NKG2A and PD-1 Dual Blockade for Tumor-Infiltrating Lymphocytes

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Solution Overview

Problem

Existing cancer treatments using PD-1 inhibitors do not effectively target all patients, and some experience relapse due to the upregulation of NKG2A receptors on tumor-infiltrating lymphocytes, limiting the efficacy of PD-1 axis blockade.

Innovation Solution

Combining NKG2A-neutralizing antibodies with PD-1 neutralizing antibodies to simultaneously inhibit the inhibitory activities of both receptors in tumor-infiltrating lymphocytes, enhancing their cytotoxic capabilities.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If PD-1 neutralizing antibodies are used to block the PD-1 axis, then anti-tumor immune response is enhanced, but NKG2A receptor upregulation occurs on tumor-infiltrating lymphocytes, limiting the efficacy of continued PD-1 axis blockade

Engineering Contradiction:

Improveefficacy of PD-1 axis blockadeVSAvoidNKG2A receptor upregulation

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent segments the immune checkpoint inhibition strategy into two distinct components: PD-1 axis blockade and NKG2A blockade. By targeting two separate inhibitory pathways independently, the treatment prevents the compensatory upregulation mechanism that limits single-pathway blockade efficacy.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent combines PD-1 neutralizing antibodies with NKG2A-neutralizing antibodies into a dual-blockade regimen. This merging of two therapeutic approaches synergistically enhances anti-tumor immune responses while overcoming the adaptive resistance mechanism of NKG2A upregulation.

Inventive Principle:

Principle #5Merging (Combining)

2Productivity

If NKG2A-neutralizing antibodies are used alone, then lymphocyte cytotoxic activity towards HLA-E positive target cells is increased, but the effect is limited by PD-1-mediated immune suppression

Engineering Contradiction:

Improvecytotoxic activity of lymphocytesVSAvoidPD-1-mediated immune suppression

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent converts the harmful PD-1-mediated immune suppression into a benefit by simultaneously blocking both PD-1 and NKG2A pathways. The compensatory NKG2A upregulation that initially limits PD-1 blockade efficacy is transformed into a target for additional therapeutic benefit when combined blockade is implemented.

Inventive Principle:

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

3Reliability

If combination therapy with NKG2A and PD-1 neutralizing antibodies is implemented, then anti-tumor immune response is significantly enhanced, but treatment complexity increases

Engineering Contradiction:

Improveanti-tumor immune responseVSAvoidtreatment regimen complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent employs two monoclonal antibodies that each perform multiple functions: PD-1 neutralizing antibodies block both PD-1/PD-L1 and PD-1/PD-L2 interactions, while NKG2A-neutralizing antibodies block the NKG2A/HLA-E interaction. This multi-functionality justifies the combination approach by addressing multiple inhibitory pathways with targeted agents.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentEP3799885B1Neutralization of inhibitory pathways in lymphocytes

Publication Date: 2025.08.13 INNATE PHARMA SA

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AI summary

The present invention relates to methods for the treatment, prevention and diagnostic of diseases using compounds that specifically bind and inhibit human NKG2A in combination with compounds that bind and inhibit human PD-1. The invention also relates to assays to identify NKG2A+PD1 + tumor infiltrating NK and/or CD8 T cells.