CD45KO CAR T Cells for Fratricide-Free Bone Marrow Ablation

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Solution Overview

Problem

Current hematopoietic cell transplantation (HCT) conditioning regimens are plagued by severe side effects due to myeloablative treatments, and existing CAR T cell therapies targeting CD45 face challenges such as on-target off-site toxicity and fratricide effects, limiting their efficacy and safety.

Innovation Solution

Development of CD45KO CD45-targeted CAR T cells and NK cells, where the CD45 gene is knocked out or mutated using CRISPR-Cas9 or TALEN, to reduce fratricide and enhance specificity, combined with a chimeric antigen receptor construct comprising an scFv targeting CD45, a spacer, a transmembrane domain, and a CD3 ζ signaling domain, to achieve potent antigen-specific anti-tumor efficacy and myeloid/lymphoid depletion.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional myeloablative conditioning regimens are used, then bone marrow ablation is achieved, but severe side effects and life-threatening complications occur

Engineering Contradiction:

Improveengraftment successVSAvoidsevere side effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent extracts and eliminates the harmful myeloablative conditioning step from the HCT process by using CAR T cells to selectively target and destroy bone marrow cells, achieving ablation without the severe systemic toxicity of conventional chemotherapy and radiation regimens

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent introduces CAR T cells as an intermediary agent that mediates the ablation of bone marrow cells. These engineered T cells serve as a selective delivery system that targets CD45-positive hematopoietic cells specifically, replacing the need for non-specific myeloablative agents

Inventive Principle:

Principle #24Intermediary (Mediator)

2Productivity

If CAR T cells targeting CD45 are used, then bone marrow ablation efficacy is improved, but fratricide effects occur reducing T cell survival

Engineering Contradiction:

Improvebone marrow ablation efficacyVSAvoidT cell survival

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent applies the inversion principle by knocking out the CD45 gene in the CAR T cells themselves, reversing the normal situation where T cells express CD45. This prevents the CAR T cells from being targeted by their own CD45-specific CAR, eliminating fratricide while preserving the ability to target CD45-positive tumor and bone marrow cells

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The patent converts the potentially harmful fratricide effect into a benefit by using the CD45 knockout status as a means to enhance CAR T cell persistence and functionality. The same CD45 target that causes fratricide is exploited through genetic modification to create a self-protective mechanism

Inventive Principle:

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

3Productivity

If CAR T cells targeting CD45 are used, then anti-tumor efficacy against hematopoietic malignancies is improved, but on-target off-site toxicity occurs in healthy tissues

Engineering Contradiction:

Improveanti-tumor efficacyVSAvoidon-target off-site toxicity

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by creating spatial and functional differentiation: CD45KO CAR T cells are engineered to express CD45-specific CAR only on their surface while lacking intracellular CD45 function. This allows selective targeting of CD45-positive malignant cells while preserving normal T cell function and reducing toxicity to healthy CD45-expressing tissues

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS20230338531A1Compositions and uses of CD45 targeted chimeric antigen receptor modified t cells

Publication Date: 2023.10.26 CITY OF HOPE

AI summary

Immune cells, including T cells, expressing a chimeric antigen receptor targeted to CD45 are described. In some cases, the immune cells lack a functional CD45 gene. In some cases, the immune cells also include a modification (a suicide sequence) that allows the cells to be killed in vivo. The immune cells are useful for treating a variety of cancers.