Anti-human cxcr3 antibodies for treatment of vitiligo

A Vitiligo, C-X-C technology, applied in the direction of antibodies, immunoglobulins, anti-animal/human immunoglobulins, etc., can solve the problem that there is no treatment for vitiligo

Pending Publication Date: 2019-10-01
SANOFI SA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although it is one of the most common autoimmune diseases, affecting 1% of the

Method used

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  • Anti-human cxcr3 antibodies for treatment of vitiligo
  • Anti-human cxcr3 antibodies for treatment of vitiligo
  • Anti-human cxcr3 antibodies for treatment of vitiligo

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0293] Example 1: Generation of Humanized Anti-CXCR3 Monoclonal Antibody

[0294] Anti-CXCR3 monoclonal antibodies were generated as described in WO2013 / 109974. Humanized clone 53 monoclonal antibody was generated as described below.

[0295] A humanized version of clone 53 capable of directing depletion of CXCR3 expressing cells was prepared. A humanized clone 53 monoclonal antibody with the VH and VK sequences shown in Table 4 was generated.

[0296] Germinal Index scores for each humanized variant shown in Table 4. The heavy chain was compared to the IGHV3-23*03 / IGHJ4*03 germline sequence; the light chain was compared to the IGKV1-9*01 / IGKJ2*01 germline sequence.

[0297] Table 4

[0298] Hu antibody VH SEQ ID NO VL SEQ ID NO Hair Growth Index 1 a

Hair Growth Index 2 b

23 18 21 0.885 0.950 24 19 21 0.872 0.933 25 20 21 0.877 0.939 26 18 22 0.890 0.955 27 19 22 0.877 0.939 29 20 22 0.881 0.944 ...

Embodiment 2

[0315] Example 2: CDR optimization

[0316] Many VH CDR and / or VL CDR variants were prepared. Binding affinity to recombinant human CXCR3 was measured using Biacore. Mutants with at least as strong binding as 53Hu37 are shown in Table 3.

Embodiment 3

[0317] Example 3: CXCR3-173 is a depleting antibody

[0318] Hamster anti-mouse CXCR3 monoclonal (clone CXCR3-173) was used as a surrogate antibody in preclinical experiments. CXCR3-173 has been previously described as a blocking antibody that does not deplete CD4+ T cells in vivo. (See Uppaluri et al., Transplantation 86:137-47 (2008)).

[0319]The following Fc variants of hamster CXCR3-173 mAb were prepared to test the effector function of the antibody: aglycosylated N297G variant of mouse IgG1 (CXCR3 mIgG1 agly); wild-type mouse IgG2a chimera (CXCR3 mIgG2a WT); Modified to eliminate capacity-depleting mouse IgG2a chimera (CXCR3 mIgG2a Dab); and wild-type mouse IgG3 (CXCR3mIgG3).

[0320] C57BL / 6 mice (Jackson Laboratories, n=5 per group) aged 8 to 10 weeks were given a single 5 mg / kg intravenous dose of antibody and blood was harvested 24 hours later for flow cytometry using the following markers Cytometry analysis: CD4 and CD8 T cells by TCRab, CD4 and CD8; memory CD4 a...

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Abstract

Provided are methods and uses of anti-CXCR3 antibodies to treat CXCR3-associated disorders such as vitiligo. In certain embodiments, the anti-CXCR3 antibodies are humanized anti-human CXCR3 antibodieswith enhanced effector function against cells expressing CXCR3 on their surface.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 437,889, filed December 22, 2016, and European Patent Application No. 17306770.3, filed December 14, 2017, the entire contents of which are incorporated herein by reference. Background technique [0003] The present invention relates to antibodies and methods of using the antibodies to treat disorders associated with CXCR3 signaling, such as vitiligo. [0004] Vitiligo is a disfiguring autoimmune skin disease in which autoreactive CD8 + T cells kill melanocytes in the epidermis, causing patchy pigmentation. Although it is one of the most common autoimmune diseases, affecting 1 percent of the world's population, there are currently no FDA-approved treatments for vitiligo. [0005] C-X-C motif chemokine receptor 3 (CXCR3) is a chemokine receptor mainly expressed on antigen-experiencing T cells (memory T cells), effector T cells, and activat...

Claims

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Application Information

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IPC IPC(8): C07K16/28A61P17/00A61P37/00
CPCC07K16/2866C07K2317/24C07K2317/41C07K2317/72C07K2317/732C07K2317/734A61K2039/505A61P17/00A61P37/00C07K2317/14C07K2317/52C07K2317/56C07K2317/565C07K2317/92C07K2317/94
Inventor W·H·布龙迪克R·楚T·D·康纳斯S·帕克H·邱M·约德J·哈里斯J·里奇满
Owner SANOFI SA
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