Humanized Anti-TNFα Antibodies Reducing Immunogenicity
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Solution Overview
Problem
Current anti-TNFα antibodies, such as infliximab, induce human anti-murine antibody responses due to their murine-derived sequences, leading to unwanted immune reactions in patients, necessitating the development of antibodies with reduced immunogenicity.
Innovation Solution
Designing TNFα antibodies with higher affinity for TNFα and fewer murine-derived amino acid residues by incorporating sequences that are more similar to human immunoglobulin sequences, thereby reducing the likelihood of generating anti-infliximab antibodies in humans.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If murine-derived antibody sequences are used to bind TNFα, then binding affinity is achieved, but immunogenicity increases causing human anti-murine antibody responses
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence composition of the antibody variable regions. Specifically, it changes the genetic origin parameters from murine to human-like sequences while maintaining the binding function. The antibody variable regions are designed with human immunoglobulin sequences that have been engineered to retain TNFα binding capability while reducing immunogenicity, directly addressing the contradiction between binding affinity and immunogenicity.
Solution Approach 2:
The patent creates a composite antibody structure by combining human constant regions with humanized variable regions that have been engineered to bind TNFα. This composite approach integrates the stability and low immunogenicity of human antibody frameworks with the TNFα binding capability, effectively resolving the contradiction between maintaining binding affinity and reducing immunogenicity in the final therapeutic product.
2Reliability
If murine variable regions are incorporated into the antibody, then TNFα binding capability is achieved, but human anti-murine antibody response increases
Solution Approach 1:
The patent changes the amino acid sequence parameters of the variable regions from murine origin to human-like sequences. The variable regions are designed with human immunoglobulin frameworks that have been engineered to maintain TNFα binding capability while significantly reducing the immunogenic differences that trigger human anti-murine antibody responses, thereby resolving the contradiction between binding capability and harmful immune responses.
Solution Approach 2:
The patent uses human immunoglobulin sequences as templates or copies to create the variable regions of the therapeutic antibody. By copying and adapting human antibody frameworks rather than using murine sequences, the patent maintains compatibility with the human immune system while preserving TNFα binding function, thus eliminating the formation of anti-infliximab antibodies.
3Reliability
If chimeric antibody structure with murine variable regions is used, then TNFα neutralization is achieved, but immune reaction to therapeutic protein occurs
Solution Approach 1:
The patent applies parameter changes by modifying the composition parameters of the antibody from chimeric (murine-human) to fully human-like sequences. The variable regions are engineered with human immunoglobulin amino acid sequences that maintain TNFα neutralization capability while eliminating the foreign murine components that trigger unwanted immune reactions, thereby resolving the contradiction between therapeutic efficacy and immune compatibility.
Solution Approach 2:
The patent creates a fully human-like composite antibody structure by integrating human constant regions with humanized variable regions that have been engineered for TNFα binding. This composite design eliminates murine components entirely while maintaining neutralization function, resolving the contradiction between achieving TNFα neutralization and avoiding unwanted immune reactions in human patients.
Data Source
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AI summary
Novel TNFa antibody polypeptides and nucleic acids are disclosed. Methods of utilizing the polypeptides to treat TNFa-related diseases are also disclosed.