Anti-PD-1 Antibodies with Engineered Human Frameworks
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Solution Overview
Problem
There is a significant unmet need for immunomodulatory compounds, such as antibodies, that can effectively modulate the Programmed Death-1 (PD-1) immune checkpoint to treat various diseases, including cancer and autoimmune disorders, as existing therapies face challenges in balancing immune response upregulation and downregulation.
Innovation Solution
Development of antibodies that bind to PD-1, specifically comprising heavy and light chain variable regions that competitively inhibit or do not inhibit the binding of PD-L1 or PD-L2, enhancing T cell effector function and cytokine secretion, and are engineered to minimize immune responses in humans.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing immunomodulatory compounds are used to modulate PD-1 checkpoint, then immune response can be regulated, but therapeutic effectiveness is limited due to inability to balance immune response upregulation and downregulation
Solution Approach 1:
The invention segments the immune response modulation by developing distinct antibody variants: one that blocks PD-L1/PD-L2 binding to upregulate immune response against tumors, and another that does not block binding to downregulate immune response in autoimmune conditions. This segmentation allows independent optimization of each therapeutic goal.
Solution Approach 2:
The invention changes the binding parameter of the antibody to PD-1 by engineering variants with different affinities and blocking capabilities. One variant has high blocking capability for PD-L1/PD-L2, while another has minimal blocking capability, allowing tailored immunomodulation for different disease states.
2Object-affected harmful factors
If antibodies are engineered to minimize immune response in humans, then serum sickness and undesired immune responses are reduced, but binding effectiveness to PD-1 may be compromised
Solution Approach 1:
The invention extracts only the essential antigen-binding regions (CDRs) from non-human antibodies and grafts them onto human antibody frameworks. This separation allows the CDRs to retain high binding effectiveness to PD-1 while the human framework minimizes immunogenicity and serum sickness.
Solution Approach 2:
The invention creates composite antibody structures combining non-human CDR sequences with human framework sequences. This composite design achieves dual objectives: maintaining high affinity binding to PD-1 through non-human CDRs while reducing immune recognition through human frameworks.
3Reliability
If antibodies competitively inhibit PD-L1 or PD-L2 binding to PD-1, then T cell effector function is enhanced, but this may not be desirable for autoimmune disease treatment
Solution Approach 1:
The invention creates a universal anti-PD-1 antibody platform with multiple functional variants that can be selected based on disease type. The same basic antibody structure can be engineered to either block or non-block PD-L1/PD-L2 binding, making it adaptable for both cancer therapy (where blocking is desired) and autoimmune disease treatment (where non-blocking is desired).
Data Source
AI summary
Antibodies that bind to programmed cell death protein 1 (PD-1), compositions comprising such antibodies, and methods of making and using such antibodies are disclosed.