Humanized Anti-CD40 Antibodies for Autoimmune Therapy
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current therapeutic agents targeting the CD40-CD40L pathway for autoimmune diseases are limited due to significant side effects and the lack of approved CD40 antibodies, necessitating the development of new humanized anti-CD40 antibodies with improved specificity, affinity, and pharmacokinetic properties.
Innovation Solution
Development of humanized monoclonal antibodies that specifically bind to human CD40 with antagonistic activity, characterized by an IC50 of less than 1 nM and no agonism in B cell proliferation, and an extended in vivo half-life in non-human primates, comprising specific heavy and light chain sequences.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapeutic agents targeting the CD40-CD40L pathway are used, then immune responses are modulated, but significant side effects occur
Solution Approach 1:
The patent applies parameter changes by humanizing the murine anti-CD40 antibody to reduce immunogenicity and improve pharmacokinetic properties. The humanized antibody variants (e.g., 19B10, 10F2, 2H11) exhibit extended half-lives in non-human primates (10-17 days) compared to murine antibodies, and demonstrate reduced side effects while maintaining therapeutic efficacy in autoimmune disease models.
2Measurement precision
If murine anti-CD40 antibodies are used, then CD40 binding activity is achieved, but short in vivo half-life and high immunogenicity result
Solution Approach 1:
The patent transforms the murine antibody into humanized variants by modifying amino acid sequences to increase homology with human antibodies. This parameter change extends the in vivo half-life from hours (murine) to 10-17 days (humanized variants in non-human primates) while reducing immunogenicity and improving pharmacokinetic properties.
Solution Approach 2:
The patent creates humanized copies of the murine anti-CD40 antibody by transferring the antigen-binding specificity (CDR regions) to a human antibody framework. The humanized variants replicate the high-affinity CD40 binding of the parent murine antibody while gaining improved pharmacokinetic properties suitable for human therapeutic use.
3Measurement precision
If high affinity CD40 binding is achieved, then immune response inhibition is enhanced, but agonistic activity may be induced
Solution Approach 1:
The patent fine-tunes the antibody structure through humanization to achieve high-affinity CD40 binding (IC50 < 1 nM) while maintaining antagonistic activity. The humanized variants specifically block the CD40-CD40L interaction without inducing agonistic B cell proliferation, demonstrating that precise structural modifications can decouple affinity from functional activity type.
Data Source
AI summary
The present invention relates to new humanized antagonistic anti-CD40 antibodies and therapeutic and diagnostic methods and compositions for using the same.