MMP and Serine Protease-Cleavable Substrates for Activatable Antibodies
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Solution Overview
Problem
There is a need to identify new substrates for proteases that can be used in therapeutic, diagnostic, and prophylactic indications, as existing substrates are limited in their effectiveness and specificity.
Innovation Solution
Development of amino acid sequences that include a first cleavable moiety (CM1) as a substrate for matrix metalloprotease (MMP) and a second cleavable moiety (CM2) as a substrate for serine protease (SP), which are used in activatable antibodies to enhance therapeutic, diagnostic, and prophylactic applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing substrates are used for proteases, then the substrates are limited in their effectiveness and specificity, but new substrates need to be identified to improve therapeutic, diagnostic, and prophylactic applications
Solution Approach 1:
The substrate is divided into two separate cleavable moieties (CM1 and CM2) that can be independently recognized and cleaved by different protease families (MMP and SP). This segmentation allows the substrate to interact with multiple protease types, thereby improving both effectiveness and versatility across different therapeutic applications
Solution Approach 2:
The invention creates a composite substrate structure containing both CM1 (MMP substrate) and CM2 (SP substrate) sequences. This composite design enables the substrate to serve multiple functions by being recognized by different protease families, thus resolving the limitation in adaptability while maintaining high reliability through specific recognition sequences
2Reliability
If antibodies are activated by protease cleavage, then therapeutic efficacy is improved, but the ability of antibodies to bind targets is reduced until activation occurs
Solution Approach 1:
The antibody is pre-modified with cleavable moieties (CM1 and CM2) that block its binding ability before activation. This preliminary modification allows the antibody to be administered safely without immediate target binding, and upon protease cleavage, the blocking moieties are removed to activate target binding and therapeutic effect
Solution Approach 2:
The antibody's binding capability is dynamically controlled through protease-mediated cleavage of the cleavable moieties. Before cleavage, the antibody remains inactive; after cleavage by specific proteases (MMP or SP), the antibody becomes active and can bind its target, providing dynamic control over therapeutic action
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 CM1-CM2 substrates enable targeted activation of antibodies by proteases, improving their therapeutic, diagnostic, and prophylactic efficacy by reducing the ability of the antibodies to bind their targets until activated.
Implementation Method 1
Proteases are enzymes that degrade proteins by cleaving the peptide bonds between amino acid residues
Implementation Method 2
Proteases are enzymes that degrade proteins by cleaving the peptide bonds between amino acid residues
Data Source
AI summary
The invention relates generally to polypeptides that include at least a first cleavable moiety (CM1) that is a substrate for at least one matrix metalloprotease (MMP) and at least a second cleavable moiety (CM2) that is a substrate for at least one serine protease (SP), to activatable antibodies and other larger molecules that include these polypeptides that include at least a CM1 that is a substrate for at least one MMP protease and at least a CM2 that is a substrate for at least one SP protease, and to methods of making and using these polypeptides that include at least a CM1 that is a substrate for at least one MMP protease and at least a CM2 that is a substrate for at least one SP protease in a variety of therapeutic, diagnostic and prophylactic indications.