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CD154 binding polypeptides and uses thereof

A technology that binds peptides and fragments. It is applied in the field of disease treatment and can solve problems such as thrombosis and antibodies that do not use clinical practice.

Active Publication Date: 2021-10-26
SEOUL NAT UNIV R&DB FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, in fact, the developed antibody was not used in clinical practice due to the side effect of thrombosis caused by platelet activation
In other words, the Fc portion of the previously developed antibody had the problem of activating platelets by binding to Fcγ receptors (FcγR) in platelets, leading to thrombosis

Method used

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  • CD154 binding polypeptides and uses thereof
  • CD154 binding polypeptides and uses thereof
  • CD154 binding polypeptides and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0116] Embodiment 1: animal test

[0117] Cynomolgus macaques (Macaca fascicularis) were maintained at the Nonhuman Primate Center of Seoul National University Hospital (Seoul, Korea) or the Korean Institute of Toxicology (Jeongeup, Jeollabuk-do, Korea). The monkeys used in the experiments were 30 to 40 months old and weighed 2.5 to 3.5 kg. A part of the study was conducted in accordance with the guidelines of the National Institutes of Health approved by the Animal Care and Use Committee (IACUC) of Seoul National University Hospital, and a part of the study was conducted in accordance with the guidelines of the National Institutes of Health proposed by the Korea Institute of Toxicology at the request of Seoul National University. guide.

Embodiment 2

[0118] Example 2: Production of anti-human CD154 antibodies

[0119] To generate anti-human CD154 antibodies, recombinant human soluble CD154 protein (sCD40L, catalog number: 310-02, Peprotech, NJ, USA) was immunized into BALAB / c mice. Female Balb / c mice (6-8 Week-old, 17-25 g; KOATECH, Pyeongtaek, Gyeonggi-do, Korea), intraperitoneally administered 3 times at 2-week intervals. Two weeks after the final immunization, 100 μg of CD154 protein was intraperitoneally injected into the immunized mouse, and 3 days later, the spleen was extracted from the mouse, and splenocytes were isolated therefrom.

[0120] For the production of monoclonal antibodies, 10 8 10 splenocytes with resistance to 9-azaguanine 7 A SP2 / 0-Ag14 mouse myeloma cell ( CRL-1581; American Type Culture Collection, Manassas, VA, USA) fusion (Koeler and Milstein, Nature 1975; 256:495-497).

[0121] After fusion, the cells were washed once with PBS, and then resuspended in DMEM (Dulbecco's modified Eagle's medi...

Embodiment 3

[0124] Example 3: Sequencing of the variable region of the anti-human CD154 antibody

[0125] In order to determine the heavy chain and light chain of the above-mentioned RD-05 antibody (including the heavy chain variable region (V H ) and the light chain variable region (V L )) The sequence of the CDRs of the gene was cloned as follows.

[0126] For gene cloning, RNA was extracted from RD-05 hybridoma cells using the RNA MiniPrep kit (Qiagen, Hilden, Germany) according to the manufacturer's instructions, and PCR was performed (Novagen Mouse Ig Primer Set #69831, MuIgV H 5'-F, MuIgGV H 3'-2 and MuIgκV L S'-B, MuIgκV L 3'-1), thereby synthesizing cDNA.

[0127] The primers and PCR conditions for the synthesis of the heavy chain cDNA used were as follows: Forward primer MuIgV H 5'-F: 5'-ACTAGTCGACATGAACTTYGGGYTSAGMTTGRTTT-3' (Y: C or T; S: C or G; M: A or C; and R: A or G); reverse primer MuIgGV H 3'-2: 5'-CCCAAGCTTCCAGGGRCCARKGGATARACIGRTGG-3' (R: A or G; K: G or T; and ...

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Abstract

A CD154-binding polypeptide that specifically recognizes CD154 is disclosed. The polypeptide according to the present disclosure effectively inhibits the CD154‑CD40 interaction without activating platelets, and thus can be effectively used for the prevention or treatment of various T cell-mediated or antibody-mediated diseases or symptoms that require inhibition of the interaction.

Description

technical field [0001] The present disclosure relates to a polypeptide specifically binding to CD154, a pharmaceutical composition containing the polypeptide, and a method for using the polypeptide to treat diseases. Background technique [0002] Cell-mediated and humoral immune responses are generated through the interaction of activated T cells with antigen-presenting cells. T cell activation not only depends on the interaction of the antigen-specific T cell receptor (TCR) with its cognate peptide-MHC complex, but also requires the cooperative binding and activation of many cell adhesion molecules and co-stimulatory molecules. [0003] CD154 is one of such co-stimulatory molecules, and co-stimulatory signaling via such CD154 is essential for T cell activation. In addition, signaling via CD40 in conjunction with CD154 is also required for antibody production following B cell activation. Therefore, inhibition of CD154-CD40 interaction can inhibit T cell activation and anti...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K16/28C07K16/46A61K39/395
CPCA61K39/395C07K2317/24C07K2317/33C07K2317/34C07K2317/76C07K2317/92A61P7/00A61P37/06A61K2039/505C07K16/2875A61K2300/00A61K39/0008C07K16/461
Inventor 朴圣会郑景天
Owner SEOUL NAT UNIV R&DB FOUND
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