MSLN–CD3 Bispecific Antibody Constructs for Solid-Tumor Targeting
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Solution Overview
Problem
Current anti-mesothelin antibodies targeting the amino terminal region of the protein show limited efficacy in treating solid tumors, and there is a need for alternative antibodies that recognize different epitopes of mesothelin to improve therapeutic outcomes for cancers such as ovarian, pancreatic, mesothelioma, lung, and gastric cancers.
Innovation Solution
Development of a bispecific antibody construct with a binding domain for human MSLN and a binding domain for CD3, specifically targeting epitopes within the MSLN variants as depicted in SEQ ID NOs: 231, 232, and 233, and Macaca fascicularis MSLN as depicted in SEQ ID NOs: 234, to enhance T cell engagement and tumor targeting.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current anti-mesothelin antibodies targeting the amino terminal region are used, then they can recognize mesothelin on tumor cells, but they show limited therapeutic efficacy in treating solid tumors
Solution Approach 1:
The patent divides the single antibody function into two separate binding domains: one targeting mesothelin on tumor cells and another targeting CD3 on T cells. This segmentation allows the construct to engage both tumor cells and immune cells simultaneously, overcoming the limited efficacy of conventional single-target antibodies while maintaining specific recognition of mesothelin epitopes
Solution Approach 2:
The bispecific antibody construct performs multiple functions: it binds to mesothelin-expressing tumor cells through the first binding domain, recruits T cells through CD3 binding by the second domain, and facilitates T cell-mediated tumor cell killing. This multi-functionality transforms the antibody from a simple recognition molecule into an active immunotherapeutic agent
2Reliability
If conventional single-specificity antibodies are used, then the antibody structure is simple, but the T cell engagement and tumor targeting capability is insufficient
Solution Approach 1:
The patent merges two separate antibody specificities into a single bispecific construct. The first binding domain targets mesothelin on tumor cells while the second binding domain targets CD3 on T cells. This merging creates a unified molecule that can simultaneously engage both cell types, enabling effective T cell-mediated tumor targeting without requiring multiple separate antibody administrations
Solution Approach 2:
The bispecific antibody acts as an intermediary molecule that bridges tumor cells and T cells. By containing binding domains for both mesothelin (on tumor cells) and CD3 (on T cells), the antibody construct mediates the interaction between these two cell types, facilitating T cell recruitment and activation against tumor targets
Data Source
AI summary
The present invention relates to a bispecific antibody construct comprising a first binding domain which binds to human MSLN on the surface of a target cell and a second binding domain which binds to human CD3 on the surface of a T cell. Moreover, the invention provides a polynucleotide encoding the antibody construct, a vector comprising said polynucleotide and a host cell transformed or transfected with said polynucleotide or vector. Furthermore, the invention provides a process for the production of the antibody construct of the invention, a medical use of said antibody construct and a kit comprising said antibody construct.