TMAPP Polypeptides with Conjugation Sites for T-Cell Specificity
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Solution Overview
Problem
Current immunotherapies face challenges in selectively modulating T-cell responses to target specific antigens while avoiding non-specific activation that can lead to tissue damage, due to the lack of precise control over T-cell receptor interactions and epitope presentation.
Innovation Solution
Development of T-cell modulatory antigen-presenting polypeptides (TMAPPs) with chemical conjugation sites for epitope and payload attachment, allowing for specific binding to T-cell receptors and modulation of T-cell activity through the use of immunomodulatory sequences, enabling targeted T-cell responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional immunotherapies are used to modulate T-cell responses, then T-cell activity can be activated, but non-specific activation occurs leading to tissue damage
Solution Approach 1:
The invention segments the antigen-presenting cell into distinct functional components: a scaffold polypeptide for structural support, chemical conjugation sites for epitope attachment, and immunomodulatory sequences for T-cell regulation. This segmentation allows precise control over which epitopes are presented and to which T-cells, thereby achieving specific activation without non-specific tissue damage.
Solution Approach 2:
The TMAPP design applies local quality by placing specific functional regions at defined locations: chemical conjugation sites are positioned at specific locations on the scaffold polypeptide to attach epitopes, while immunomodulatory sequences are strategically placed to regulate T-cell responses. This localized functional distribution enables precise control over T-cell activation specificity.
2Productivity
If epitopes are presented to T-cells to generate specific immune responses, then targeted immunity is achieved, but control over T-cell receptor interactions is insufficient
Solution Approach 1:
The invention incorporates immunomodulatory sequences that provide feedback control over T-cell receptor interactions. These sequences can enhance or suppress T-cell activation based on the specific epitope presented and the T-cell population, allowing precise regulation of the immune response magnitude and specificity.
Solution Approach 2:
The TMAPP system enables parameter changes in epitope presentation by allowing chemical conjugation of different epitopes to the scaffold polypeptide. This flexibility permits adjustment of epitope types, concentrations, and presentation kinetics to optimize T-cell activation parameters for specific therapeutic applications.
3Adaptability or versatility
If multiple epitopes are conjugated to TMAPPs to broaden antigen coverage, then versatility of immune response is improved, but complexity of conjugation and epitope selection increases
Solution Approach 1:
The scaffold polypeptide is designed as a universal platform with multiple chemical conjugation sites that can accommodate various epitope types. This multi-functional design allows a single TMAPP scaffold to present different epitopes for diverse antigen targets, achieving broad antigen coverage without requiring separate conjugation protocols for each epitope type.
Solution Approach 2:
The chemical conjugation sites are pre-positioned on the scaffold polypeptide during manufacturing, eliminating the need for complex post-production conjugation steps. This preliminary preparation simplifies the overall process by allowing direct assembly of epitopes onto the pre-configured scaffold.
4Adaptability or versatility
If chemical conjugation sites are added to TMAPPs for epitope and payload attachment, then functionality and versatility are enhanced, but structural complexity of the polypeptide increases
Solution Approach 1:
The chemical conjugation sites are nested within the scaffold polypeptide structure rather than adding external complexity. The scaffold polypeptide is designed with integrated conjugation sites that fit within its structural framework, allowing epitope and payload attachment without significantly increasing overall structural complexity.
Data Source
AI summary
The present disclosure provides antigen-presenting polypeptides, including single-chain antigen-presenting polypeptides and multimeric antigen-presenting polypeptides comprising one or more chemical conjugation sites for incorporation of, for example, epitope containing polypeptides. The present disclosure provides nucleic acids comprising nucleotide sequences encoding antigen-presenting polypeptides comprising one or more chemical conjugation sites, as well as cells genetically modified with the nucleic acids. The single-chain and multimeric antigen-presenting polypeptides and their epitope conjugates are useful for modulating the activity of a T-cell, and accordingly, the present disclosure provides methods of modulating activity of a T-cell in vitro and in vivo as a method of treatment.