CAR Protein CD19 Specificity Leukemia Recurrence
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Solution Overview
Problem
Current leukemia treatments face challenges in effectively targeting and eliminating all leukemia cells, leading to recurrence due to cancer cell tolerance and the lack of well-defined tumor-specific antigens, particularly for B cell malignancies.
Innovation Solution
Development of a pharmaceutical chimeric antigen receptor (CAR) protein specifically designed to target CD19 antigens, comprising a CD19 antigen-binding fragment, a transmembrane domain, and a signaling domain, which is genetically modified to be expressed in lymphocytes for enhanced specificity and efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional chemotherapy and targeted therapy are used to treat leukemia, then cancer cells can be killed, but cancer cells develop tolerance and recurrence occurs
Solution Approach 1:
The patent changes the therapeutic approach from conventional chemotherapy to CAR-T cell therapy, fundamentally altering the treatment mechanism. The CAR-T cells are genetically engineered with specific chimeric antigen receptors that continuously recognize and attack leukemia cells, providing a durable response that overcomes drug tolerance development
Solution Approach 2:
The patent implements self-service by engineering T cells to autonomously recognize and kill leukemia cells through the CAR receptor. The modified T cells serve themselves by continuously proliferating and attacking target cells without requiring ongoing external chemotherapy administration, thereby achieving long-term durability
2Reliability
If tumor-specific antigens are not well defined, then it is difficult to target all leukemia cells, but using broad targets like CD19 may harm normal cells
Solution Approach 1:
The patent applies local quality by designing the CAR receptor with a specific binding domain (scFv) that recognizes CD19 with high affinity. This localized specificity ensures that only CD19-positive leukemia cells are targeted, while normal CD19-negative cells are spared, resolving the contradiction between targeting accuracy and normal cell protection
3Measurement precision
If chimeric antigen receptors are designed with high specificity to CD19, then leukemia cells can be precisely targeted, but the complexity of genetic modification increases
Solution Approach 1:
The patent segments the CAR receptor into distinct functional domains (extracellular binding domain, transmembrane domain, intracellular signaling domain) that can be independently designed and assembled. This modular segmentation simplifies the genetic engineering process while maintaining high antigen recognition specificity
Solution Approach 2:
The patent creates a composite chimeric protein structure by combining antibody-derived single-chain variable fragment (scFv) with T cell receptor signaling components. This composite design achieves high CD19 specificity while utilizing well-characterized signaling domains, thereby managing complexity through proven modular components
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 CAR protein effectively recognizes and targets CD19-positive cells, leading to significant cytotoxicity and immune response, potentially reducing leukemia recurrence by specifically killing cancer cells while minimizing harm to normal cells.
Implementation Method 1
a CD19 antigen-binding fragment... The heavy chain variable domain includes a first amino acid sequence selected from SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12 or any combination thereof, and the light chain variable domain includes a second amino acid sequence selected from SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11 or any combination thereof
Implementation Method 2
The transmembrane domain includes a transmembrane domain of CD28, IgG1, CD4, CD8α or any combination thereof
Implementation Method 3
The signaling domain includes at least one immunoreceptor tyrosine-based activation motif (ITAM), at least one co-stimulatory molecule (CM) or the combination thereof
Data Source
AI summary
Disclosed herein are a pharmaceutical composition and a disease therapy method. The pharmaceutical composition relates to an artificial chimeric antigen receptor (CAR). Specifically, the pharmaceutical composition includes a CAR protein that is highly specific to CD19 antigen, a vector that is capable of inducing a cell to generate the certain CAR 19 protein and a population of a modified mammal cell including the CAR19 protein, the vector or combination thereof. Furthermore, the artificial CAR19 includes a CD19 antigen-binding fragment, a transmembrane domain, and a signaling domain. The CD19 antigen-binding fragment is a single-chain variable fragment (scFv) having specific amino acid sequences. Additionally, the method relates to a cancer therapy by using said modified mammal cells. Furthermore, the method includes the steps of purifying a population of autologous cells, modifying the population of autologous cells with an artificial CAR, and administrating the modified autologous cells.