Extracellular Ras Detection With ABP Combinations in 3D Tumor Models
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Solution Overview
Problem
Existing cancer immunotherapies targeting intracellular Ras proteins are limited by their reliance on the human leukocyte antigen (HLA) system, and 3D tumor models fail to accurately represent the tumor microenvironment, hindering effective combination therapies and detection methods for extracellular Ras expression.
Innovation Solution
Development of antigen-binding proteins (ABPs) that target extracellular Ras antigen independently of the HLA system, combined with modulator compounds, and the use of a 3D tumor cell model to test these combinations for enhanced anti-tumor effects, along with methods to detect extracellular Ras expression on viable cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T-cell receptors or antibody single-chain variable fragments targeting Ras mutant peptides expressed via HLA class I or II are used, then cancer immunotherapy can be achieved, but the therapy is restricted to specific HLA alleles and requires the HLA system
Solution Approach 1:
The invention extracts the Ras peptide from the HLA context and presents it in a soluble form that can be targeted by ABPs without requiring HLA presentation. This removes the HLA restriction barrier while maintaining the immunotherapeutic effect against Ras-mutant cancer cells.
Solution Approach 2:
The patent introduces ABPs as intermediary molecules that bind to soluble Ras peptides. These ABPs serve as mediators between the immune system and Ras-mutant cancer cells, enabling targeted therapy without direct HLA-T cell interaction.
2Ease of manufacture
If 2D cell culture models are used for testing therapies, then experimental simplicity is maintained, but accurate representation of tumor microenvironment and combination therapy effects is lost
Solution Approach 1:
The invention transitions from 2D cell culture to 3D tumor models, adding a spatial dimension that better represents the tumor microenvironment. This enables more accurate assessment of combination therapy effects while maintaining experimental feasibility.
3Measurement precision
If detection methods for extracellular Ras expression are developed, then diagnosis and treatment monitoring can be improved, but detection of predominantly extracellular Ras on living cells remains challenging
Solution Approach 1:
The invention creates a soluble copy or mimic of extracellular Ras that can be detected by ABPs. This allows for accurate detection and quantification of extracellular Ras expression on living cells without requiring invasive procedures.
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 ABP combinations demonstrate improved anti-tumor effects and provide accurate detection of extracellular Ras, offering better signal-to-noise ratios and enabling effective diagnosis, prevention, and treatment of proliferative disorders like cancer, including those with mutated Ras proteins.
Implementation Method 1
an antigen-binding protein (ABP) or an isolated nucleic acid comprising a sequence encoding the ABP, wherein the ABP comprises at least a first antigen binding domain capable of binding to an extracellular Ras antigen
Data Source
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AI summary
The present invention relates to a combination of an antigen binding protein (ABP) or an isolated nucleic acid comprising a sequence encoding the ABP and a modulator compound for use as medicament. The ABP comprises at least a first antigen binding domain capable of binding to an extracellular Ras antigen. The invention also relates to a pharmaceutical composition comprising the combination and a composition or kit comprising an antigen binding protein (ABP) or an isolated nucleic acid comprising a sequence encoding the ABP and a modulator compound. The invention also relates to an in vitro 3D cell culture model and an in vitro method for detecting the expression of predominantly extracellular Ras proteins on the surface of predominantly living cells.