Humanized Anti-CD19 CAR for T Cell Persistence and Reduced Toxicity

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Solution Overview

Problem

Current anti-CD19 CAR therapies face challenges with T cells not surviving and remaining active in vivo for a long duration, and the risk of generating human anti-mouse immune responses leading to toxicity.

Innovation Solution

A humanized chimeric antigen receptor (CAR) with a optimized anti-CD19 binding domain, comprising a single chain antibody fragment with humanized framework regions and complementarity determining regions, linked to a hinge, transmembrane, and cytoplasmic domain including 4-1BB and CD3ζ signaling domains.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current anti-CD19 CAR therapies are used, then tumor targeting capability is achieved, but T cell survival and persistence in vivo is reduced

Engineering Contradiction:

Improvetumor targeting capabilityVSAvoidT cell survival and persistence

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent applies parameter changes by modifying the CAR structure to include a humanized scFv binding domain with optimized framework regions and CDRs, changing the molecular parameters of the antigen-binding component to improve T cell persistence while maintaining tumor targeting capability

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention uses composite materials by creating a chimeric structure that combines humanized antibody components (scFv with human framework regions and CDRs) with T cell signaling domains (CD3ζ and 4-1BB), forming a composite receptor that integrates antigen recognition with enhanced survival signaling

Inventive Principle:

Principle #40Composite materials

2Reliability

If current anti-CD19 CAR therapies are used, then tumor targeting is achieved, but human anti-mouse immune responses are generated leading to toxicity

Engineering Contradiction:

Improvetumor targetingVSAvoidhuman anti-mouse immune responses and toxicity

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent converts the harm of immunogenicity into a benefit by humanizing the scFv domain, which reduces the immune response against the CAR itself, thereby allowing the therapeutic to persist longer and work more effectively without being neutralized by human anti-mouse antibodies

Inventive Principle:

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

Solution Approach 2:

The invention changes the species origin parameter of the binding domain from mouse to humanized, substituting human framework regions and optimizing CDRs to reduce immunogenicity while preserving antigen-binding function

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS12331114B2Humanized anti-CD19 chimeric antigen receptor, its nucleic acid sequence and its preparation

Publication Date: 2025.06.17 INDIAN INSTITUTE OF TECHNOLOGY BOMBAY

AI summary

The present invention relates to novel humanized anti-CD19chimeric antigen receptor containing an optimized anti-CD19 binding domain effective against the treatment of disease associated with expression of the Cluster of Differentiation 19 protein (CD19), and to a nucleic acid molecule encoding the humanized CAR. The invention also encompasses a process forth preparation of the CAR, composition containing the CAR, vectors containing the polynucleotide encoding the CAR and cells expressing the Carat their surface, in particular for their use in immunotherapy.