Agonist Antibodies to CD40 with Enhanced Activity
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current agonistic anti-human CD40 antibodies for cancer and chronic infections have limitations in enhancing immune response and may exhibit unwanted effector functions, necessitating the development of antibodies with enhanced agonist activity and reduced effector function.
Innovation Solution
Development of isolated humanized murine monoclonal antibodies with modified constant regions, specifically hexamerization mutations such as E345K or E345R, and IgG2 hinge domains to enhance agonist activity while minimizing effector functions like complement-dependent cytotoxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If agonistic anti-CD40 antibodies are used to enhance immune response, then immune response enhancement is improved, but unwanted effector functions are activated
Solution Approach 1:
The patent applies parameter changes by modifying the constant region of the antibody (specifically introducing hexamerization mutations like E345K or E345R) to alter the aggregation state and effector function profile. This changes the physical-chemical parameters of the antibody to achieve enhanced agonist activity while reducing unwanted effector functions such as complement-dependent cytotoxicity
Solution Approach 2:
The patent applies local quality by making specific localized modifications to the constant region of the antibody rather than the entire molecule. The hexamerization mutations are introduced at specific positions (E345K/R, E430G, S440Y) to selectively enhance agonist activity while minimizing effector functions in different regions of the antibody molecule
2Reliability
If standard agonistic anti-CD40 antibodies are used, then CD40 binding is achieved, but agonist activity is insufficient
Solution Approach 1:
The patent applies merging by combining multiple mutations (E345K/R, E430G, S440Y) in the constant region to achieve synergistic enhancement of agonist activity. The hexamerization propensity is merged with CD40 binding capability to create an antibody that simultaneously achieves strong target binding and enhanced agonist function
Solution Approach 2:
The patent applies composite materials by creating a hybrid antibody structure that combines the variable region for CD40 binding with a modified constant region that promotes hexamerization. This composite structure integrates the binding function with the enhanced agonist function, creating an antibody with superior overall performance
Data Source
AI summary
Provided herein are agonist antibodies that bind to human CD40 with enhanced agonist activity. Such antibodies comprise Fc regions with amino acid substitutions that enhance the agonist activity of the antibody compared with a similar IgG1 antibody. Such substitutions include sequence variants in the IgG2 hinge region and sequence variants that enhance hexamerization of the antibodies. The invention also provides methods of treatment of cancer or chronic infection by administering the antibodies of the invention to a subject in need thereof.