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Agents that interfere with thymic stromal lymphopoietin (TSLP) receptor signaling

A technology of lymphocytes and progenitors, applied in the direction of anti-cytokine/lymphokine/interferon immunoglobulin, medical preparations containing active ingredients, antibodies, etc., can solve problems such as contradiction discovery

Pending Publication Date: 2022-04-26
TAVOTEK BIOTHERAPEUTICS (HONG KONG) LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

TSLP in metastatic breast cancer is an area of ​​intense research, but there have been conflicting findings in mouse models and human breast tumor cell lines

Method used

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  • Agents that interfere with thymic stromal lymphopoietin (TSLP) receptor signaling
  • Agents that interfere with thymic stromal lymphopoietin (TSLP) receptor signaling
  • Agents that interfere with thymic stromal lymphopoietin (TSLP) receptor signaling

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0268] Example 1: TSLP binding affinity of mouse anti-TSLP antibody TAVO202

[0269] Through hybridoma screening, TAVO202 was identified as a mouse anti-human TSLP antibody. Binding of TAVO202 to recombinant human TSLP was assessed using an ELISA-based binding assay. In this assay, 1 μg / mL recombinant human TSLP (R&D Systems) was coated on an ELISA plate. Increasing concentrations of TAVO202 antibody were applied to the plates and their binding to recombinant human TSLP was detected by HRP-conjugated anti-mouse secondary antibody. TAVO202 was observed to bind recombinant human TSLP in a dose-dependent manner with an EC50 of 2.4 ng / mL ( figure 1 A).

[0270] Binding of TAVO202 to mouse TSLP was also assessed in a similar ELISA assay by coating the plates with mouse TSLP (R&D Systems). TAVO202 did not show significant binding affinity to mouse TSLP ( figure 1 B).

Embodiment 2

[0271] Example 2: In vitro assay for neutralization of TSLP by TAVO202

[0272] A TSLP-mediated cell proliferation assay was developed to assess the functional activity of TAVO202. In this assay, human IL-7 receptor alpha (IL-7Rα) and TSLP receptor (TSLPR) were co-transfected into BAF3 mouse progenitor B cells. Recombinant human TSLP was added to the transfected cells, and cell proliferation was quantified two days later using a cell proliferation assay. Recombinant human TSLP was observed to stimulate proliferation of transfected BAF3 cell lines in a dose-dependent manner with an EC50 of 0.18 ng / mL ( figure 2 A).

[0273] To assess the functional activity of TAVO202, increasing concentrations of TAVO202 along with 0.5 ng / mL human TSLP were applied to BAF3 cells co-transfected with IL-7Rα and TSLPR. TAVO202 was observed to dose-dependently neutralize the activity of TSLP in stimulating the proliferation of transfected BAF3 cells with an IC50 of 6.6 ng / mL ( figure 2 B). ...

Embodiment 3

[0276] Example 3: Humanization of mouse anti-human TSLP antibody TAVO202

[0277] The mouse anti-human TSLP antibody TAVO202 was humanized by grafting mouse CDRs onto human germline scaffolds. Some key mouse residues were preserved by backmutation for greater stability and better expression while minimizing immunogenicity. For TAVO202, a humanized V was designed based on IGHV1-69*02 with a pair of back mutations H variant (202H2), and two humanized Vs were designed based on IGKV1-9*01 and IGKV6-21*01, respectively L Variants (202L3 and 202L4) ( Figure 4 ). by humanized V H Variant with two humanized V L A combination of variants, by pairing the 202H2 variant with 202L3 and 202L4, respectively, generated two humanized TAVO202 antibodies with IgG2 Fc, designated TAVO6264 and TAVO6265 ( Figure 4 ). Likewise, two humanized TAVO202 antibodies with IgG1 Fc containing L234F, L235E, D265A, F405L mutations were also generated by pairing the 202H2 variant with 202L3 and 202L4, ...

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Abstract

The present disclosure relates to antibodies (e.g., human antibodies) and antigen-binding fragments thereof that specifically bind to and neutralize (human) thymic stromal lymphopoietin (TSLP). Such molecules can have modified Fc regions that have the ability to increase antibody half-life, increase resistance to proteases, and / or reduce interaction with Fc gamma receptors. These molecules are useful for the treatment of allergic and non-allergic inflammation associated with TSLP related disorders or diseases.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims the benefit of priority from US Provisional Application No. 62 / 873,051, filed July 11, 2019, which is incorporated herein by reference in its entirety. [0003] Instructions for Electronically Submitted Text Files [0004] The contents of the electronically filed text file are hereby incorporated by reference in their entirety: Sequence Listing Copied in Computer-readable Format (File Name: TABI_002_01WO_SeqList_ST25; Record Date July 3, 2020; File Size 49 Kbytes). Background technique [0005] Thymic stromal lymphopoietin (TSLP) is an interleukin 7-like cytokine that plays a key role in the regulation of immune responses and differentiation of hematopoietic cells. TSLP is widely expressed in epithelial cells of the lung, skin, and gut, Hassel bodies in the thymic medulla, mucosa-associated lymphoid tissue, and tonsils (Liu, Soumelis et al. 2007, Rochman and Leonard 2008, Sokol, Barton et al. 200...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395C07K16/24
CPCC07K16/244C07K2317/92C07K2317/76C07K2317/24C07K2317/33C07K2317/90C07K2317/524C07K2317/71C07K2317/72A61K2039/505A61P11/06A61K39/3955A61K45/06C07K2317/52C07K2317/565C07K2317/73C07K2317/94
Inventor 谭玉清张镝师丽华冯文昌
Owner TAVOTEK BIOTHERAPEUTICS (HONG KONG) LTD
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