Neo-2/15 Mutant Polypeptides for Selective Treg Stimulation

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Solution Overview

Problem

Existing therapies for expanding T-regulatory cells (Tregs) are limited by the concomitant stimulation of conventional T cells and natural killer cells, necessitating the development of new approaches that selectively stimulate Tregs without activating these cells.

Innovation Solution

The use of Neo-2/15 mutants, which are computationally designed to attenuate binding to the medium affinity IL-2 receptor, coupled with a targeting agent to specifically stimulate T-regulatory cells, creating potent selective T-regulatory cell agonists (TRAs) that preferentially activate Tregs over non-Tregs.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If low dose IL-2 therapy is used to expand Tregs, then Treg expansion is achieved, but conventional T cells and natural killer cells are also stimulated

Engineering Contradiction:

ImproveTreg cell expansionVSAvoidconcomitant stimulation of conventional T cells and NK cells

Core Design Contradiction:

Quantity of substanceVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by engineering specific amino acid substitutions in the Neo-2/15 mutant (positions 15, 40, 44, and 95) to create differential binding affinities. These localized changes in protein structure result in selective stimulation of Tregs versus conventional T cells and NK cells, achieving cell-type-specific effects through precise molecular modifications

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by modifying the amino acid sequence parameters of the Neo-2/15 mutant to alter its binding characteristics. The specific substitutions (D15S/A, N40S/A/G, I44S/A/N/T/Y, Q95K/R/T/S/Y/E/A/H) change the molecular parameters of receptor interaction, enabling selective activation of Tregs while avoiding activation of other cell types

Inventive Principle:

Principle #35Parameter changes

2Reliability

If conventional T cell stimulation is avoided, then selective Treg activation is achieved, but therapeutic efficacy for autoimmune conditions may be reduced

Engineering Contradiction:

Improveselectivity of Treg activationVSAvoidtherapeutic efficacy

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The Neo-2/15 mutant acts as an intermediary molecule that selectively bridges the gap between IL-2 signaling and Treg activation. By engineering specific binding properties, it mediates Treg stimulation while excluding conventional T cells and NK cells from activation, thus maintaining selectivity without compromising therapeutic potential

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20250361308A1NEO-2/15 Variants and Uses Thereof for Preferentially Stimulating T-Regulatory Cells

Publication Date: 2025.11.27 NEUROGENE INC

AI summary

Provided herein are polypeptides comprising a Neo-2/15 mutant, polypeptides comprising a Neo-2/15 mutant and an agent for targeting T-regulatory cells, and methods of their use for treating disease. Related nucleic acids, vectors, host cells, pharmaceutical compositions and kits are also providing. Methods of making the polypeptides, as well as methods of treating a subject in need thereof are also provided, as well as CD25 antigen binding proteins.