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il-17a conjugates and uses thereof

A technology of IL-17A and conjugates, applied in the application, drug combination, fusion polypeptide and other directions, can solve the problems of pathological development and deterioration of interleukin-17A, and achieve the effect of high affinity and long half-life

Active Publication Date: 2018-02-27
SHANGHAI HENGRUI PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although interleukin-17A plays a role in expanding the immune defense response and protecting the body in the process of host anti-infection and tissue repair, interleukin-17A is highly expressed in many autoimmune disease patients and tumor patients, and excessive interleukin- The level of 17A has a worsening effect on the development of pathology, because it can induce the expression of many inflammatory factors

Method used

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  • il-17a conjugates and uses thereof
  • il-17a conjugates and uses thereof
  • il-17a conjugates and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1 Mouse monoclonal antibody against human IL-17A

[0066] Monoclonal antibodies to human IL-17A (hIL-17A) were obtained as follows. 6-8 week-old female BALB / c mice (Shanghai Xipuer-Bikay Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2008-0016) and 6-8 week-old female SJL mice (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., animal production license number: SCXK (Beijing) 2012-0001) were divided into two groups of high and low doses, with 10 BALB / c mice and 10 SJL mice in each group.

[0067] The high and low dose groups were respectively immunized with a series of natural hIL-17A variants (His-hIL-17A, where hIL The amino acid sequence of -17A can be found in Genbank human IL-17A protein accession number NP-002181, and the expressed protein was purified sequentially with Ni affinity column (Superdex) 75SEC). The inoculation time was the 0th, 14th, 35th, and 56th day.

[0068] On day 0, the high-dose group re...

Embodiment 2

[0085] Example 2 Humanization of murine anti-human IL-17A antibody

[0086] The humanization of the murine anti-human IL-17A monoclonal antibody mAb049 was basically carried out according to the methods published in many documents in the field. Briefly, humanization is performed by replacing the parental (murine antibody) constant domains with human constant domains, and selecting human antibody sequences based on the homology between the murine and human antibodies.

[0087] 1. CDR region of murine anti-IL-17A antibody

[0088] The amino acid residues of VH / VL CDRs are determined and annotated by the Kabat numbering system. The CDR sequence of murine mAb049 in the present invention is described in the following table:

[0089] Table 1: CDR sequences of murine anti-IL-17A antibodies

[0090]

[0091] 2. Select human germline FR sequence

[0092] On the basis of the typical structure of the obtained murine antibody VH / VL CDR, the heavy and light chain variable region seq...

Embodiment 3

[0123] Example 3 In vivo pharmacokinetic detection of humanized anti-IL-17 antibody

[0124] Human IL-17 binds to and stimulates the mouse IL-17 receptor, leading to an increase and subsequent secretion of the KC(CXCL1) chemokine in male mice. Time and dose variation experiments were performed to identify the optimal dose of human IL-17 and the optimal timing of mouse KC induction (see Test Example 5). These experiments showed that a dose of 150 mg / kg of human IL-17 and a time period of 2 hours after IL-17 administration caused the highest levels of KC in mouse serum. The full-length antibody of the present invention was intravenously administered to mice at 3, 30, 300, or 3000 μg / kg 20 hours before subcutaneous injection of human IL-17. Two hours after human IL-17 administration, mice were sacrificed and KC levels were determined by ELISA using a commercial kit according to the manufacturer's instructions (Mouse CXCL1 / KC Quantikine ELISA Kit, R&D SYSTEM, #SMKC00B). An isoty...

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Abstract

Provided is an antibody that specifically recognizes IL-17A and can bind to IL-17A. It can be used to treat inflammatory and autoimmune diseases caused by high expression of interleukin-17A, including psoriasis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, inflammatory arthritis, etc.

Description

technical field [0001] The present invention relates to an IL-17A conjugate and its use as a therapeutic agent, especially as a therapeutic agent for various inflammatory or autoimmune diseases. Background technique [0002] The cytokines of the interleukin-17 family are named interleukin-17A to interleukin-17F, respectively. At the same time, people also found their receptor family: interleukin-17 receptor A to interleukin-17 receptor E. These interleukin-17 cytokines can bind to corresponding receptor members to mediate different inflammatory responses. [0003] The most representative member of this family is interleukin-17A. Lymphocytes that migrate to infected or injured sites in the body secrete interleukin-17A. On the one hand, interleukin-17A can induce the expression of inflammatory factors and chemokines, thereby recruiting more immune cells to reach the inflammatory site and aggravate the inflammatory response; on the other hand, interleukin-17A can also induce...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K16/24C12N15/13C12N15/63A61K39/395A61P37/02A61P19/02
CPCC07K16/248A61K2039/505C07K14/54C07K2319/00A61P17/06A61P19/02A61P25/00A61P29/00A61P37/00A61P37/02A61K39/395C07K16/244C07K2317/567C07K2317/565C07K16/24C12N15/63C07K2317/24C07K2317/51C07K2317/515C07K2317/56C07K2317/76C07K2317/92C07K2317/94
Inventor 张连山刘佳建曹国庆孙飘扬
Owner SHANGHAI HENGRUI PHARM CO LTD
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