Artificial APC Library for Rapid Neoantigen Screening
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods for screening T-cell responses to cancer-specific neoantigens are limited by the availability of native antigen-presenting cells and the time-consuming process of inducing their maturation, particularly in Asian populations where a comprehensive library of HLA-matched APCs is lacking.
Innovation Solution
A method is developed to generate a library of artificial antigen-presenting cells (aAPC) co-expressing prevalent HLA-I and HLA-II alleles in Asian populations, along with the co-stimulatory molecule CD80, to facilitate rapid and comprehensive screening of immunogenic neoantigens.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If native antigen-presenting cells are used for neoantigen screening, then the screening can be performed with patient-specific cells, but the procedure is time-consuming due to the need to induce maturation and the limited number of available cells
Solution Approach 1:
The patent uses artificial antigen-presenting cells (aAPCs) as an intermediary system. These aAPCs are engineered to express specific HLA molecules and co-stimulatory molecules, serving as a substitute for patient-specific APCs. They can present neoantigens and activate T cells without requiring time-consuming maturation processes, thus resolving the contradiction between reliability and time loss.
Solution Approach 2:
The patent creates artificial copies of antigen-presenting cells with defined HLA molecules and co-stimulatory molecules. These copied cells (aAPCs) replicate the essential functions of native APCs for antigen presentation and T cell activation, eliminating the need for prolonged culture and maturation while maintaining screening reliability.
2Adaptability or versatility
If a comprehensive library of HLA-matched artificial APCs is constructed, then coverage of all HLA types in Asian populations is improved, but the device complexity and manufacturing difficulty increase
Solution Approach 1:
The patent segments the comprehensive HLA coverage into multiple distinct aAPC lines, each expressing a specific HLA class I or class II molecule. This segmentation allows the complex task of covering all HLA types to be divided into manageable individual cell lines, simplifying the overall construction and implementation of the library.
Solution Approach 2:
The patent develops a universal platform of aAPCs that can be used across different patient populations with varying HLA types. By creating a panel of aAPCs expressing common HLA alleles in Asian populations, the system achieves broad adaptability and versatility without requiring custom development for each patient, thus managing complexity while maintaining high coverage.
3Ease of manufacture
If K562 cells are used as artificial APCs, then high transfection efficiency and absence of endogenous HLA expression are achieved, but the HLA profile may not faithfully replicate patient tumor cells
Solution Approach 1:
The patent applies local quality by engineering specific HLA molecules and co-stimulatory molecules into the K562 cell background. Rather than attempting to replicate the entire complex HLA profile of patient tumor cells, the system selectively introduces specific HLA class I and class II molecules along with co-stimulatory molecules like CD80, CD86, and ICAM-1, creating locally optimized cells for their intended screening function.
Data Source
AI summary
A rapid, comprehensive and sensitive method for neoantigen screening from recurrent cancer mutations comprising: (A) STEP 1: selecting recurrent cancer mutations dividing into three tiers based on ranking features; (B) STEP 2: Generating a library of artificial antigen presenting cells (aAPC) co-expressing HLA types (including a list of 13 most frequent HLA class I types covering 66% of Asian population or 67% of Vietnamese population, and a list of 04 most frequent HLA class II types covering 41% Asian population or 50% of Vietnamese population) and a co-stimulatory molecule; and (C) STEP 3: Using the library of aAPC at step (B) for rapid and comprehensive screening for selecting of immunogenic peptides (neoantigens) from the off-the-shelf peptides at step (A) activate T cells via immunological assays (ELISpot or intracellular staining flow cytometry).