Mesothelin-targeted CD40 agonistic multispecific antibody constructs for the treatment of solid tumors
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing CD40 agonist antibodies for treating cancer are limited by systemic toxicities and insufficient tumor localization, which reduces their efficacy in activating CD40 signaling in tumor-associated APCs.
Innovation Solution
A multispecific antibody construct that binds both CD40 and mesothelin (MSLN) is engineered to activate CD40 only in the presence of MSLN-expressing cells, with mutations to limit Fc receptor binding, ensuring localized activation and minimizing systemic toxicities.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If monoclonal anti-CD40 antibodies are used to activate CD40 signaling, then anti-tumor effects are enhanced, but systemic toxicities such as cytokine release syndrome and liver damage occur
Solution Approach 1:
The patent applies local quality by engineering the antibody construct to have different binding properties in different contexts: the Fc domain is mutated to reduce binding to FcγRIIB on non-tumor APCs, while the construct maintains full CD40 agonist activity when bound to MSLN-expressing tumor cells. This creates localized activation at the tumor site while minimizing systemic activation of healthy tissues.
Solution Approach 2:
The patent uses MSLN (mesothelin) as an intermediary target to mediate the activation process. The multispecific antibody construct requires simultaneous binding to both CD40 and MSLN for full agonist activity, making MSLN-expressing tumor cells the intermediary that directs and confines CD40 activation primarily to tumor tissue, thereby reducing off-target effects on healthy APCs.
2Productivity
If CD40 agonist antibodies are administered at higher doses to improve anti-tumor effects, then T cell infiltration is enhanced, but immune-related adverse effects increase
Solution Approach 1:
The mutated Fc domain with reduced binding affinity to FcγRIIB creates local quality differentiation: the antibody selectively activates CD40 on tumor-associated APCs while sparing healthy APCs. This allows for effective T cell infiltration enhancement without proportionally increasing systemic immune activation and associated adverse effects.
Solution Approach 2:
The patent changes the binding affinity parameter of the Fc domain to FcγRIIB by introducing mutations, thereby altering the activation threshold and kinetics. This parameter change enables the antibody to achieve sufficient CD40 activation for T cell infiltration while reducing excessive systemic activation that leads to adverse effects.
3Reliability
If Fc receptor binding is reduced to minimize systemic activation, then CD40 agonist activity is enhanced at the tumor site, but overall immune activation may be diminished
Solution Approach 1:
The patent merges two antibody specificities into a single multispecific construct: one arm targets CD40 to provide agonist activity, while the other arm targets MSLN to provide tumor selectivity. This merging ensures that CD40 activation occurs preferentially at the tumor site where both targets are present, maintaining robust localized immune activation without excessive systemic effects.
Solution Approach 2:
The antibody construct functions as a composite molecule combining CD40-targeting and MSLN-targeting domains with a mutated Fc domain. This composite structure integrates multiple functions: tumor-selective binding via MSLN, CD40 agonist activity, and reduced off-target activation via Fc mutations, achieving both localized efficacy and reduced systemic toxicity.
Data Source
AI summary
The present invention relates to a human agonistic CD40 multispecific antibody construct for treatment of solid tumors by engineering a molecule that specifically targets the CD40 pathway on tumor-associated APCs, without systemic CD40 activation.