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Anti-tigit antibodies

An antibody and antigen technology, applied in the direction of antibodies, antibody medical components, anti-tumor drugs, etc., can solve problems such as low affinity

Pending Publication Date: 2020-04-10
ITEOS BELGIUM SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

DNAM / CD226, a known co-stimulatory receptor also expressed on NK and T cells, competes with TIGIT for binding CD155 and CD112 but with lower affinity, suggesting that tight control of the activation of these effector cells avoids the risk of expressing the CD155 ligand uncontrolled cytotoxicity of normal cells

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0314] Example 1: Selection of TIGIT antigen binding protein

[0315] TIGIT ABP is selected from a synthetic library of human antibodies expressed and presented on the surface of yeast cells in the form of IgG, usually such as, for example, WO2009036379; WO2010105256; WO2012009568; and Xu et al., Protein Eng Des Sel., Vol. 26(10), No. 663 -As described on page 670 (2013), and more specifically as provided below. The sequence and characteristics of the ABP isolated from the recombinant library are provided in Figures 1 to 6.

[0316] As mentioned earlier, make eight each have ~10 9 Propagation of diverse primary human synthetic yeast libraries (see, for example, Xu et al., 2013; WO2009036379; WO2010105256 and WO2012009568). For the first two rounds of selection, as described (see, for example, Siegel et al., 2004), a magnetic bead sorting technique using the Miltenyi MACS system was performed. Simply put, the yeast cells (about ~ 10 10 Individual cells / library) were incubated with...

Embodiment 2

[0317] Example 2: Antibody optimization

[0318] Three maturation strategies were used to optimize the original clone: ​​light chain diversification; HCDR1 and HCDR2 diversification; and HCDR3 diversification in the selected HCDR1 and HCDR2 diversity pool.

[0319] Light chain diversification: Extract the heavy chain variable region from the original output (as described above) and convert it to a diversity of 1 x 10 6 The light chain library. The selection was performed as described above, and one round of MACS sorting and three rounds of FACS sorting were performed, and 10 nM or 1 nM biotinylated TIGIT-HIS antigen (Creative Biomart) was used for each round.

[0320] HCDR1 and HCDR2 selection: Recombination of HCDR3 from clones selected from the light chain diversification program to have a diversity of 1 x 10 8 Pre-made libraries of HCDR1 and HCDR2 variants, and use monomeric HIS-TIGIT antigens for selection. Affinity pressure was applied by using decreasing concentrations of biot...

Embodiment 3

[0322] Example 3: Antibody production and purification

[0323] A. Produced in yeast

[0324] In order to generate a sufficient amount of optimized and non-optimized selected antibodies for further characterization, yeast clones were grown to saturation and then induced at 30°C for 48 hours with shaking. After induction, the yeast cells were pelleted, and the supernatant was harvested for purification. The IgG was purified using a protein A column and eluted with acetic acid at pH 2.0. Fab fragments are generated by papain digestion and purified in a two-step process of protein A (GE LifeSciences) and KappaSelect (GE Healthcare LifeSciences).

[0325] B. Produced in mammalian cells

[0326] In order to generate a sufficient amount of optimized and non-optimized selected antibodies for further characterization, a DNA vector encoding a specific antibody clone is generated and transduced into HEK cells. Order human codon-optimized synthetic DNA fragments of antibody variable domains a...

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Abstract

Anti-TIGIT antibodies and antigen binding fragments thereof that inhibit TIGIT-mediated signalling are provided, together with combinations comprising said antibodies or antigen binding fragments thereof and methods for their use.

Description

Background technique [0001] Cancer immunotherapy relies on the regulation of the immune system to improve the recognition and response of tumor cells. This regulation can be achieved through various mechanisms including activation of co-stimulatory molecules present on immune cells or via inhibition of co-suppressive receptors. The activation of the immune response is a complex mechanism involving many cell populations, such as antigen-presenting cells that are important for initiating an antigen-specific response and effector cells that are responsible for destroying tumor cells. There are many mechanisms that regulate the activity of effector cells, such as cytotoxic T cells, and represent the target of choice in the context of cancer immunotherapy. [0002] TIGIT (T cell immune receptor with Ig and ITIM domains), also known as WUCAM, VSIG9 or Vstm3, is used in NK, CD8+ and CD4+ T cells and regulatory T cells (Treg cells, or “Treg” for short). ) Is preferentially expressed on ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28
CPCC07K16/2803A61K2039/505A61K2039/507C07K2317/92C07K16/2818C07K16/2878C07K2317/33C07K2317/515C07K2317/75C07K2317/76A61P35/00C07K2317/565C07K2317/24C07K2317/21Y02A50/30A61P31/12C07K16/2821C07K16/2827C07K16/4208A61K39/39541A61K45/06C07K2317/56C07K2317/94C07K2317/732
Inventor A·库珀C·奎瓦S·丹尼斯C·胡夫德J·邱恩德G·德赖森斯F·兰博莱茨
Owner ITEOS BELGIUM SA
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