Oligonucleotides Reducing CD73 Expression via mRNA Hybridization

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Solution Overview

Problem

Current treatments for autoimmune disorders, psychiatric disorders, and cancers, particularly those involving CD73, face limitations due to low tissue penetration of monoclonal antibodies and potential incomplete inhibition of CD73's tumor-promoting functions, along with side effects from small molecule inhibitors.

Innovation Solution

Development of oligonucleotides that hybridize with CD73 mRNA or pre-mRNA, specifically modified with bridged nucleic acids, to reduce CD73 protein expression, combined with pharmaceutical compositions that include antitumor or immune-stimulating agents, to effectively inhibit CD73 activity with minimal toxic side effects.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If monoclonal antibodies are used to target CD73, then CD73 activity can be inhibited, but tissue penetration is insufficient due to large molecular size

Engineering Contradiction:

ImproveCD73 inhibition efficacyVSAvoidmolecular size

Core Design Contradiction:

ReliabilityVSLength of moving object

Solution Approach 1:

The patent segments the therapeutic approach by using smaller oligonucleotide molecules (12-20 nucleotides) instead of large monoclonal antibodies. These oligonucleotides can penetrate tissue more effectively while still achieving CD73 inhibition through hybridization with CD73 mRNA, thereby resolving the contradiction between inhibition efficacy and tissue penetration.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent replaces the mechanical binding mechanism of antibody-antigen interaction with a biochemical hybridization mechanism. Oligonucleotides hybridize with CD73 mRNA through complementary base pairing, triggering RNase H-mediated degradation. This substitution allows for smaller molecular size and better tissue penetration while maintaining therapeutic efficacy.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

2Reliability

If small molecule inhibitors are used to block CD73, then enzymatic activity can be inhibited, but additional tumor-promoting functions of CD73 may not be prevented

Engineering Contradiction:

Improveenzymatic activity inhibitionVSAvoidfunctional coverage

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies preliminary action by targeting CD73 at the mRNA level before protein synthesis occurs. By hybridizing with CD73 mRNA and triggering its degradation, the oligonucleotides prevent both enzymatic activity and other protein functions simultaneously, resolving the contradiction between enzymatic inhibition and functional coverage.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent extracts the problem of incomplete functional inhibition by acting upstream at the mRNA level rather than on the mature protein. This extraction approach allows prevention of all CD73-derived functions (enzymatic and non-enzymatic) by eliminating the mRNA template, thereby achieving comprehensive functional coverage.

Inventive Principle:

Principle #2Taking out (Extraction)

3Reliability

If oligonucleotides are used to reduce CD73 mRNA levels, then CD73 protein expression decreases, but achieving sufficient hybridization efficiency is challenging

Engineering Contradiction:

ImproveCD73 protein expression reductionVSAvoidhybridization efficiency

Core Design Contradiction:

ReliabilityVSManufacturing precision

Solution Approach 1:

The patent applies parameter changes by optimizing oligonucleotide characteristics including length (12-20 nucleotides), sequence composition, and chemical modifications. These parameter adjustments enhance hybridization efficiency and specificity while maintaining the ability to reduce CD73 protein expression effectively.

Inventive Principle:

Principle #35Parameter changes

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The oligonucleotides significantly reduce CD73 mRNA and protein levels, enhancing antitumor immune responses and preventing tumor invasion and metastasis with low toxicity, offering a promising approach for treating various disorders characterized by CD73 imbalance.

Implementation Method 1

the oligonucleotide hybridizes with a nucleic acid sequence of an ectoenzyme (NT5E or CD73) pre-mRNA

Methodology Applied

Scientific EffectHybridization:

Implementation Method 2

The modified nucleotide is for example selected from the group consisting of a bridged nucleic acid such as LNA, cET, ENA

Methodology Applied

Scientific EffectBridged nucleic acid modification:

Data Source

PatentUS20240076673A1Oligonucleotides reducing the amount of CD73 mRNA and CD73 protein expression

Publication Date: 2024.03.07 SECARNA PHARMA GMBH & CO KG

AI summary

The present invention refers to immunosuppression-reverting oligonucleotides comprising 12 to 18 nucleotides, wherein at least one of the nucleotides is modified, and the oligonucleotide hybridizes with an hybridizing active region of the nucleic acid sequence of an ectoenzyme (CD73) of SEQ ID NO.1 (human) and/or SEQ ID NO.2 (human). The invention is further directed to a pharmaceutical composition comprising such oligonucleotide. The oligonucleotide and the pharmaceutical composition are used in a method of preventing and/or treating a disorder, where a CD73 imbalance is involved.