Humanized Anti-NGF Antibody E3 for Osteoarthritis Pain
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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 for effective treatment of osteoarthritis.
Innovation Solution
A humanized and affinity-matured anti-NGF antagonist antibody, E3, specifically binding to human and rodent nerve growth factor (NGF), with optimized amino acid sequences for its heavy and light chain variable regions, including complementarity determining regions (CDRs), is developed to improve therapeutic efficacy and reduce immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If rodent-derived anti-NGF antibodies are used, then NGF binding activity is achieved, but human anti-murine immune response is induced and effector functions are inefficient
Solution Approach 1:
The patent applies parameter changes by humanizing the antibody sequence - changing the species origin parameter from rodent to human through sequence modification. The humanized anti-NGF antibody maintains NGF binding capability while eliminating the foreign antigenic determinants that trigger human anti-murine immune responses, thereby improving effector function efficiency and reducing immune rejection.
Solution Approach 2:
The patent creates a humanized version that copies the essential functional features of rodent anti-NGF antibodies (NGF binding and blocking activity) while replacing the immunogenic rodent framework with human framework sequences. This allows the antibody to function effectively in humans without triggering immune rejection.
2Reliability
If rodent-derived anti-NGF antibodies are used, then NGF binding activity is achieved, but immune rejection occurs
Solution Approach 1:
The patent changes the species parameter of the antibody framework from rodent to human while preserving the CDR regions that confer NGF binding activity. This parameter change eliminates the foreign antigenic nature of the antibody, preventing immune rejection while maintaining therapeutic efficacy.
3Reliability
If humanized anti-NGF antagonist antibodies are developed, then immune response is reduced and efficacy is enhanced, but antibody design complexity increases
Solution Approach 1:
The patent segments the antibody into functional regions (CDRs for antigen binding) and framework regions (for structural stability and immunogenicity). By retaining only the essential CDR sequences from rodent antibodies and replacing the framework with human sequences, the design process becomes systematic and manageable while achieving the dual goals of reduced immunogenicity and maintained efficacy.
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 E3 antibody demonstrates high affinity binding to NGF, effectively inhibiting NGF-dependent survival of neurons and reducing inflammation, thereby improving stiffness and pain in osteoarthritis patients with reduced immune reaction.
Implementation Method 1
A humanized and affinity-matured antibody, E3, specifically binding human and rodent nerve growth factor (NGF), comprising specific amino acid sequences for its heavy and light chains, and complementarity determining regions (CDRs)
Data Source
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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.