CD33 Exon 2 Deficient Stem Cells for Targeted Immunotherapy

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Solution Overview

Problem

Current immunotherapies for cancer, particularly those targeting CD33, face challenges in distinguishing between cancer cells and normal hematopoietic cells, leading to poor treatment outcomes for hematopoietic malignancies like acute myeloid leukemia, especially in older patients who cannot undergo intensive chemotherapy.

Innovation Solution

Administering an agent targeting CD33 along with genetically engineered hematopoietic cells that are deficient in CD33, using CRISPR-Cas9 to mutate or delete exon 2 of the CD33 gene, allowing these cells to evade cell death caused by the agent, thereby selectively targeting and killing cancer cells while sparing normal cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If CD33 targeting agents are administered to treat hematopoietic malignancies, then cancer cells expressing CD33 are killed, but normal hematopoietic cells are also damaged leading to poor treatment outcomes

Engineering Contradiction:

Improvetreatment efficacyVSAvoidtoxicity to normal hematopoietic cells

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The invention segments the patient's hematopoietic system into two distinct populations: (1) engineered CD33-deficient hematopoietic stem cells that are resistant to the targeting agent and can repopulate the bone marrow, and (2) endogenous CD33-expressing cells (including cancer cells) that remain targets for the therapy. This segmentation allows selective elimination of cancer cells while preserving and regenerating normal hematopoietic cells through the engineered resistant population.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention applies preliminary action by pre-engineering hematopoietic stem cells to be deficient in CD33 expression before administering the CD33 targeting agent. This preliminary genetic modification creates a protected reservoir of normal cells that will survive the subsequent therapy and can repopulate the bone marrow, preventing the depletion of normal hematopoietic cells that would otherwise occur.

Inventive Principle:

Principle #10Preliminary action

2Reliability

If intensive chemotherapy is administered to treat acute myeloid leukemia, then cancer cell killing is improved, but older patients cannot tolerate the treatment

Engineering Contradiction:

Improvecancer cell killing efficacyVSAvoidpatient tolerance and safety

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The invention changes the fundamental parameter of CD33 expression status in a subset of hematopoietic stem cells from CD33-positive to CD33-negative through genetic engineering. This parameter change creates a resistant population that can withstand CD33-targeted therapy, effectively lowering the toxic burden on the patient's normal hematopoietic system while maintaining anti-cancer efficacy.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If CAR T cells are used to target cancer antigens, then specific cancer cells are killed, but the therapy is limited to a narrow range of cell surface antigens

Engineering Contradiction:

Improvecancer cell targeting specificityVSAvoidrange of targetable antigens

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

Instead of modifying the immune cell (CAR T cell approach) to recognize specific antigens, the invention inverts the strategy by modifying the target cell (hematopoietic stem cell) to lack the antigen (CD33). This inversion allows any CD33-targeting agent to selectively kill CD33-positive cancer cells while sparing the engineered CD33-negative stem cells, thereby expanding versatility without compromising specificity.

Inventive Principle:

Principle #13The other way round (Inversion)

Data Source

PatentUS11718659B2CD33 exon 2 deficient donor stem cells for use with CD33 targeting agents

Publication Date: 2023.08.08 THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK

AI summary

Disclosed herein are compositions and methods relating to agents that target a lineage-specific cell-surface antigen and a population of hematopoietic cells that are deficient in the lineage-specific cell-surface antigen for immunotherapy of hematological malignancies.