MAGEB2 Bispecific Antibody Constructs for Tumor-Selective T-Cell Lysis
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Solution Overview
Problem
Current cancer treatments lack effective therapeutics targeting MAGEB2, a protein aberrantly expressed in various tumors, due to the challenges of specifically binding to the small MAGEB2 peptide presented by MHC class I molecules on cancer cells without affecting normal cells.
Innovation Solution
Development of bispecific antibody constructs that bind specifically to the MAGEB2 peptide-HLA complex on tumor cells and human CD3 on immune effector cells, facilitating T-cell redirected lysis of cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional cancer treatments are used, then they can treat various cancers, but they lack specificity and affect normal cells along with tumor cells
Solution Approach 1:
The treatment approach is segmented into two distinct binding domains: one specifically targeting the MAGEB2 peptide-HLA complex on tumor cells, and another targeting CD3 on T cells. This segmentation enables selective engagement of immune cells with tumor cells expressing the specific antigen, sparing normal cells that do not express MAGEB2.
Solution Approach 2:
The bispecific antibody exhibits local quality by having different binding specificities at its two ends: one end binds with high specificity to the MAGEB2 peptide-HLA complex (distinguishing tumor cells from normal cells), while the other end binds to CD3 on immune effector cells. This localized functional differentiation enables selective tumor targeting.
2Reliability
If small molecule pharmaceuticals are used, then they can penetrate cells, but they have lower specificity compared to protein-based pharmaceuticals
Solution Approach 1:
The bispecific antibody functions as a composite molecular structure combining features of two different monoclonal antibodies into a single molecule. This composite structure integrates two distinct binding specificities (MAGEB2 peptide-HLA and CD3) within one therapeutic agent, achieving high specificity without requiring multiple separate molecules.
3Reliability
If full length bispecific antibodies are used, then they retain traditional mAb structure with two Fab arms and one Fc region, but they may have increased complexity in manufacturing and purification
Solution Approach 1:
The invention extracts and utilizes only the essential functional domains needed for bispecific binding: two Fab regions with different specificities. By focusing on the minimal necessary structure (the binding domains) rather than including the full Fc region and associated structures, the molecule achieves the required functionality with simplified manufacturing and purification processes.
Data Source
AI summary
The present invention relates to antibody constructs comprising a domain which binds to a MAGEB2 peptide complexed with an HLA and optionally, another domain which binds to CD3. Moreover, the invention provides polynucleotides encoding the antibody constructs, vectors comprising said polynucleotides and host cells transformed or transfected with said polynucleotides or vectors. Furthermore, the invention provides processes for producing the antibody constructs of the invention, medical uses of said antibody constructs, and kits comprising said antibody constructs.