Humanized Anti-NGF Antibody E3 for Pain Relief
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Solution Overview
Problem
Current anti-NGF antibodies, particularly those derived from rodents, induce a human anti-murine response and have inefficient effector functions in humans, necessitating the development of humanized anti-NGF antagonist antibodies that can effectively bind and inhibit nerve growth factor (NGF) in humans.
Innovation Solution
A humanized and affinity-matured antibody, E3, specifically designed to bind human and rodent NGF, with optimized heavy and light chain variable regions and complementarity determining regions (CDRs) to achieve high affinity and specificity, reducing NGF-dependent survival of neurons and mediating pain relief.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If rodent-derived anti-NGF antibodies are used, then they can bind to NGF and inhibit its activity, but they induce human anti-murine antibody responses and have inefficient effector functions in humans
Solution Approach 1:
The patent uses humanized antibody technology as an intermediary solution. The CDRs from rodent antibodies (which provide high NGF binding affinity) are grafted onto human antibody framework regions. This intermediary structure allows the antibody to maintain rodent-derived binding specificity while presenting a human molecular structure to the human immune system, thereby preventing human anti-murine antibody responses and improving effector function efficiency in human patients
Solution Approach 2:
The patent applies affinity maturation techniques to optimize the binding parameters of the humanized antibody. Through iterative mutagenesis and selection processes, specific amino acid residues in the CDR regions are modified to enhance binding affinity to NGF. This parameter optimization ensures that the humanized antibody achieves binding strength comparable to or exceeding that of the original rodent antibodies, while maintaining the human framework structure
2Reliability
If rodent anti-NGF antibodies are used, then they can mediate pain relief, but their effector functions are inefficient in humans
Solution Approach 1:
The humanized antibody framework serves as an intermediary that bridges the gap between rodent-derived binding specificity and human immune system compatibility. By replacing the rodent framework with human framework regions, the antibody can effectively engage human immune effector cells (such as NK cells and macrophages) through human Fc receptor interactions, thereby restoring efficient effector functions while maintaining the ability to bind NGF and mediate pain relief
3Object-affected harmful factors
If humanized antibodies are developed to avoid immune responses, then human anti-murine responses are reduced, but developing and optimizing these antibodies becomes more complex
Solution Approach 1:
The antibody molecule is segmented into distinct functional regions: the CDR regions (responsible for antigen binding) are derived from rodent antibodies, while the framework regions (providing structural support) are derived from human antibodies. This segmentation allows each region to be optimized independently - the CDRs for high affinity binding and the framework for human compatibility - simplifying the overall design process while achieving the desired dual functionality
Solution Approach 2:
The humanized antibody framework is designed to be universal, serving multiple functions: providing structural stability, enabling human immune system compatibility, facilitating efficient effector function mediation, and allowing for standardized production and purification. This multi-functionality reduces the need for separate optimization of each function, thereby reducing overall complexity despite the initial challenge of humanization
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
E3 antibody demonstrates high affinity for NGF with a dissociation constant (KD) of 0.07 nM and slow dissociation kinetics, effectively inhibiting NGF-dependent survival of mouse trigeminal neurons at low concentrations, providing significant pain relief for conditions like rheumatoid arthritis and osteoarthritis.
Implementation Method 1
A humanized and affinity-matured antibody, E3, specifically binds human and rodent nerve growth factor ("NGF")
Data Source
AI summary
The invention concerns anti-NGF antibodies (such as anti-NGF antagonist antibodies), and polynucleotides encoding the same. The invention further concerns use of such antibodies and/or polynucleotides in the treatment and/or prevention of pain, including post-surgical pain, rheumatoid arthritis pain, and osteoarthritis pain.