Covalent Peptide Modulators Block HLA-E Immune Evasion

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Solution Overview

Problem

Despite existing efforts to block the inhibitory activity of CD94/NKG2A, there is a continued need for effective treatment modalities to inhibit CD94/NKG2A function in cancer.

Innovation Solution

The development of synthetic peptides and peptidomimetics that modulate the HLA-E-CD94/NKG2A interaction, specifically activating CD94/NKG2A signaling, by binding to HLA-E and preventing its interaction with the CD94/NKG2A receptor.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If HLA-E expression is increased to evade NK cell and T cell attacks, then cancer cells gain resistance to immune destruction, but the inhibitory CD94/NKG2A receptor signaling is activated which suppresses immune cell cytotoxic activity

Engineering Contradiction:

Improvecancer cell immune evasion capabilityVSAvoidinhibitory signaling to immune cells

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent extracts and blocks the harmful HLA-E-CD94/NKG2A interaction by introducing synthetic peptides that bind to HLA-E with high affinity, preventing the inhibitory signal from reaching the CD94/NKG2A receptor on NK and T cells, thereby removing the harmful inhibitory effect while preserving cancer cell HLA-E expression

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The synthetic peptides act as intermediary molecules that interfere with the direct interaction between HLA-E and CD94/NKG2A. These peptides bind to HLA-E and block the receptor binding interface, serving as a mediator that prevents the harmful signaling pathway without affecting the overall HLA-E expression on cancer cells

Inventive Principle:

Principle #24Intermediary (Mediator)

2Productivity

If CD94/NKG2A receptor blocking antibodies are used to enhance immune activity, then NK cell and T cell cytotoxicity increases, but the complexity of therapeutic modalities increases and existing treatments are insufficient

Engineering Contradiction:

Improveimmune cell cytotoxic activityVSAvoidtherapeutic modality complexity

Core Design Contradiction:

ProductivityVSDevice complexity

Solution Approach 1:

The patent changes the molecular parameters of the HLA-E binding interface by designing synthetic peptides with specific amino acid sequences and structures that optimize binding affinity and selectivity. This allows for enhanced immune activation with potentially simpler therapeutic delivery compared to full antibody modalities

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The synthetic peptides are smaller, simpler molecules compared to full antibodies, potentially allowing for easier production, faster clearance, and reduced immunogenicity. These peptide-based therapeutics represent a simplified alternative to complex antibody-based treatments while maintaining the desired immune activating function

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Data Source

PatentUS20250074942A1Compositions and methods for covalent peptide-based modulators of HLA-e

Publication Date: 2025.03.06 CALICO LIFE SCI LLC

AI summary

This disclosure relates to synthetic peptides, peptidomimetics, and complexes of synthetic peptides and peptidomimetics with HLA-E, methods of making such peptides, peptidomimetics, and complexes, and methods of using such peptides, peptidomimetics and complexes for blocking, inhibiting, or preventing the interaction of HLA-E with CD94/NKG2A or activation of CD94/NKG2A by HLA-E. The synthetic peptides, peptidomimetics, and complexes of synthetic peptides and peptidomimetics with HLA-E can further comprise warheads to introduce covalent linkages between the synthetic peptides and peptidomimetics with HLA-E.