CD33 Binding Agents Surface Presence
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Solution Overview
Problem
Current CD33-targeting therapies for myeloid cell malignancies and myelodysplastic syndrome, such as acute myeloid leukemia, face challenges in achieving improved efficacy and sustained treatment effects due to rapid internalization of CD33 binding agents and limited understanding of CD33 signaling pathways.
Innovation Solution
Development of novel CD33 binding agents with specific amino acid sequences in their variable regions and mutations in the Fc domain to enhance affinity and internalization kinetics, allowing for prolonged surface presence and increased antibody-dependent cellular cytotoxicity (ADCC) activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If conventional CD33 binding agents are used, then they can bind to CD33 on myeloid cells, but they are rapidly internalized and cleared from the cell surface, reducing treatment duration and efficacy
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequences in the variable regions (CDRs) of the antibody molecules. Specifically, the invention optimizes the complementarity determining regions to alter binding kinetics and internalization rates, thereby extending the duration of surface presence while maintaining therapeutic efficacy against CD33-positive myeloid cells
Solution Approach 2:
The invention employs dynamics by creating antibody variants with tuned internalization kinetics. The modified CD33 binding agents exhibit controlled internalization rates that allow prolonged surface presence followed by gradual internalization, enabling sustained therapeutic action rather than rapid clearance
2Reliability
If CD33 binding agents are designed for high affinity binding, then they bind strongly to CD33, but this may accelerate internalization and reduce surface presence time
Solution Approach 1:
The patent applies parameter changes by independently optimizing binding affinity parameters and internalization rate parameters through specific amino acid substitutions in the CDR regions. This allows the achievement of high affinity binding while simultaneously controlling the internalization kinetics to maintain adequate surface presence duration for therapeutic effect
3Reliability
If immunotoxins are used to deliver toxic payload to CD33 positive cells, then therapeutic effect is achieved, but rapid internalization of the binding agent limits sustained treatment
Solution Approach 1:
The patent applies preliminary action by ensuring prolonged surface presence of the CD33 binding agent before internalization occurs. This extended surface dwell time allows for sustained delivery of toxic payload to CD33-positive myeloid cells, improving treatment sustainability while maintaining the immunotoxin mechanism of action
Solution Approach 2:
The invention employs dynamics by creating binding agents with optimized internalization kinetics that balance payload delivery with sustained presence. The modified antibodies exhibit controlled internalization rates that enable continuous therapeutic action over an extended period, addressing the limitation of rapid clearance in conventional immunotoxins
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 novel CD33 binding agents demonstrate high affinity and favorable internalization kinetics, leading to enhanced ADCC activity and improved therapeutic efficacy by maintaining a longer presence on target cells, potentially offering better treatment outcomes for myeloid cell malignancies.
Implementation Method 1
novel CD33 binding agents binding to human CD33 and that are defined by having a heavy chain variable region comprising CDR1, CDR2 and CDR3, and a light chain variable region comprising CDR4, CDR5 and CDR6
Implementation Method 2
enhanced affinity and internalization kinetics, allowing for prolonged surface presence and increased antibody-dependent cellular cytotoxicity (ADCC) activity
Data Source
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AI summary
The present invention relates to immunotherapies that are based on myeloid cell depletion. In particular, the present invention relates to CD33 binding agents for use in such therapies, e.g. in the treatment of myeloid cell malignancies and myelodysplastic syndrome (MDS).