Modified NK Cells Enhancing ADCC and Homing via CD16V158 and CCR7

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Solution Overview

Problem

Existing methods for expanding NK cells for cancer immunotherapy often result in phenotypic changes that compromise their homing capacity and cytotoxic function, and genetic manipulation using viral transduction is challenging due to low transduction efficiency and viability issues.

Innovation Solution

Modified NK cells are produced by transfecting NK cells with heterologous nucleic acid molecules encoding CD16 protein with a valine at amino acid position 158 and/or CCR7 protein, using mRNA electroporation to enhance their viability, cytotoxicity, and homing ability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If NK cells are expanded in vitro for immunotherapy, then large numbers of clinical grade NK cells can be obtained, but phenotypic changes occur that compromise homing capacity and cytotoxic function

Engineering Contradiction:

Improvenumber of NK cellsVSAvoidhoming capacity and cytotoxic function

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The patent modifies specific parameters of NK cells by introducing transgenes (CD16V158, CCR7, NKG2D) that change their phenotypic characteristics. This allows the cells to maintain their cytotoxic function and homing capacity even after in vitro expansion, resolving the contradiction between obtaining large numbers of cells and preserving their functional reliability.

Inventive Principle:

Principle #35Parameter changes

2Adaptability or versatility

If viral transduction is used to introduce genes into NK cells, then genetic modification can be achieved, but transduction efficiency is low and NK cell viability is substantially reduced

Engineering Contradiction:

Improvegenetic modification capabilityVSAvoidNK cell viability

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent replaces viral transduction mechanisms with non-viral methods including electroporation, nucleofection, and lipid-based transfection. These alternative mechanisms achieve successful gene introduction without the harmful effects of viral infection, thereby maintaining high NK cell viability while still achieving genetic modification.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Solution Approach 2:

The patent changes the method parameters from viral-based to non-viral-based transfection approaches. This parameter change in the transduction method eliminates the viability loss associated with viral infection while maintaining the ability to introduce therapeutic genes into NK cells.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If NK cells are genetically manipulated to improve in vivo viability and cytotoxicity, then therapeutic efficacy is enhanced, but the complexity of the modification process increases

Engineering Contradiction:

Improvein vivo viability and cytotoxicityVSAvoidgenetic manipulation process

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent introduces specific genetic parameters (transgenes for CD16V158, CCR7, NKG2D) that can be independently optimized to improve viability and cytotoxicity. By focusing on these specific parameters rather than complex multi-gene modifications, the process remains manageable while achieving the desired therapeutic enhancement.

Inventive Principle:

Principle #35Parameter changes

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 NK cells demonstrate improved transgene expression, viability, proliferative capacity, and cytotoxic function, enabling enhanced tumor targeting and antibody-dependent cellular cytotoxicity (ADCC) without major negative effects on the NK cell population.

Implementation Method 1

transfecting the population of NK cells with a heterologous nucleic acid molecule encoding a CD16 protein comprising a valine at amino acid position 158, a heterologous nucleic acid molecule encoding a CCR7 protein

Methodology Applied

Scientific EffectGene expression:

Implementation Method 2

the population of NK cells are expanded in vitro prior to transfection with the nucleic acid molecule

Methodology Applied

Scientific EffectElectroporation:

Data Source

PatentUS20250136940A1NK cells with an increased antibody-dependent cellular toxicity (ADCC) against tumors

Publication Date: 2025.05.01 THE GOVERNMENT OF THE UNITED STATES OF AMERICA AS REPRESENTED BY THE SECRETARY DEPARTMENT OF HEALTH & HUMAN SERVICES

AI summary

Disclosed herein are modified NK cells, compositions comprising modified NK cells, and methods for treating a tumor or hyperproliferative disease in a subject. In some embodiments, the modified NK cells include NK cells including a heterologous nucleic acid molecule encoding a CD16 protein comprising a valine at amino acid position 158 (CD16-V158), a heterologous nucleic acid molecule encoding a CCR7 protein, or both. In some embodiments, methods include treating a subject with a tumor by administering a composition comprising an anti-cancer monoclonal antibody and administering a composition comprising the modified NK cells to the subject. Also disclosed are methods of making modified NK cells by obtaining a population of NK cells from a subject and transfecting the population of NK cells with a heterologous nucleic acid molecule encoding CD16-V158, a heterologous nucleic acid molecule encoding a CCR7 protein, or both.