Tethered IL-12 Polypeptide Anchoring to Reduce Systemic Toxicity

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Solution Overview

Problem

Interleukin-12 (IL-12) therapy for cancer treatment is limited by severe systemic toxicity and marginal efficacy due to strong immunosuppressive environments and adverse effects, despite its potent anti-tumor activity.

Innovation Solution

Delivery of mRNA encoding an IL-12 polypeptide that anchors IL-12 to the cell membrane, forming a tethered IL-12 polypeptide with reduced systemic distribution, maintaining bioactivity and inducing an anti-tumor immune response by increasing CD8+ T cell proliferation and IFNγ secretion.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If IL-12 is administered systemically for cancer treatment, then anti-tumor activity is improved, but systemic toxicity increases

Engineering Contradiction:

Improveanti-tumor activityVSAvoidsystemic toxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by anchoring IL-12 to the cell membrane, creating a tethered form that concentrates the cytokine at the tumor site rather than distributing it systemically. This membrane localization ensures that IL-12 exerts its anti-tumor effects primarily where needed while minimizing exposure to healthy tissues, thereby reducing systemic toxicity while maintaining anti-tumor activity

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent uses the cell membrane as an intermediary structure to deliver IL-12 locally. By tethering IL-12 to membrane anchors, the system creates a localized delivery mechanism that mediates between the need for systemic anti-tumor activity and the need to avoid systemic toxicity, allowing controlled release at the tumor site

Inventive Principle:

Principle #24Intermediary (Mediator)

2Shape

If viral vectors are used to deliver membrane-anchored IL-12, then membrane anchoring is achieved, but health risks increase due to oncogenic potential and immunogenicity

Engineering Contradiction:

Improvemembrane anchoringVSAvoidhealth risks

Core Design Contradiction:

ShapeVSObject-affected harmful factors

Solution Approach 1:

The patent replaces persistent viral vectors with transient mRNA molecules that serve as temporary templates for protein synthesis. The mRNA is translated into the membrane-anchored IL-12 protein and then degraded naturally, providing the needed membrane anchoring function without the long-term risks of viral integration or persistence. This disposable approach eliminates oncogenic potential while maintaining the desired membrane localization

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Solution Approach 2:

The patent substitutes the mechanical/biological system of viral vector delivery with an in vitro transcription system that produces mRNA. Instead of using viral machinery to deliver genetic material, the system uses biochemical synthesis to create mRNA templates that can be safely introduced into cells, replacing the problematic viral delivery mechanism with a non-infectious alternative

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Data Source

PatentUS11873327B2Polynucleotides encoding tethered interleukin-12 (IL12) polypeptides and uses thereof

Publication Date: 2024.01.16 MODERNATX INC

AI summary

The present disclosure relates to polynucleotides encoding tethered interleukin-12 (IL-12) polypeptides comprising an IL-12 polypeptide and a membrane domain. The present disclosure also relates to vectors comprising the polynucleotides; host cells comprising the polynucleotides or vectors, polypeptides encoded by the polynucleotides; compositions comprising the polynucleotides, vectors, host cells, or polypeptides and a delivery agent; and uses thereof, including treatment of cancer.