Multimeric DR5 Binding Molecules for Apoptosis Induction
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Solution Overview
Problem
Current monoclonal antibodies targeting TNF superfamily receptor proteins, such as DR5, have limited clinical efficacy despite in vitro and in vivo effectiveness, as they often require cross-linkers for cytotoxicity and apoptosis induction, and do not achieve significant potency in treating cancers with high DR5 expression.
Innovation Solution
Development of multimeric binding molecules, including dimeric, pentameric, or hexameric structures with bivalent binding units composed of IgA or IgM heavy chain constant regions, which specifically and agonistically bind to TNF superfamily receptor proteins, enabling cross-linking and apoptosis induction without the need for additional cross-linkers, thereby enhancing potency and specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If monoclonal antibodies are used to target DR5, then specificity is improved, but potency is worsened due to requirement for cross-linkers
Solution Approach 1:
The patent combines multiple binding domains (at least three) into a single multimeric binding molecule, merging the functions of binding and cross-linking into one integrated structure. This eliminates the need for separate cross-linkers while maintaining the ability to induce receptor trimerization and apoptosis, thereby resolving the contradiction between specificity and potency.
Solution Approach 2:
The multimeric binding molecule is segmented into multiple binding domains that can independently bind to DR5 receptors. This segmentation allows the molecule to simultaneously engage multiple receptors, achieving the necessary cross-linking effect for potency while preserving the specificity of individual binding domains.
2Power
If additional cross-linkers are used to enhance cytotoxicity, then potency is improved, but device complexity is worsened
Solution Approach 1:
The patent merges the cross-linking function into the binding molecule itself by incorporating at least three binding domains in a multimeric structure. This integration eliminates the need for additional separate cross-linker components, thereby enhancing cytotoxicity while reducing overall system complexity.
Solution Approach 2:
The multimeric binding molecule is designed to self-cross-link DR5 receptors through its multiple binding domains. The molecule serves its own cross-linking function without requiring external cross-linking agents, thereby simplifying the therapeutic approach while maintaining enhanced cytotoxicity.
3Power
If multimeric binding molecules are used to induce apoptosis, then potency is improved, but manufacturing complexity is worsened
Solution Approach 1:
The multimeric binding molecule is designed with universal applicability to TNF superfamily receptors. By using a modular design where multiple binding domains are combined in a multimeric structure, the same platform can target different receptors (DR5, DR4, etc.), thereby achieving enhanced apoptosis induction while streamlining manufacturing through a universal platform approach.
4Ease of manufacture
If bivalent IgG antibodies are used, then ease of manufacture is improved, but apoptosis induction capability is worsened
Solution Approach 1:
The patent combines at least three binding domains into a single multimeric binding molecule, merging the functions of binding and cross-linking into one integrated structure. This eliminates the need for separate cross-linkers while maintaining the ability to induce receptor trimerization and apoptosis, thereby resolving the contradiction between specificity and potency.
Solution Approach 2:
The multimeric binding molecule is segmented into multiple binding domains that can independently bind to DR5 receptors. This segmentation allows the molecule to simultaneously engage multiple receptors, achieving the necessary cross-linking effect for potency while preserving the specificity of individual binding domains.
Data Source
AI summary
This disclosure provides dimeric, pentameric, and hexameric Tumor Necrosis Factor (TNF) superfamily receptor protein binding molecules and methods of using such binding molecules to direct apoptosis-mediated killing of TNF receptor-expressing cells.