BDCA2-Specific CAR-Engineered NK Cells for BPDCN Treatment

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Solution Overview

Problem

Current treatments for Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) are inadequate, with no uniform standard of care and existing chemotherapies leading to quick relapse, and there is a need for a more effective and safer cancer therapy targeting BDCA2-expressing cells.

Innovation Solution

Engineering NK and T cells to express a chimeric antigen receptor specific for BDCA2 (BDCA2-CAR), which allows these cells to specifically kill BDCA2-expressing cancer cells while minimizing cytokine release syndrome and toxicity, utilizing a CAR construct with an antigen binding domain, transmembrane domain, and intracellular signaling domain.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If traditional chemotherapy regimens are used for BPDCN treatment, then initial remission can be achieved, but relapse occurs quickly and survival remains poor

Engineering Contradiction:

Improvetreatment efficacyVSAvoidremission duration

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent uses CAR-engineered NK cells as an intermediary therapeutic agent that specifically targets BDCA2-expressing BPDCN cells. These engineered cells act as a mediator between the immune system and cancer cells, providing sustained anti-tumor activity without the rapid relapse seen in traditional chemotherapy. The CAR-NK cells continuously recognize and eliminate target cells, extending remission duration.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent changes the fundamental parameter of treatment mechanism from non-specific chemotherapy to highly specific CAR-mediated immunotherapy. By engineering NK cells with BDCA2-specific chimeric antigen receptors, the treatment achieves targeted killing of cancer cells while preserving normal cells, fundamentally altering the efficacy and durability parameters of BPDCN treatment.

Inventive Principle:

Principle #35Parameter changes

2Productivity

If CAR-T cell therapy is used to target BDCA2-expressing cells, then high killing efficiency is achieved, but cytokine release syndrome and toxicity increase

Engineering Contradiction:

Improvekilling efficiencyVSAvoidcytokine release syndrome

Core Design Contradiction:

ProductivityVSObject-generated harmful factors

Solution Approach 1:

The patent employs NK cells instead of T cells as the carrier for CAR therapy. NK cells are shorter-lived and naturally undergo apoptosis after their effector function is completed, making them a 'short-living' therapeutic agent. This reduces the duration of cytokine production and lowers the risk of prolonged cytokine release syndrome and chronic toxicity compared to CAR-T cells.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Solution Approach 2:

The patent converts the potential harm of excessive cytokine production by using NK cells that have more controlled cytokine release profiles compared to T cells. The shorter lifespan of NK cells transforms what could be a harmful prolonged immune activation into a beneficial self-limiting therapy that achieves tumor killing while minimizing severe adverse events.

Inventive Principle:

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

3Reliability

If chemotherapy is used for BPDCN treatment, then initial remission can be achieved, but treatment safety and long-term survival are compromised

Engineering Contradiction:

Improveremission achievementVSAvoidtreatment toxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies the principle of local quality by engineering CAR receptors with specific affinity for BDCA2 antigen on cancer cells. This creates a localized and specific therapeutic action at the tumor site while sparing normal tissues. The CAR-NK cells concentrate their killing activity where the antigen is present, achieving remission with minimal systemic toxicity compared to traditional chemotherapy.

Inventive Principle:

Principle #3Local quality

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 engineered BDCA2-CAR NK and T cells effectively target and kill BDCA2-expressing cancer cells with high efficiency, reducing toxicity and cytokine release, offering a potentially safer and more effective treatment option for BPDCN compared to traditional CAR-T cell therapies.

Implementation Method 1

engineered NK and T cells expressing a chimeric antigen receptor that is specific for the antigen BDCA2

Methodology Applied

Scientific EffectAntigen-antibody binding:

Implementation Method 2

the engineered CAR-NK and -T cells can specifically kill BDCA2 expressing cells, which are highly resistant to their natural killing, with high efficiency

Methodology Applied

Scientific EffectCytotoxic cell killing:

Implementation Method 3

the BDCA2-CAR NK cells secrete less cytokines than CAR T cells indicating less cytokine release syndrome (CRS) in a subject to be treated with such cells

Methodology Applied

Scientific EffectCytokine secretion:

Data Source

PatentUS11701387B2Chimeric antigen receptor specific for BDCA2 antigen

Publication Date: 2023.07.18 MILTENYI BIOTEC BV & CO KG

AI summary

The present invention discloses a chimeric antigen receptor (CAR) comprising an antigen binding domain specific for BDCA2, a population of engineered cells expressing said CAR and a pharmaceutical composition thereof. Said engineered cells are for treatment of cancer in a subject, wherein the cancerous cells of said cancer express BDCA2 such as Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN).