Fusion Protein Trimeric Display via Bacteriophage Dec
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Solution Overview
Problem
Current therapeutic TNFSF proteins, such as CD40L, face challenges in achieving effective signaling due to structural requirements, leading to high doses that result in toxic off-target effects, and antibodies designed to bypass these issues struggle to maintain the correct trimeric structure for signaling unless at high concentrations.
Innovation Solution
A fusion protein comprising an antigen binding domain linked to a bacteriophage decoration protein (Dec) is developed, allowing for the display of trimeric proteins in a polyvalent nanoparticle format, maintaining native structure and facilitating robust signaling through polyvalent presentation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If high doses of therapeutic TNFSF proteins are administered to achieve effective signaling, then the beneficial therapeutic effect is improved, but toxic off-target effects increase
Solution Approach 1:
The invention segments the therapeutic approach by using antibody fragments (scFv) instead of full antibodies, and further segments the antigen presentation by displaying multiple copies of the antigen on nanoparticle surfaces. This segmentation allows for optimized binding affinity and signaling efficiency at lower doses, reducing toxic effects while maintaining therapeutic efficacy.
Solution Approach 2:
The invention transitions from linear antigen-antibody interaction to three-dimensional nanoparticle display, where multiple antigen copies are arranged on the surface of nanoparticles. This dimensional change creates polyvalent interactions that significantly enhance binding avidity and signaling efficiency, allowing effective therapy at lower doses with reduced toxicity.
2Reliability
If antibodies are used to bypass structural requirements and achieve high affinity binding, then signaling efficiency is improved, but the ability to crosslink in correct trimeric structure is lost unless high concentrations are used
Solution Approach 1:
The invention uses segmented antibody fragments (scFv) that retain binding capability but lack the Fc region, allowing them to function as monovalent binding units. When displayed on nanoparticle surfaces, these fragments work together in a polyvalent manner to achieve both high affinity binding and proper trimeric crosslinking without requiring high concentrations.
Solution Approach 2:
The nanoparticle serves as an intermediary structure that organizes multiple antibody fragments in space, enabling them to simultaneously achieve high affinity binding to individual antigen sites while maintaining the correct trimeric geometry for signaling. This intermediary structure resolves the contradiction between monovalent binding and polyvalent crosslinking.
3Ease of operation
If soluble CD40L is administered to provide therapeutic effect, then availability for systemic circulation is improved, but the ability to form clustered contacts for robust signaling is lost
Solution Approach 1:
The invention nests multiple copies of soluble CD40L within the structure of nanoparticles, creating a hierarchical organization where individual CD40L molecules are contained within a larger particulate structure. This nesting allows the soluble form to circulate systemically while presenting multiple copies in a clustered arrangement that restores robust signaling capability.
Solution Approach 2:
The invention changes the physical parameters of soluble CD40L by incorporating it into nanoparticles, which alters its distribution and presentation characteristics. This parameter change allows the protein to maintain solubility and circulate systemically while achieving high local concentration and proper spatial organization for robust signaling at the target site.
Data Source
AI summary
The invention provides a fusion protein comprising an antigen binding domain linked to a bacteriophage decoration (Dec) protein along with a polynucleotide comprising the nucleic acid sequence of the fusion protein and a vector comprising the polynucleotide. Additionally, the invention provides a composition comprising the fusion protein and a virus-like particle (VLP), and a method of treating a disease in a mammal comprising administering a therapeutically effective amount of the composition to the mammal. The invention also provides a method of vaccinating against a disease comprising administering a composition comprising the fusion protein and a VLP encapsulating a protein.