenly mixed with the transfection reagent PEI 1:3, then allowed to stand for 20 minutes, and then added to appropriate cells (HEK293F cells), at 37°C, 6 %CO 2 Cultivate in a shaker incubator for 5-6 days; collect the cell supernatant and combine with Protein A beads at room temperature for 1 hour; wash the beads with phosphate buffer solution pH7.0, and then use 0.1M pH3.0 Glycine to elute the protein ;

[0198] Ultrafilter the eluted protein into PBS, measure the yield and take a sample for SDS-PAGE detection, and store the rest of the protein in a -80°C refrigerator;

Embodiment 2

[0199] Example 2: Preparation of CCR8 monoclonal antibody

[0200] In this example, a fully human antibody yeast screening platform was used to screen CCR8-specific monoclonal antibodies through CCR8+CHO cell stable transfection.

Embodiment 3

[0201] Example 3 Preparation of anti-CCR8 nanobody

[0202] A certain amount of hCCR8 antigen was mixed with an equal volume of Freund's adjuvant, and an alpaca was immunized once a week for several times in total to stimulate B cells to express antigen-specific nanobodies. After immunization, 100mL peripheral blood lymphocytes were extracted and total RNA was extracted; cDNA was synthesized and VHH was amplified by nested PCR; and a phage display library was constructed.

[0203] Through screening and identification, multiple strains of nanobodies were obtained.

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PUM

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Abstract

The invention provides an anti-CCR8*CTLA-4 bispecific antibody and an application thereof, and particularly provides a bispecific antibody, which comprises: (a) an antibody or an element for resistingcytotoxic T lymphocyte associated antigen 4 (CTLA-4); and (b) an antibody or an element against CCR8 linked to the antibody or the element against cytotoxic T lymphocyte associated antigen 4 (CTLA-4). The bispecific antibody disclosed by the invention can be simultaneously combined with CTLA-4 and CCR8, so that the activity of a group of regulatory T cells (Treg) with immunosuppressive activity infiltrated in tumor tissues is specifically targeted and eliminated, and the bispecific antibody is particularly suitable for immunotherapy of tumors.

Description

technical field [0001] The invention belongs to the field of tumor immunology, and in particular relates to an anti-CCR8×CTLA-4 bispecific antibody and application thereof. Background technique [0002] With the successful marketing of multiple tumor immunomodulatory drugs targeting PD-1 / PD-L1, tumor immunotherapy has achieved revolutionary success. However, due to the infiltration of a large number of immunosuppressive cells in tumor tissue, the clinical response rate of PD-1 / PD-L1 tumor immunotherapy in patients with different types of tumors is still at a very low level. [0003] There are many reasons that limit the clinical response rate of PD-1 / PD-L1 immunotherapy, including the number of killer T cells infiltrating tumor tissue, the presence of a large number of immunosuppressive factors such as TGFβ, IDO, and adenosine in the tumor microenvironment, and the presence of Treg, Infiltration of various immunosuppressive cells such as MDSC in tumor tissue. [0004] Ther...

Claims

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Application Information

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IPC IPC(8): C07K16/46C12N15/13A61K39/395A61P35/00A61P35/02
CPCA61K39/39558A61K2039/507A61P35/00A61P35/02C07K16/28C07K16/2866C07K16/468
Inventor 李斌伊刚
Owner 普米斯生物技术(苏州)有限公司
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