CAAR T Cells Targeting Autoreactive B Cells

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Solution Overview

Problem

Current therapies for autoimmune diseases like pemphigus vulgaris are non-specific, leading to severe side effects such as fatal infections and secondary cancers due to general immune suppression, as they target all B cells rather than just autoreactive B cells.

Innovation Solution

Development of a chimeric autoantibody receptor (CAAR) specific for autoantibodies, comprising an extracellular domain of autoantigens like desmoglein 3, a transmembrane domain, and an intracellular signaling domain, which is expressed on genetically modified T cells to selectively target and kill autoreactive B cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If general immune suppression therapy is used to treat autoimmune diseases, then the autoimmune symptoms are reduced, but the risk of fatal infections and secondary cancers increases

Engineering Contradiction:

Improvetreatment efficacyVSAvoidinfection risk and cancer risk

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The therapy segments the B cell population by using a chimeric receptor that specifically recognizes autoantibodies on autoreactive B cells, allowing selective targeting of pathogenic cells while preserving non-autoreactive B cells that provide protective immunity

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The chimeric receptor confers localized specificity to T cells, enabling them to distinguish and attack only autoreactive B cells expressing specific autoantibodies rather than suppressing all B cells uniformly

Inventive Principle:

Principle #3Local quality

2Reliability

If rituximab is used to deplete B cells, then pemphigus symptoms improve with high healing rate, but relapse occurs in greater than 80% of patients and serious infections occur in 7% of patients

Engineering Contradiction:

Improvehealing rateVSAvoidrelapse resistance and infection resistance

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The chimeric receptor therapy segments the B cell population by specifically targeting autoreactive B cells through autoantibody recognition, achieving B cell depletion efficacy while preserving non-autoreactive B cells to prevent relapse and infection

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The chimeric receptor creates a feedback mechanism where T cells continuously monitor for and eliminate autoreactive B cells that express target autoantibodies, providing sustained protection against relapse without requiring continuous broad immune suppression

Inventive Principle:

Principle #23Feedback

3Reliability

If non-specific lymphocyte proliferation inhibition is used, then autoimmune disease symptoms are controlled, but off-target toxicity and side effects increase

Engineering Contradiction:

Improvedisease controlVSAvoidoff-target toxicity

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The chimeric receptor introduces local quality to T cell activity by equipping them with specific recognition capability for autoantibodies, enabling precise targeting of autoreactive B cells while leaving other lymphocyte populations and normal B cell functions unaffected

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS20230303653A1Compositions and methods of chimeric autoantibody receptor t cells

Publication Date: 2023.09.28 THE TRUSTEES OF THE UNIV OF PENNSYLVANIA

AI summary

The invention includes compositions comprising at least one chimeric autoantibody receptor (CAAR) specific for an autoantibody, vectors comprising the same, compositions comprising CAAR vectors packaged in viral particles, and recombinant T cells comprising the CAAR. The invention also includes methods of making a genetically modified T cell expressing a CAAR (CAART) wherein the expressed CAAR comprises a desmoglein extracellular domain.