Larazotide Derivatives Enhance Checkpoint Inhibitor Efficacy

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Solution Overview

Problem

Many patients do not respond adequately or develop resistance to immune checkpoint inhibitor therapies, such as PD-1 blockade therapy, limiting their efficacy in treating cancer.

Innovation Solution

Administering larazotide or its derivatives to enhance tight junction integrity in the intestinal epithelium, potentially potentiating the effectiveness of immune checkpoint inhibitor therapies by reducing paracellular permeability and improving the integrity of both intestinal and endothelial barriers.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If immune checkpoint inhibitor therapy is administered to treat cancer, then immune response against tumor is enhanced, but treatment efficacy is limited due to patient non-response or resistance

Engineering Contradiction:

Improvetreatment efficacyVSAvoidresponse rate variability

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

Larazotide acts as an intermediary substance that modifies the intestinal barrier function to enhance immune checkpoint inhibitor efficacy. The peptide reduces paracellular permeability in the gut, preventing leakage of bacterial products and antigens that could otherwise dampen immune responses, thereby potentiating the cancer treatment effect.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention changes the physiological parameter of intestinal permeability by administering larazotide, which tightens tight junctions between epithelial cells. This parameter change (reducing permeability) creates a more favorable condition for immune checkpoint inhibitor therapy to work effectively.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If larazotide is administered to reduce intestinal permeability, then immune checkpoint inhibitor efficacy is enhanced, but additional treatment complexity is introduced

Engineering Contradiction:

Improveimmune checkpoint inhibitor efficacyVSAvoidtreatment regimen complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

Larazotide serves as a pharmacological intermediary that addresses the underlying issue of intestinal permeability without requiring complex procedural interventions. As an orally administrable peptide, it simplifies the approach compared to more invasive barrier modification techniques.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

Larazotide is administered before or concurrently with immune checkpoint inhibitors to pre-condition the intestinal barrier. This preliminary action of tightening tight junctions prepares the physiological environment to optimize subsequent immunotherapy effectiveness.

Inventive Principle:

Principle #10Preliminary action

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

Larazotide or its derivatives, such as (d)-larazotide, enhance the efficacy of immune checkpoint inhibitor therapies by improving tumor response and overall survival in cancer patients, including those resistant to prior treatments, by maintaining a healthy gut mucosa and reducing intestinal permeability.

Implementation Method 1

Larazotide is a peptide that promotes tight junction integrity and reduces paracellullar permeability, including permeability of the intestinal epithelium

Methodology Applied

Scientific EffectTight junction integrity:

Implementation Method 2

larazotide administration, or administration of a larazotide derivative (e.g., having one or more (d)-amino acids, potentiates immune checkpoint inhibitor therapy

Methodology Applied

Scientific EffectParacellular permeability reduction:

Data Source

PatentUS11278587B2Treatment of cancer with larazotide derivatives in combination with immune checkpoint inhibitors

Publication Date: 2022.03.22 INTERLUDE BIOPHARMA CO

AI summary

The present invention provides compositions and methods for treating a patient having cancer, as well as methods for potentiating an immune checkpoint inhibitor therapy. The methods comprise administering larazotide or a derivative thereof such as (d)-larazotide to a subject in need, including subjects undergoing checkpoint inhibitor therapy, and subjects scheduled to undergo immune checkpoint inhibitor therapy.