SLAMF6 Splice-Switching Oligonucleotides for T Cell Anti-Tumor Immunity

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Solution Overview

Problem

Existing therapies for modulating SLAMF6 isoforms in cancer treatment are ineffective in enhancing anti-tumor immunity and often result in detrimental effects, such as reduced cytotoxic activity.

Innovation Solution

Development of splice-switching antisense oligonucleotides (ASOs) that specifically target and modulate the expression of SLAMF6 isoforms, particularly enhancing SLAMF6var3 expression while reducing SLAMF6var1, thereby improving T cell functionality and anti-tumor immunity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing therapies are used to modulate SLAMF6 isoforms, then treatment is administered, but anti-tumor immunity is not enhanced and cytotoxic activity is reduced

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidreduced cytotoxic activity

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The therapy segments the SLAMF6 isoform modulation by using specific antisense oligonucleotides that selectively target different isoforms (SLAMF6var1, SLAMF6var2, SLAMF6var3) at different stages of the splicing process. This allows differential modulation of isoform expression to achieve enhanced anti-tumor immunity while preserving cytotoxic activity.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention inverts the conventional approach by using antisense oligonucleotides to block the production of dominant-negative isoforms (SLAMF6var1 and SLAMF6var2) that suppress anti-tumor immunity, rather than attempting to directly enhance the protective isoform SLAMF6var3. This inversion strategy reverses the harmful effect and restores cytotoxic activity.

Inventive Principle:

Principle #13The other way round (Inversion)

2Reliability

If SLAMF6 isoforms are modulated to enhance anti-tumor immunity, then T cell responsiveness improves, but existing methods fail to achieve specific isoform modulation

Engineering Contradiction:

Improveanti-tumor immunityVSAvoidisoform expression control

Core Design Contradiction:

ReliabilityVSManufacturing precision

Solution Approach 1:

The invention applies preliminary action by using antisense oligonucleotides that bind to pre-mRNA transcripts of SLAMF6 isoforms during the splicing process, preventing the formation of dominant-negative isoforms before they can be translated. This preliminary intervention at the RNA level ensures precise control over which isoforms are expressed, achieving the desired T cell responsiveness enhancement.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The antisense oligonucleotides serve as intermediaries that mediate between the therapeutic goal (enhancing anti-tumor immunity) and the molecular target (SLAMF6 isoforms). These oligonucleotides specifically bind to pre-mRNA sequences, acting as mediators that redirect splicing outcomes to favor protective isoforms while blocking dominant-negative isoforms, thereby achieving precise isoform expression control.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Ease of operation

If conventional SLAMF6 modulation approaches are used, then treatment is provided, but detrimental effects occur including reduced cytotoxic activity

Engineering Contradiction:

Improvetreatment administrationVSAvoiddetrimental effects

Core Design Contradiction:

Ease of operationVSObject-generated harmful factors

Solution Approach 1:

The invention converts the harmful effect of dominant-negative SLAMF6 isoforms (SLAMF6var1 and SLAMF6var2) into a benefit by using antisense oligonucleotides to specifically block their production. By targeting and suppressing these harmful isoforms, the therapy transforms the problematic isoform expression pattern into a therapeutic advantage, enhancing anti-tumor immunity while preserving cytotoxic activity.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

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 ASOs enhance T cell responsiveness to activation stimuli, increase IL-2 secretion, and significantly reduce tumor load in melanoma models, demonstrating improved therapeutic efficacy in cancer treatment.

Implementation Method 1

antisense oligonucleotides (ASOs), including splice-switching oligonucleotides (SSOs)... specifically hybridizable with a nucleic acid target... modulating the relative expression levels of SLAMF6 isoforms

Methodology Applied

Scientific EffectHybridization:

Data Source

PatentUS12576100B2Nucleic acid agents modulating SLAMF6 isoforms

Publication Date: 2026.03.17 HADASIT MEDICAL RESEARCH SERVICES & DEVELOPMENT LTD

AI summary

The invention relates to nucleic acid agents modulating the expression of SLAMF6 isoforms, compositions comprising same and methods for their use in immunomodulation. Specifically, provided are splice-switching oligonucleotides and constructs useful in cancer immunotherapy.