Modified PPE Proteins With Reduced A1AT Binding for Cancer Cell Killing

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Solution Overview

Problem

Existing cancer treatments, such as radiation and chemotherapy, lack the specificity to effectively target cancer cells without harming healthy cells, necessitating the development of enzymes with selective cancer cell-toxicity.

Innovation Solution

Modified porcine pancreatic elastase (PPE) proteins with specific amino acid alterations, such as Q211F, T55A, D74A, R75A, R75E, S214A, R237A, N241A, and N241Y, which reduce binding to alpha-1 antitrypsin and enhance cancer cell-killing activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If wild-type PPE protein is used, then it has natural binding affinity to alpha-1 antitrypsin, but its cancer cell-killing activity is limited

Engineering Contradiction:

Improvecancer cell-killing activityVSAvoidbinding to alpha-1 antitrypsin inhibitor

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies parameter changes by modifying specific amino acid residues (Q211, T55, D74, R75, S214, R237, N241) in the PPE protein sequence to alter its binding parameters with alpha-1 antitrypsin, thereby changing the enzyme's activity profile to favor cancer cell killing while reducing inhibitor binding

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent applies local quality by making targeted amino acid substitutions at specific positions (Q211F, T55A, D74A, R75A, R75E, S214A, R237A, N241A, N241Y) within the PPE protein structure, where each local modification is designed to specifically reduce binding to alpha-1 antitrypsin while preserving or enhancing cancer cell-killing activity

Inventive Principle:

Principle #3Local quality

2Productivity

If radiation and chemotherapy are used, then they can kill many cancer cells, but they also cause cytotoxic effects on healthy cells

Engineering Contradiction:

Improvecancer cell killing efficiencyVSAvoidside effects on healthy cells

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The modified PPE proteins exhibit local quality by being selectively toxic to cancer cells through specific amino acid alterations that enhance their ability to target and kill cancer cells while sparing healthy cells, providing localized therapeutic action rather than systemic cytotoxicity

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent converts the natural binding affinity of PPE to alpha-1 antitrypsin (which limits its efficacy) into a benefit by identifying and modifying the specific residues responsible for this binding, thereby transforming the enzyme's natural properties into enhanced anti-cancer activity with reduced side effects

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 modified PPE proteins demonstrate increased cancer cell-killing activity, up to 1000-fold higher than wild-type PPE, with reduced binding to alpha-1 antitrypsin, leading to effective tumor regression and decreased tumor mass.

Implementation Method 1

at least one amino acid alteration that reduces binding to serine protease inhibitors such as alpha-1 antitrypsin (A1AT)

Methodology Applied

Scientific EffectProtein-protein binding interaction:

Data Source

PatentUS12516307B2Modified porcine pancreatic elastase proteins

Publication Date: 2026.01.06 ONCHILLES PHARMA INC

AI summary

Provided are modified porcine pancreatic elastase (PPE) proteins, including proproteins, comprising at least one amino acid alteration that reduces binding to serine protease inhibitors such as alpha-1 antitrypsin (A1AT), thereby increasing cancer-cell killing activity, and related pharmaceutical compositions and methods of use for treating diseases such as cancers.