C-Terminal Capped Polypeptides for Lower Anti-Drug Antibody Binding
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Solution Overview
Problem
Existing polypeptides interact excessively with molecules such as anti-drug antibodies, leading to issues like aggregation and reduced efficacy in therapeutic applications.
Innovation Solution
Incorporating a cap domain, specifically a His cap domain, at the exposed C-terminus of polypeptides to reduce interactions with anti-drug antibodies and other molecules, thereby minimizing aggregation and improving stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a polypeptide is used as a therapeutic agent, then it can bind to target molecules and exert therapeutic effect, but it interacts excessively with anti-drug antibodies and other molecules causing aggregation and reduced efficacy
Solution Approach 1:
A cap domain is introduced as an intermediary element between the polypeptide and anti-drug antibodies. This cap domain acts as a protective mediator that prevents direct harmful interactions while allowing the polypeptide to maintain its therapeutic function. The cap domain is positioned at the N-terminus and serves as a buffer that reduces binding affinity for anti-drug antibodies.
Solution Approach 2:
The polypeptide structure is segmented into distinct functional regions: the cap domain at the N-terminus, the target binding region in the middle, and the C-terminus. This segmentation allows each region to perform its specific function independently - the cap domain prevents harmful interactions, while the target binding region maintains therapeutic activity.
2Stability of the object's composition
If the polypeptide sequence is modified to reduce anti-drug antibody interactions, then stability improves, but the complexity of the polypeptide structure increases
Solution Approach 1:
The amino acid sequence parameters are modified by introducing a cap domain with specific amino acid composition at the N-terminus. This parameter change (adding specific residues) reduces interaction with anti-drug antibodies and improves stability without requiring complex structural modifications throughout the entire polypeptide chain.
Solution Approach 2:
Instead of modifying the entire polypeptide structure, the cap domain applies local quality improvement at the N-terminus. This localized modification provides the necessary stability and reduced immunogenicity without increasing overall structural complexity.
3Reliability
If a cap domain is added to the polypeptide, then interaction with anti-drug antibodies is reduced, but the molecular weight and size of the polypeptide increase
Solution Approach 1:
The cap domain is designed as a small, simple structural element that provides protective function without significant weight penalty. It acts as a disposable-like protective layer that is easily added and provides sustained protection against anti-drug antibodies throughout the therapeutic course.
Data Source
AI summary
The presently described invention teaches isolated polypeptides, including diagnostic, prognostic, and therapeutic polypeptides, such as, for example, polypeptides that are capable of binding to themselves or other polypeptides, said isolated polypeptides comprising an exposed carboxy-terminus (“C-terminus”) fused to a cap domain (e.g., a His cap domain, (His)6 (i.e., HHHHHH (SEQ ID NO:26)), SLSLSPGK (SEQ ID NO:36), AS, or TVAPTESS (SEQ ID NO: 37)). The presently described invention further teaches nucleic acids and/or expression vectors encoding the polypeptides; cells containing the polypeptides, nucleic acids, and/or expression vectors; and compositions comprising the polypeptides. Methods of making the polypeptides, and methods of using the polypeptides are also taught.