Engineered TCR Molecules for Low-Level RLPAKAPLL-HLA-E Recognition
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Solution Overview
Problem
Current therapies for tuberculosis (TB) are inadequate due to Mycobacterium tuberculosis's complex immune response and immune escape mechanisms, necessitating new therapeutic interventions targeting the HLA-E restricted peptide RLPAKAPLL for effective treatment.
Innovation Solution
Development of specific binding molecules, such as TCR alpha and beta chain variable domains with engineered CDRs and framework regions, that bind to the RLPAKAPLL HLA-E complex, facilitating T cell recognition and clearance of infected cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies are used for tuberculosis treatment, then existing treatment protocols can be applied, but the complex immune response and immune escape mechanisms of Mycobacterium tuberculosis make the bacteria difficult to treat
Solution Approach 1:
The patent segments the complex immune response by targeting a specific, limited peptide-MHC complex (RLPAKAPLL-HLA-E) rather than attempting to address the entire complex immune system. This focal approach simplifies the therapeutic strategy to a specific binding molecule that recognizes a single epitope, making the treatment more reliable despite the overall complexity of TB pathology.
Solution Approach 2:
The patent changes the parameter of target specificity from non-specific to highly specific by designing binding molecules that recognize a particular peptide sequence (RLPAKAPLL) presented by a specific MHC molecule (HLA-E). This parameter change transforms the approach from general immune modulation to precise molecular targeting, improving treatment reliability.
2Measurement precision
If HLA-E restricted peptide RLPAKAPLL is targeted for therapy, then specific binding molecules can be designed with high affinity and specificity, but the peptide presentation levels on infected cells may be low
Solution Approach 1:
The patent changes the binding parameters by engineering TCRs with enhanced affinity for the RLPAKAPLL-HLA-E complex. Through selective pressure and mutagenesis, the TCRs achieve high-affinity binding (low micromolar to nanomolar KD) that can detect and respond to low levels of peptide presentation on infected cells, overcoming the limitation of low antigen density.
Solution Approach 2:
The patent uses T cell receptor molecules as biological copies that can be engineered and standardized. These engineered TCRs serve as templates for creating therapeutic agents that replicate the high-specificity binding capability, allowing the same high-affinity recognition to be achieved across multiple treatment units despite varying peptide presentation levels.
3Productivity
If T cell receptor based immunotherapeutic intervention is used, then potent T cell responses can be elicited against TB-infected cells, but off-target recognition may occur
Solution Approach 1:
The patent applies local quality by concentrating the binding specificity at the CDR3 region of the TCR, which directly contacts the peptide-MHC complex. This localized specificity ensures that the high potency T cell response is directed exclusively at RLPAKAPLL-HLA-E while minimizing off-target recognition, as the CDR3 sequence is engineered to recognize only this specific epitope.
Solution Approach 2:
The patent incorporates feedback mechanisms through the natural T cell activation threshold and cytokine production regulation. Engineered TCRs with high specificity provide feedback that activates T cells only when the correct peptide-MHC complex is present, preventing off-target responses while maintaining potent activity against infected cells.
Data Source
AI summary
The present invention relates to specific binding molecules which bind to the HLA-E restricted peptide RLPAKAPLL (SEQ ID NO: 1) derived from Mycobacterium tuberculosis enoyl-ACP reductase. Said specific binding molecules may comprise CDR sequences embedded within a framework sequence. The CDRs and framework sequences may correspond to a T cell receptor (TCR) variable domain and may further comprise non-natural mutations relative to a native TCR variable domain. The specific binding molecules of the invention are particularly suitable for use as novel immunotherapeutic reagents for the treatment of infectious disease.