Anti-TRBC1 Binding Domains for Selective T-Cell Depletion
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Solution Overview
Problem
Current treatments for T-cell lymphoma and leukemia are ineffective and associated with severe immunosuppression and toxicity due to the lack of a specific antigen to target malignant T-cells without affecting normal T-cells, and existing immunotherapies like Alemtuzumab cause profound T-cell depletion leading to cellular immunodeficiency.
Innovation Solution
Development of humanized antigen-binding domains, such as chimeric antigen receptors (CARs), therapeutic antibodies, antibody-drug conjugates, and bi-specific T-cell engagers that selectively target TRBC1-expressing T-cells, while sparing TRBC2-expressing healthy cells, using specific VH and VL domains with defined CDR sequences.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional immunotherapies like Alemtuzumab are used to target T-cell malignancies, then tumor cells are depleted, but severe immunosuppression and cellular immunodeficiency occur due to profound T-cell compartment depletion
Solution Approach 1:
The patent segments the T-cell receptor beta constant region into two distinct isoforms (TRBC1 and TRBC2) that are mutually exclusive on individual cells. This segmentation allows selective targeting of malignant TRBC1-expressing cells while sparing normal TRBC2-expressing cells, thereby achieving tumor depletion without profound immunosuppression
Solution Approach 2:
The invention applies local quality by creating an antibody (JOVI-1) with specific complementarity determining regions that bind selectively to the TRBC1 isoform. This localized specificity ensures that only T-cells expressing TRBC1 are targeted, leaving TRBC2-expressing normal T-cells unaffected, thus eliminating widespread immunosuppression while maintaining anti-tumor efficacy
2Reliability
If a pan-B-cell antigen is targeted to treat B-cell malignancy, then B-cell compartment is depleted, but this results in relatively minor immunosuppression that is readily tolerated by patients
Solution Approach 1:
The patent applies segmentation to the T-cell receptor beta constant region, dividing it into TRBC1 and TRBC2 isoforms. This allows selective depletion of TRBC1-expressing malignant cells while preserving TRBC2-expressing normal cells, achieving a similar beneficial outcome to B-cell targeting where only a subset of cells is affected, minimizing immunosuppression
Solution Approach 2:
The JOVI-1 antibody is designed with local quality through its specific CDR sequences that recognize only the TRBC1 isoform. This localized binding specificity ensures that normal TRBC2-expressing T-cells are spared, resulting in minimal immunosuppression comparable to the tolerable effects seen in B-cell targeting therapies
3Reliability
If Alemtuzumab is used to target CD52-expressing cells, then some efficacy is achieved in T-cell malignancies, but profound cellular immunodeficiency and markedly elevated infection risk occur
Solution Approach 1:
The patent segments the T-cell population based on TRBC1/TRBC2 expression, allowing selective targeting of the malignant compartment while preserving the normal compartment. This segmentation approach achieves anti-tumor efficacy without the profound immunodeficiency caused by non-selective CD52 targeting
Solution Approach 2:
The JOVI-1 antibody exhibits local quality through its TRBC1-specific binding, ensuring that only malignant cells expressing TRBC1 are targeted. This localized specificity prevents the widespread T-cell depletion that causes cellular immunodeficiency and infection risk, while maintaining treatment efficacy
4Productivity
If current chemotherapy treatments are used for T-cell lymphoma, then some tumor reduction is achieved, but less than 30% of patients are cured and 5-year survival is only 30%
Solution Approach 1:
The patent employs self-service by utilizing the patient's own T-cell compartment and TRBC1/TRBC2 segmentation to achieve selective tumor targeting. The therapy leverages the patient's immune system resources, specifically the differential expression of TRBC1 on tumor cells versus TRBC2 on normal cells, to achieve high cure rates without relying on non-selective chemotherapy
Data Source
AI summary
The present disclosure relates to anti-TRBCl antigen binding domains characterized by the sequences of the variable chains. The CDRs sequences of the variable chains are: (VH CDR1) GYTFT, (VH CDR2) NPYNDDIQS, (VH CDR3) GAGY-NFDGAYRFFDF; and (VL CDR1) RSSQRLVHSNGNTYL, (VL CDR2) RVSNRFP, (VL CDR3) SQSTHVPYT. The claimed humanized antibodies derive from the murine JOVI antibody. Uses in cancer therapy.