Multispecific Polypeptide with Constrained CD3 Binding
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Solution Overview
Problem
Current therapeutic antibodies rely on effector functions mediated via Fc-gamma-receptors and complement proteins, primarily involving innate immune cells, and there is a need for antibodies that can target the CD3/TCR pathway for therapeutic and diagnostic applications.
Innovation Solution
Development of multispecific polypeptide constructs containing an immunoglobulin Fc region and a CD3-binding region, coupled by a linker, with antigen binding domains that bind tumor-associated antigens and co-stimulatory or inhibitory receptor binding regions, allowing for targeted engagement of CD3 only upon antigen binding.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If therapeutic antibodies target the CD3/TCR pathway to activate T-cells, then immune response against tumor cells is enhanced, but interaction with peripheral T-cells increases causing off-target effects
Solution Approach 1:
The antibody construct is designed with a constrained CD3-binding domain that cannot bind to CD3 until a preliminary action occurs - specifically, until the antibody first binds to its target antigen on the tumor cell surface. This preliminary antigen binding event triggers a conformational change that exposes or enables the CD3 binding capability, ensuring T-cell activation only occurs at the intended target site and not with peripheral T-cells in circulation.
2Adaptability or versatility
If multispecific polypeptide constructs are designed with multiple binding domains, then functionality and versatility are improved, but molecular complexity increases
Solution Approach 1:
The multisspecific polypeptide construct is segmented into distinct functional modules: a target antigen-binding domain, a constrained CD3-binding domain, and optional co-stimulatory or inhibitory receptor-binding domains. Each segment performs a specific function, and they are connected through linkers that allow independent folding and binding. This modular segmentation enables the complex multifunctional construct to be designed, assembled, and controlled in a systematic manner, reducing the practical complexity despite the multiple binding capabilities.
Data Source
AI summary
The invention relates generally to multispecific polypeptides that bind at least CD3, a second antigen, and a receptor of a T cell, such as a costimulatory receptor or an inhibitory receptor, in which the multispecific polypeptide constructs are able to engage CD3. In some embodiments, the multispecific polypeptide constructs bind a costimulatory receptor and provide costimulatory binding activity. In some embodiments, the multispecific polypeptide constructs bind an inhibitory receptor and block inhibitory activity. In some aspects, the multispecific polypeptides have constrained CD3 binding and bind to or engage CD3 only upon binding to the second antigen, such as a tumor associated antigen. In some embodiments, the multispecific polypeptides contain cleavable linkers that, when cleaved, result in dual effector functions. Also provided are methods of making and using these multispecific polypeptides in a variety of therapeutic, diagnostic and prophylactic indications.