CD33-Modified Hematopoietic Rescue Cells for Anti-CD33 Therapy
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Solution Overview
Problem
Anti-CD33 cancer therapies often deplete both cancerous and noncancerous CD33+ cells, leading to hematopoietic system depletion, necessitating the use of rescue cells with CD33 gene modifications to repopulate the system.
Innovation Solution
Development of novel cells with modifications in the CD33 gene, utilizing guide RNAs (gRNAs) to insert or delete sequences, and compositions comprising gRNAs that target specific domains to reduce CD33 expression in hematopoietic stem and progenitor cells, thereby making them resistant to anti-CD33 therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If anti-CD33 cancer therapy is administered, then cancer cells are depleted, but noncancerous hematopoietic cells are also depleted
Solution Approach 1:
The patent applies local quality by creating heterogeneity in the CD33 antigen among different cell populations. Specifically, it generates hematopoietic stem and progenitor cells with modified CD33 expression levels (ranging from reduced to completely absent) while maintaining normal CD33+ cancer cells. This allows the therapy to selectively affect cancer cells while sparing the modified rescue cells, thereby resolving the contradiction between effective cancer cell depletion and preservation of noncancerous cells
Solution Approach 2:
The patent applies inversion by reversing the typical approach: instead of trying to protect normal cells from CD33-targeted therapy while they express CD33, it inverts the strategy by creating normal cells that deliberately lack or have reduced CD33 expression. These inverted-normal cells (with modified CD33) then serve as rescue cells that are resistant to the therapy, while the wild-type CD33+ cancer cells remain vulnerable. This inversion resolves the contradiction by making the therapy selective for cancer cells while protecting modified normal cells
2Reliability
If rescue cells with CD33 gene modification are administered, then hematopoietic system repopulation is achieved, but complexity of cell preparation increases
Solution Approach 1:
The patent applies self-service by enabling the rescue cells to autonomously protect themselves against anti-CD33 therapy through endogenous CD33 gene modification. The cells are engineered with modified CD33 expression levels that provide inherent resistance to the therapy, eliminating the need for external protective mechanisms or complex support systems. This self-protective capability simplifies the overall cell preparation and administration process while ensuring reliable hematopoietic repopulation
Solution Approach 2:
The patent applies preliminary action by pre-modifying the CD33 gene in hematopoietic stem and progenitor cells before administering them as rescue cells. The cells are prepared in advance with reduced or absent CD33 expression through gene editing techniques, ensuring they are already resistant to anti-CD33 therapy when administered. This preliminary modification simplifies the rescue process by eliminating the need for complex post-administration protective measures, thereby reducing overall process complexity while ensuring reliable repopulation
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 modified cells effectively reduce CD33 expression, minimizing the depletion of noncancerous cells and allowing for hematopoietic system repopulation during or after anti-CD33 therapy, maintaining hematopoietic function.
Implementation Method 1
a gRNA comprising a targeting domain which binds a target domain of Table 1
Data Source
AI summary
Some aspects of this disclosure provides, e.g., novel cells having a modification (e.g., insertion or deletion) in the endogenous CD33 gene. Some aspects of the disclosure provide compositions, e.g., gRNAs, that can be used to make such a modification.