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Tlr9-targeted spherical nucleic acids having potent antitumor activity

A spherical, nucleic acid-based technology, applied in the direction of anti-tumor drugs, organic active ingredients, medical preparations of non-active ingredients, etc., can solve the problems of lack of curative effect and slow down the effective clinical application of TLR7/8 and 9 agonists

Pending Publication Date: 2019-05-31
EXICURE INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, concerns about lack of efficacy, off-target phosphorothioate effects, and toxicity have slowed the effective clinical adoption of TLR 7 / 8 and 9 agonists

Method used

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  • Tlr9-targeted spherical nucleic acids having potent antitumor activity
  • Tlr9-targeted spherical nucleic acids having potent antitumor activity
  • Tlr9-targeted spherical nucleic acids having potent antitumor activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0146] Example 1. TLR9-targeting spherical nucleic acids as monotherapy and in combination with anti-PD-1 antibody in syngeneic tumors Strong antitumor activity was shown in the model

[0147] result

[0148] Experiment 1: Subcutaneous and intratumoral administration of IS-SNA (CT26 tumor)

[0149] Intratumoral administration of IS-SNA bearing CT26 tumors (approximately 100 mm in size 3 ) of Balb / c tumor-bearing mice. IS-SNA ( figure 1 ). Tumor volume was measured twice a week until the tumor size reached 2000mm 3 . The results indicated that both intratumoral and subcutaneous delivery of IS-SNA exhibited potent antitumor effects in a dose-dependent manner. The results also showed that the survival of mice increased with the dose of IS-SNA.

[0150] Subcutaneous delivery of IS-SNA ( figure 2 ) or intratumoral delivery ( image 3 ) showed a similar level of antitumor effect.

[0151] Experiment 2: Intratumoral administration of IS-SNA (MC38 tumor)

[0152] Intratu...

Embodiment 2

[0185] Example 2. Spherical nucleic acids targeting TLR9 induce immune responses in monkeys and interact with anti-PD-1 antibodies in mice antitumor immunity

[0186] Summary

[0187] The antitumor activity of TLR9 agonists has been evaluated clinically without success. Spherical nucleic acids (SNAs) are novel agents based on compact spherical arrangements of oligonucleotides on nanoparticle cores, overcoming the limitations of linear therapeutic oligonucleotides. The TLR9 agonist SNA increases in vitro cellular uptake and TLR9 activation compared to linear oligonucleotides. In vivo, SNAs induced higher TH1-type cytokines than linear oligonucleotides in both mice and monkeys. In murine tumor models, SNA inhibited tumor growth and prolonged mouse survival. The combination of SNA and anti-PD-1 enhanced the antitumor effect compared with either agent alone. Tumor tissues and draining lymph nodes of SNA-treated mice showed increased cytotoxic T cells and decreased Treg and...

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Abstract

Aspects of the invention relate to immunostimulatory spherical nucleic acids (IS- SNA) for the treatment of a disorder, such as cancer. The IS-SNA may be administered together with a checkpoint inhibitor.

Description

[0001] Associate application [0002] This application requires U.S. Provisional Application Serial No. 62 / 333,139 and 2017 April Priority to U.S. Provisional Application Serial No. 62 / 480,936, entitled "TLR-Targeting Spherical Nucleic Acids Potent Antitumor Activity," filed on March 3, which is hereby incorporated by reference in its entirety. Background of the invention [0003] The immune system is a highly evolved and exceptionally sophisticated endogenous mechanism for eliminating foreign, harmful and unnecessary substances, including pathogens and senescent or malignant host cells. It is known that it is possible to modulate the immune system for therapeutic or prophylactic purposes by introducing compounds that modulate the activity of specific immune cells. Among the immunostimulatory compounds under development, Toll-like receptor (TLR) agonists have shown outstanding potential. In some instances, TLR4 agonists such as monophosphoryl lipid A (MPL) have entered late ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/117A61K31/7088A61K31/7125A61K9/127A61K47/50A61K39/395A61P35/00C12N5/0783C12N15/11
CPCC12N15/117A61K31/7088A61K31/7125A61K9/127A61K45/00A61K47/50A61P35/00C12N2310/17C12N2320/32A61K2300/00A61K39/3955C07K16/2818C07K16/2827A61K2039/54A61K2039/545C12N2310/315C12N2310/3515C12N2310/3517C12N2310/51A61K47/6911A61K45/06C12N2320/31C12N2310/532
Inventor S·纳拉加特拉B·安德森E·坎迪马拉
Owner EXICURE INC
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