Bob1-Specific TCR for B Cell Malignancy Therapy
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Solution Overview
Problem
Current adoptive T cell therapies for hyperproliferative diseases, such as B cell malignancies and multiple myeloma, face limitations as they often target extracellular antigens, and the loss of these antigens on cancer cells restricts therapy effectiveness, while intracellular antigens like Bob1, encoded by POU2AF1, are challenging due to self-reactivity concerns.
Innovation Solution
Development of nucleic acid compositions, vector systems, and modified cells that encode and express T cell receptor components specific to the Bob1 peptide LPHQPLATY, presented by MHC Class I HLA-B*35:01, enabling targeted immune responses in patients with B cell malignancies and multiple myeloma.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T cell therapies target extracellular antigens, then the therapy can be implemented, but the loss of these antigens on cancer cells restricts therapy effectiveness
Solution Approach 1:
The patent extracts the antigen recognition function from the extracellular space and relocates it to the intracellular domain by targeting Bob1, an intracellular transcription factor. This extraction of the antigen target from the cell surface to the intracellular compartment allows T cells to recognize cancer cells even when extracellular antigens are lost or downregulated.
Solution Approach 2:
The patent introduces MHC Class I molecules as intermediaries that present intracellular Bob1 peptides to T cell receptors. This intermediary mechanism allows indirect recognition of intracellular antigens, enabling T cells to detect and respond to cancer cells expressing Bob1 even when direct extracellular antigen recognition is compromised.
2Reliability
If T cell therapies target intracellular antigens like Bob1, then therapy effectiveness is improved, but self-reactivity concerns arise
Solution Approach 1:
The patent applies local quality by making the T cell receptor specificity localized to a particular MHC Class I allele context (HLA-B*35:01). The Bob1-specific TCR is designed to recognize the peptide-MHC complex only in this specific context, allowing selective targeting of cancer cells expressing both Bob1 and HLA-B*35:01 while sparing normal cells that may express Bob1 but lack the specific MHC context.
Solution Approach 2:
The patent changes the recognition parameter from direct antigen binding to peptide-MHC complex recognition. By requiring both the Bob1 peptide and the specific MHC Class I HLA-B*35:01 molecule for T cell activation, the system creates a dual-specificity requirement that reduces off-target effects and self-reactivity while maintaining effective cancer cell targeting.
3Reliability
If T cell receptors specific to Bob1 peptide are developed, then specific immune response is enhanced, but the complexity of nucleic acid composition and vector design increases
Solution Approach 1:
The patent segments the T cell receptor into separate alpha and beta chain components, each encoded by distinct nucleic acid sequences. This segmentation allows independent optimization and verification of each chain's functionality, simplifying the overall design and assembly process while maintaining the ability to generate specific antigen recognition.
Solution Approach 2:
The patent employs universal vector systems that can accommodate and express the Bob1-specific TCR nucleic acid sequences. These vectors are designed with universal features including promoter elements, selection markers, and regulatory sequences that can be applied to multiple different TCR specificities, reducing the need for custom vector design for each new antigen target.
Data Source
AI summary
Novel nucleic acid compositions, vector systems, modified cells and pharmaceutical compositions that encode or express T cell receptor components directed against Bob 1 are provided herein. These novel components may be used to enhance an immune response in a subject diagnosed with a hyperproliferative disease or condition. Associated methods for treating such subjects are therefore also provided herein.