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Humanized cxcr3 antibodies with depleting activity and methods of use thereof

A humanization, antibody technology, applied in chemical instruments and methods, medical preparations containing active ingredients, antibodies, etc.

Inactive Publication Date: 2020-03-24
SANOFI SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, T1D has a significant chronic disease burden and remains a major public health problem worldwide

Method used

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  • Humanized cxcr3 antibodies with depleting activity and methods of use thereof
  • Humanized cxcr3 antibodies with depleting activity and methods of use thereof
  • Humanized cxcr3 antibodies with depleting activity and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0300] Example 1: Generation of Humanized Anti-CXCR3 Monoclonal Antibody

[0301] Anti-CXCR3 monoclonal antibodies were generated as described in WO2013 / 109974. Humanized clone 53 monoclonal antibody was generated as described below.

[0302] 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.

[0303] 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.

[0304] Table 4

[0305] 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

[0321] Example 2: CDR optimization

[0322] 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

[0323] Example 3: CXCR3-173 is a depleting antibody

[0324] 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)).

[0325] 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).

[0326] 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 were analyzed by TCRab, CD4 and CD...

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Abstract

Provided are humanized CXCR3 antibodies and methods of using the antibodies to treat CXCR3-associated disorders such as type 1 diabetes mellitus (TID), particularly new-onset TID, and psoriasis. In certain embodiments, the anti-CXCR3 antibodies are humanized anti-human CXCR3 antibodies with enhanced effector function against cells expressing CXCR3 on their surface. Also provided are nucleic acid sequences encoding the antibodies, and pharmaceutical compositions comprising the antibodies.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 437,867, filed December 22, 2016, and European Patent Application No. 17305042.8, filed January 21, 2017, the entire contents of which are incorporated herein by reference. technical field [0003] Provided are humanized anti-CXCR3 antibodies and methods of using the antibodies to treat disorders associated with CXCR3 signaling, such as type 1 diabetes (diabetes mellitus type 1 / type 1 diabetes mellitus (T1D)) and psoriasis. Background technique [0004] Type 1 diabetes is characterized by the inability to produce sufficient insulin to maintain glucose homeostasis. This disorder is thought to result from autoimmune-mediated destruction of pancreatic beta cells. Autoimmunity associated with type 1 diabetes involves the involvement of B and T autoreactive lymphocytes. The development of type 1 diabetes may be mediated by autoreactive T cel...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28A61P37/06
CPCC07K16/2866A61K2039/505C07K2317/14C07K2317/24C07K2317/41C07K2317/52C07K2317/524C07K2317/56C07K2317/565C07K2317/72C07K2317/73C07K2317/76C07K2317/90C07K2317/92C07K2317/94A61P37/06A61P17/06A61P3/10A61K38/195C07K2317/732A61K39/395
Inventor W·布朗迪克R·丘T·D·康纳斯S·帕克H·邱M·尤德
Owner SANOFI SA
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