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Receptor selective retinoid and rexinoid compounds and immune modulators for cancer immunotherapy

A technology of retinol and flavonol, applied in immunoglobulin, anti-animal/human immunoglobulin, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, etc., can solve problems such as limiting activity

Active Publication Date: 2019-02-05
IO THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0001]The immune surveillance system provides host defense against foreign antigens but also limits activity against self-antigens, thereby preventing autoimmune disease

Method used

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  • Receptor selective retinoid and rexinoid compounds and immune modulators for cancer immunotherapy
  • Receptor selective retinoid and rexinoid compounds and immune modulators for cancer immunotherapy
  • Receptor selective retinoid and rexinoid compounds and immune modulators for cancer immunotherapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0113] RARα signaling induces Foxp3 expression

[0114] It is important to determine which RAR (RARα, RARβ, RARγ) signaling pathway is important in the induction of Foxp3 expression. To determine this, use flow cytometry through GFP-based - Phenotype sorting and isolation Purification of original CD4 from Foxp3-GFP mice + CD25 - FoxP3 - cell. In the presence of IL-2 and TGF-β, these cells are polyclonally activated with αCD3 in vitro. To identify RARs involved in RA-induced Foxp3 expression, cultured cells were incubated with RAR selective agonists. Then evaluate GFP on cultured cells + (Foxp3 + )Frequency of. Regarding the use of selective agonists, only RARα agonists have a significant effect on the expression of Foxp3, inducing almost 100% Foxp3+ T cells, and enhancing the expression of α4β7 and CCR9 (intestinal homing receptor) (Figure 1). RARγ and RARβ agonists have no effect. These results indicate that RARα selective agonists can be used to reduce symptoms of inflammat...

Embodiment 2

[0116] Compound 5183 is specific for RARα

[0117] In order to determine whether a compound having the structure of Formula I is a RARα selective agonist, a displacement assay was used to test the ability of compound 5183 to bind to RARα, RARβ and RARγ to measure agonist binding affinity and a transactivation assay to measure agonist activity. These results indicate that compound 5183 selectively binds RARα with high affinity (Table 1) and specifically activates RARα ( figure 2 ). This RARα selective agonist can minimize the side effects associated with pan-activation, including mucosal skin toxicity, headaches and pro-inflammatory events in clinical studies.

[0118] Table 1 The binding affinity of 5183 to RARα, RARβ and RARγ

[0119] RARα

Embodiment 3

[0121] RARα selective agonists regulate T cell differentiation

[0122] In order to determine whether RARα selective agonists can affect T cell differentiation, T cells were incubated with RARα selective agonists to determine its effect on Foxp3 expression. Purification of primary CD4 from Foxp3-GFP mice by GFP-based phenotype sorting and separation using flow cytometry + CD25 - FoxP3 - cell. In the presence of IL-2 and TGF-β, these cells are polyclonally activated with αCD3 in vitro. These cells were then cultured in a medium containing various concentrations of compound 5183 (RARα selective agonist), and the expression of FoxP3-GFP was analyzed by flow cytometry. The RARα selective agonist compound 5183 enhanced the differentiation of immunosuppressive Treg cells and inhibited the differentiation of naive T cells into inflammatory TH17 cells in vitro (Table 2).

[0123] Table 2 Effects of RARα agonists on T cell differentiation

[0124]

[0125] In order to expand the above find...

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Abstract

Disclosed herein are methods for treating cancer comprising administering at least one immune checkpoint inhibitor and at least one Retinoic Acid Receptor or Retinoid X Receptor active agent.

Description

Background technique [0001] The immune surveillance system provides the host with defense against foreign antigens, but also limits the activity against self-antigens, thereby preventing autoimmune diseases. Cell surface immune checkpoint molecules are endogenous regulators of immune response, which limit autoimmunity by enabling co-suppressive signal transduction pathways. The immune checkpoint pathway is important in tumor growth, which results in the depletion of T cells and allows the tumor to evade immune surveillance and allows uncontrolled tumor growth. Molecules such as monoclonal antibodies (mAbs) can be designed to target immune checkpoints, and such molecules can antagonize co-suppressive immune pathways, restore immune surveillance and generate anti-tumor immune responses. [0002] In addition, the full anti-tumor effect of immunotherapy can only be obtained when they are used in combination with other compounds that can overcome the development of resistance to immun...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395C07K16/28C07K16/30
CPCA61K39/39541A61K31/192A61K31/352A61K31/382A61K31/505A61K31/5513A61K45/06C07K16/2818C07K2317/76A61P35/00A61K2300/00A61K31/196A61K2039/505A61K39/3955C07K16/30A61K31/4436
Inventor 罗山赛·A·钱德拉拉特纳马丁·E·桑德斯
Owner IO THERAPEUTICS
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