CD38 Epitope Editing for Safer Anti-CD38 Cell Therapy
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Solution Overview
Problem
Current immunotherapies for hematological malignancies like acute myeloid leukemia (AML) and multiple myeloma face challenges due to the expression of target proteins on both cancer cells and healthy hematopoietic cells, leading to toxicity and limited efficacy, and there is a need for therapeutic agents that can effectively target cancer cells while minimizing harm to normal cells.
Innovation Solution
Genetically engineered hematopoietic stem/progenitor cells (HSPCs) and T cells with edited CD38 genes, using CRISPR systems, to reduce binding to anti-CD38 antibodies like daratumumab, allowing targeted therapy with reduced toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If anti-CD38 antibodies like daratumumab are used to target cancer cells, then therapeutic efficacy is improved, but toxicity to healthy hematopoietic cells increases
Solution Approach 1:
The patent applies local quality by introducing specific point mutations (such as S274F, E278K, or R280H) at precise locations within the CD38 protein structure. These localized changes alter the antigenic epitopes recognized by daratumumab and other anti-CD38 antibodies, thereby protecting healthy hematopoietic cells from antibody-mediated toxicity while preserving the function of CAR-T cells that use engineered CD38 receptors
2Reliability
If CAR-T cells are used to target CD38 on cancer cells, then treatment effectiveness is improved, but immunosuppression and hematopoietic toxicity occur
Solution Approach 1:
The patent segments the CD38 protein into distinct functional and antigenic regions by introducing point mutations that specifically alter antibody-binding epitopes while preserving other functional domains. This segmentation allows the CD38 protein to maintain its role in CAR-T cell recognition and signaling while becoming resistant to binding by therapeutic anti-CD38 antibodies like daratumumab
Solution Approach 2:
The patent applies parameter changes by modifying specific amino acid residues (such as S274F, E278K, R280H) that change the biochemical and biophysical properties of the CD38 protein surface. These parameter changes alter the epitope structure to prevent antibody binding while maintaining protein stability and CAR-T cell recognition capabilities
3Reliability
If therapeutic anti-CD38 antibodies are administered, then cancer cell targeting is improved, but binding to healthy HSPCs causes harmful effects
Solution Approach 1:
The patent applies preliminary anti-action by pre-modifying the CD38 protein in healthy hematopoietic stem and progenitor cells through genetic engineering before exposure to therapeutic anti-CD38 antibodies. The introduced point mutations create anticipatory resistance, preventing the antibodies from binding to and damaging healthy cells while allowing the same antibodies to effectively target untreated cancer cells
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 engineered cells provide effective treatment for hematological conditions by minimizing binding to therapeutic antibodies, reducing toxicity, and enabling targeted therapy for cancer cells while maintaining normal cell functionality.
Implementation Method 1
The cells may be genetically engineered using a CRISPR system. The CRISPR system includes a guide nucleic acid, particularly guide RNAs, and a nuclease.
Implementation Method 2
the genetically engineered HSPC or T cell includes at least one mutation in the genetically engineered CD38 gene that results in a polypeptide bearing a mutation at position S274. In some embodiments, the mutation at position S274 is S274F.
Data Source
AI summary
Genetically engineered cells (e.g., HSPCs or T cells), such as hematopoietic stem cells, having one or more genetically edited genes of cell-surface proteins, and therapeutic uses thereof, either alone or in combination with immune therapy that targets the cell-surface protein(s).