CD40 Antigen-Binding Protein With Fc Mutations for Wider Therapeutic Window
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Solution Overview
Problem
Existing CD40 antibodies face a narrow therapeutic window with low efficacy and significant safety concerns, such as toxic side effects and low tolerated doses, limiting their effectiveness in clinical applications for treating tumors.
Innovation Solution
Development of an antigen binding protein targeting CD40 with high affinity and enhanced agonistic activity, particularly after crosslinking, comprising specific variable region amino acid sequences and potential post-translational modification sites, to broaden the therapeutic window and improve safety.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing CD40 antibodies are used to treat tumors, then anti-tumor effect is achieved, but toxic side effects and low tolerated dose occur
Solution Approach 1:
The patent modifies the antibody structure by introducing specific amino acid substitutions (e.g., L234A, L235A, G237A in the Fc region) to change the biophysical parameters of CD40 crosslinking. These parameter changes enhance agonistic activity while reducing toxic side effects, thereby improving the therapeutic index.
Solution Approach 2:
The invention applies local quality modification by specifically targeting the Fc region of the antibody with point mutations (L234A, L235A, G237A) to alter crosslinking properties. This localized modification enhances the desired anti-tumor effect while minimizing systemic toxicity, resolving the contradiction between efficacy and safety.
2Productivity
If CD40 antibody dosage is increased to improve efficacy, then anti-tumor effect is enhanced, but safety is compromised
Solution Approach 1:
By changing the molecular parameters of the antibody through Fc region mutations, the patent achieves enhanced agonistic activity at lower doses. This parameter modification allows efficacy improvement without proportionally increasing toxicity, thus resolving the dose-dependent safety- efficacy trade-off.
3Reliability
If agonistic activity of CD40 antibody is enhanced, then anti-tumor effect is improved, but crosslinking control becomes insufficient
Solution Approach 1:
The patent applies local quality modification by introducing specific point mutations only in the Fc region (L234A, L235A, G237A) to enhance agonistic activity. This localized approach improves CD40 crosslinking control without requiring complex structural modifications elsewhere in the antibody molecule.
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 antigen binding protein exhibits a larger therapeutic window, enhancing patient response rates under safe and tolerable dosage conditions, demonstrating improved efficacy and safety in preclinical models.
Implementation Method 1
An agonistic anti-CD40 antibody, similar to CD40L, can crosslink and activate CD40 on the surface of immune cells and tumor cells
Data Source
AI summary
Disclosed in the present invention are an antigen binding protein targeting CD40, and the preparation therefor and the use thereof. The antigen binding protein targeting CD40 has the characteristics of a high affinity to CD40 and a strong agonistic activity on signaling pathways, particularly the enhanced agonistic activity after crosslinking, so that the antigen binding protein targeting CD40 has a larger therapeutic window, and is expected to bring about new opportunities for the treatment of various tumors.