Chimeric Polypeptides Convert Cold Tumors via Signal Peptide Release
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current cancer therapies face challenges in converting 'cold' tumors, which lack lymphocytes, into 'hot' tumors responsive to immunotherapy, particularly due to TAP-deficiency and limited MHC coverage, leading to therapeutic failures.
Innovation Solution
Development of chimeric polypeptides comprising an antigen-binding domain, an immunogenic signal peptide, and a cleavable moiety, where the signal peptide is efficiently targeted to cancer cells, internalized, and released to mediate HLA binding and surface expression, making cancer cells detectable by immune cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional immunotherapy approaches are used, then treatment response is achieved in some patients, but therapeutic failure occurs in patients with TAP-deficiency and cold tumors
Solution Approach 1:
The invention changes the fundamental parameter of antigen presentation by using signal peptides that bypass the TAP-dependent pathway. Instead of relying on conventional MHC class I presentation through TAP-deficient pathways, the signal peptides utilize an alternative route through the secretory pathway, allowing immune recognition in TAP-deficient tumors while maintaining reliability across diverse patient populations
Solution Approach 2:
The chimeric polypeptide acts as an intermediary molecule that bridges the gap between tumor cells and the immune system. The signal peptide portion serves as a mediator that can be presented by MHC class II molecules on APCs, thereby activating T cells even when the tumor cells themselves cannot present antigens through the conventional TAP-dependent MHC class I pathway
2Reliability
If intratumoral injection of viral peptides is used, then anti-tumor immunity is enhanced, but the method is not viable for many tumors and has limited population applicability
Solution Approach 1:
The chimeric polypeptide is designed to be self-sufficient upon administration. Once injected systemically, it autonomously targets tumor cells through the antigen-binding domain, internalizes, and processes itself to generate immunogenic peptides, eliminating the need for complex intratumoral injection procedures or specialized delivery infrastructure
Solution Approach 2:
The chimeric polypeptide structure combines multiple functions in a single molecule: tumor targeting (antigen-binding domain), immunogenic peptide generation (signal peptide), and controlled release (cleavable moiety). This multi-functional design makes it universally applicable to various tumor types regardless of accessibility, overcoming the limitations of intratumoral injection
3Reliability
If single epitope vaccines are used, then specific T cell response is generated, but MHC coverage is limited and T cell immune robustness is insufficient
Solution Approach 1:
The invention merges multiple signal peptide sequences from different sources (human and bacterial) into a single chimeric polypeptide construct. This combination creates a diversified set of immunogenic peptides that can be presented by multiple different MHC class II alleles, thereby expanding MHC coverage while maintaining robust T cell activation across diverse patient populations
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 chimeric polypeptides effectively convert cold tumors into hot tumors, enhancing immune recognition and killing of cancer cells, overcoming TAP-deficiency and MHC limitations, thereby improving treatment outcomes.
Implementation Method 1
the signal peptide is efficiently targeted to cancer cells, internalized, and released
Data Source
AI summary
Chimeric polypeptides comprising a first subunit comprising an antigen-binding domain, a second subunit comprising at least one immunogenic peptide comprising a signal peptide and a third subunit comprising a cleavable moiety, wherein the third subunit is between the first and second subunits is provided. Nucleic acid molecules encoding the chimeric polypeptide, cells expressing the nucleic acid molecules, pharmaceutical compositions comprising the chimeric polypeptide, and methods of treating cancer by administrating the chimeric polypeptide or pharmaceutical compositions are also provided.