Inhibiting Domain Polypeptide for Targeted Antigen Release
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Solution Overview
Problem
Current antibody drugs face challenges in targeting cancer cells specifically while minimizing adverse reactions in normal tissues due to the expression of target antigens in both cancer and normal cells, leading to systemic distribution and activation of antibodies, which can cause adverse reactions.
Innovation Solution
A polypeptide comprising an antigen binding domain and a carrying moiety with an inhibiting domain that suppresses antigen binding activity, allowing targeted restoration of antigen binding activity in disease tissues while minimizing systemic distribution, utilizing a protease cleavage sequence for targeted release and activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If an antibody drug is administered systemically to target cancer cells, then therapeutic efficacy against cancer cells is improved, but adverse reactions in normal tissues occur due to antigen expression in both cancer and normal cells
Solution Approach 1:
The antibody is divided into two functional parts: an antigen-binding domain and a carrying moiety with inhibiting domain. The antigen-binding domain is separated from the full antibody structure, allowing independent control of binding activity and half-life properties
Solution Approach 2:
The antigen-binding domain is pre-modified with a carrying moiety that provides a longer half-life before administration. This preliminary modification ensures the domain remains in circulation longer but cannot bind antigen until the inhibiting domain is removed by protease cleavage at the target site
2Object-affected harmful factors
If the antigen binding domain has a short half-life in blood, then systemic distribution and activation are minimized reducing adverse reactions, but therapeutic efficacy is reduced
Solution Approach 1:
The antigen-binding domain is combined with a carrying moiety that has different half-life properties. The composite structure (polypeptide) has a longer half-life than the antigen-binding domain alone, allowing extended circulation time while maintaining controlled antigen binding through the inhibiting domain
3Reliability
If the antigen binding domain is activated systemically, then therapeutic coverage is maximized, but adverse reactions increase due to normal tissue antigen expression
Solution Approach 1:
The carrying moiety acts as an intermediary that modifies the pharmacokinetic properties of the antigen-binding domain. It provides a longer half-life and serves as a delivery vehicle that controls where and when the antigen-binding domain becomes active through protease cleavage
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The polypeptide effectively reduces adverse reactions by ensuring antigen binding activity is restored only in disease tissues, enhancing therapeutic efficacy while minimizing systemic activation and distribution, thus reducing normal tissue targeting.
Implementation Method 1
utilizing a protease cleavage sequence for targeted release and activation
Data Source
AI summary
The present invention relates to a polypeptide comprising an antigen binding domain and a carrying moiety having an inhibiting domain that inhibits the antigen binding activity of the antigen binding domain, and having a longer half-life than that of the antigen binding domain existing alone, methods for producing and screening for the polypeptide, a pharmaceutical composition comprising the polypeptide, methods for producing and screening for a single-domain antibody whose antigen binding activity is inhibited by associating with particular VL, VH or VHH, and a fusion polypeptide library including a single-domain antibody whose antigen binding activity is inhibited by associating with particular VL, VH or VHH.