Bispecific Binding Agent Surface Protein Degradation
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Solution Overview
Problem
Current therapies for cancer, such as those targeting surface proteins on malignant cells, often have limited durability and do not effectively counteract the proliferative or immunosuppressive effects of these proteins, leading to incomplete immune evasion by cancer cells.
Innovation Solution
Development of bispecific binding agents that target both membrane-associated ubiquitin E3 ligases and specific surface proteins, promoting their ubiquitination and degradation, thereby reducing the proliferative and immunosuppressive capabilities of cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibodies are used to bind and inhibit surface proteins, then the activity of surface proteins is inhibited, but the therapeutic effect lacks durability and cancer cells can evade immune response
Solution Approach 1:
The patent extracts the surface protein from the cell surface through ubiquitination-mediated degradation, removing the harmful protein entirely rather than merely blocking its activity. This is achieved by recruiting E3 ligases to ubiquitinate the target surface protein, leading to its proteasomal degradation and elimination, thereby preventing immune evasion and providing durable therapeutic effect
Solution Approach 2:
The patent changes the fate of the surface protein from a stable, functional state to a degraded, eliminated state by introducing ubiquitination. This parameter change in protein stability and cellular localization transforms the therapeutic mechanism from transient inhibition to permanent removal, enhancing durability and preventing cancer cell adaptation
2Object-generated harmful factors
If surface proteins are inhibited by binding agents, then their activity is blocked, but the proliferative and immunosuppressive effects of cancer cells are not effectively counteracted
Solution Approach 1:
The patent converts the harmful surface proteins that enable cancer proliferation and immune suppression into targets for degradation. By designing bispecific binding agents that recruit E3 ligases to these surface proteins, the harmful proteins are transformed into substrates for ubiquitination and degradation, thereby converting the cancer cell's weapon into its vulnerability and effectively counteracting proliferative and immunosuppressive effects
3Duration of action of moving object
If conventional antibody therapies are used, then surface protein activity is inhibited, but the therapeutic response is not durable and cancer cells develop resistance
Solution Approach 1:
The patent performs preliminary action by recruiting E3 ligases to ubiquitinate surface proteins before they can mediate cancer proliferation or immune suppression. This preemptive degradation prevents the surface proteins from carrying out their harmful functions, establishing durable therapeutic response and preventing resistance development by eliminating the target rather than merely blocking it
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 bispecific binding agents effectively degrade target surface proteins, enhancing the immune response against cancer cells and providing a more durable therapeutic effect compared to existing treatments.
Implementation Method 1
binding of the bispecific binding agent leads to ubiquitination of the target surface protein and its subsequent degradation
Data Source
AI summary
The present disclosure relates to, among other things, methods for degrading targeted surface proteins using the ubiquitin pathway by using a bispecific binding agent or an immunoconjugate that binds the targeted surface protein and a membrane-associated ubiquitin E3 ligase. The present disclosure also relates to methods for degrading targeted surface proteins using the ubiquitin pathway using an engineered transmembrane protein that binds the targeted surface protein and exhibits ubiquitin E3 ligase activity. The disclosure also provides compositions and methods useful for producing such bispecific binding agents and engineered transmembrane proteins, immunoconjugates, nucleic acids encoding same, host cells genetically modified with the nucleic acids, as well as methods for modulating an activity of a cell and/or for the treatment of various diseases such as cancers.