Humanized Anti-CD19 Antibody Framework Modification
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Solution Overview
Problem
Existing monoclonal antibodies targeting CD19 are often made from mouse cells, leading to an immune response in humans and reduced efficacy over time due to human immune system recognition as foreign.
Innovation Solution
Development of a humanized antibody that binds to human CD19, specifically incorporating heavy chain variable region (HVR) and light chain variable region (LVR) sequences, including complementarity determining region (CDR) and framework region (FR) sequences, to enhance specificity and longevity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mouse monoclonal antibodies are used to target CD19, then the antibody can bind to human CD19, but the human immune system recognizes it as foreign and mounts an immune response
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of the antibody's framework regions to match human immunoglobulin sequences more closely, while preserving the complementarity determining regions (CDRs) that bind CD19. This changes the immunological parameters of the antibody to reduce recognition as foreign, thereby reducing immune response while maintaining CD19 binding specificity.
Solution Approach 2:
The patent extracts and retains only the essential binding functionality in the CDR regions while replacing the framework regions with humanized sequences. This extraction approach separates the critical binding function from the immunogenic framework, allowing the antibody to bind CD19 effectively while avoiding human immune recognition.
2Productivity
If mouse monoclonal antibodies are administered repeatedly, then initial treatment effect is achieved, but efficacy decreases over time due to immune system adaptation
Solution Approach 1:
By changing the antibody's framework region sequences to humanized versions, the patent extends the duration of therapeutic action. The humanized antibody is not recognized as foreign by the human immune system, preventing the development of neutralizing antibodies that would reduce efficacy over time. This allows for sustained therapeutic effect across multiple administrations.
3Reliability
If humanized antibody sequences are used, then immune response is reduced and longevity is enhanced, but manufacturing complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the antibody into distinct functional regions: complementarity determining regions (CDRs) that maintain mouse-derived binding specificity for CD19, and framework regions that are humanized to reduce immunogenicity. This segmentation allows independent optimization of binding function versus immunological compatibility, managing overall complexity through modular design.
Solution Approach 2:
The patent applies local quality by making different parts of the antibody have different properties: the CDR regions maintain their original mouse sequences to preserve high-affinity CD19 binding, while the framework regions are localized humanized to minimize immune recognition. This localized differentiation optimizes both binding efficacy and therapeutic longevity without requiring complete redesign of the entire antibody structure.
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 humanized antibody effectively targets CD19 with improved specificity and reduced immune response, maintaining therapeutic efficacy over multiple administrations.
Implementation Method 1
a humanized antibody that binds to human CD19. The humanized antibody may include a heavy chain variable region (HVR) sequence including the amino acid sequence of SEQ ID NO: 27 and a light chain variable region (LVR) sequence including the amino acid sequences of SEQ ID NO: 34, the amino acid sequences of SEQ ID NO: 35, or the amino acid sequences of SEQ ID NO: 36
Data Source
AI summary
Embodiments herein relate to humanized CD19 antibodies and disease treatment using the antibodies. For example, a subject having a CD19 positive tumor may be administered a therapeutically effective amount of the humanized antibody.