Modified Fc BiTE Combinations for Tumor Heterogeneity
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Bispecific T cell engagers (BiTEs) have limited efficacy in treating solid tumors due to their short half-life and inability to target tumor heterogeneity, leading to treatment escape through downregulation of tumor-associated antigens.
Innovation Solution
Development of bispecific T cell engaging antibodies with modified Fc domains that promote heterodimerization and increase serum half-life, combined with specific binding to CD3 and tumor antigens like FSHR or HER2, to enhance tumor targeting and persistence.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If conventional BiTEs are used to target tumor cells, then T cell redirection activity is achieved, but serum half-life is short which reduces therapeutic availability
Solution Approach 1:
The patent applies parameter changes by modifying the Fc domain of the BiTE antibody to include heterodimerization-promoting mutations (such as L234A/L235A 'hole' mutations or Y234/Y235 'key' mutations). These mutations change the physical-chemical parameters of the antibody structure, enabling extended serum half-life through altered clearance rates while maintaining the therapeutic function of T cell redirection to tumor cells
Solution Approach 2:
The patent creates composite antibody structures by combining two different Fc domains with complementary mutations to form a heterodimeric BiTE. This composite structure leverages the synergistic effects of both parental antibodies' Fc regions, achieving extended half-life through reduced renal clearance and optimized FcRn binding, while maintaining dual antigen specificity
2Adaptability or versatility
If a single BiTE targets a specific tumor-associated antigen, then targeted therapy is achieved, but tumor heterogeneity leads to treatment escape through antigen downregulation
Solution Approach 1:
The patent segments the tumor targeting function by creating a combination of two distinct BiTEs, each targeting a different tumor-associated antigen (e.g., HER2 and FSHR). This segmentation allows the therapy to simultaneously engage multiple antigen targets on heterogeneous tumor cells, preventing treatment escape through antigen downregulation while maintaining adaptable tumor targeting
Solution Approach 2:
The patent implements universality by designing BiTEs with Fc domains that provide multiple functions: (1) extended serum half-life through heterodimerization and FcRn binding, (2) enhanced T cell activation through optimized CD3 engagement, and (3) adaptable tumor targeting through dual antigen specificity. This multi-functional design ensures reliable treatment efficacy across diverse tumor types and stages
3Duration of action of stationary object
If Fc domain mutations are introduced to extend half-life, then serum persistence is improved, but structural complexity increases
Solution Approach 1:
The patent applies local quality by introducing mutations only in specific regions of the Fc domain (positions 234-235 in the CH2 domain) that are critical for heterodimerization and FcRn binding, while leaving the rest of the antibody structure intact. This localized modification approach extends serum persistence through optimized clearance and binding properties without unnecessarily increasing overall structural complexity
Data Source
AI summary
The present invention provides compositions comprising two or more bispecific T cell engaging antibodies or nucleic acid molecules encoding the same, and methods for treating or preventing a disease or disorder using the same.