Activatable Antibodies With Steric Shield Blocking
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Solution Overview
Problem
Conventional antibodies often cause undesirable side effects due to binding to targets in both diseased and normal tissues, leading to reduced therapeutic efficacy and potential discontinuation of treatment.
Innovation Solution
Development of activatable antibodies with steric shields that block antigen-binding sites, comprising polypeptide shield moieties fused to the N-termini of heavy and light chain variable regions, which are disrupted at diseased sites to allow specific binding to targets, reducing off-target interactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antibodies are used to bind to target antigens, then therapeutic activity is achieved, but side effects occur due to binding to targets in normal tissues
Solution Approach 1:
The patent applies preliminary action by incorporating a steric shield into the antibody structure before administration. The steric shield is a polypeptide moiety fused to the antibody that pre-blocks the antigen-binding site, preventing the antibody from binding to target antigens in normal tissues before the antibody reaches the diseased site. This preliminary blocking mechanism eliminates off-target binding and associated side effects while maintaining therapeutic activity at the disease site through disease-activated release of the steric shield.
2Adaptability or versatility
If antibodies bind to targets in both diseased and normal tissues, then coverage of target is achieved, but therapeutic index is reduced
Solution Approach 1:
The patent applies local quality by creating a steric shield with disease-specific properties. The steric shield is designed to be released under specific disease conditions (such as acidic pH or proteolytic enzymes found in tumor microenvironments), thereby activating the antibody's binding capability locally at the disease site while maintaining inhibition in normal tissues. This localized activation ensures the antibody only binds to targets in diseased tissues, improving the therapeutic index while maintaining target coverage where needed.
3Object-affected harmful factors
If steric shield is introduced to block antigen-binding site, then side effects are reduced, but antibody activation is prevented
Solution Approach 1:
The patent applies dynamics by designing a steric shield that can dynamically change its state based on disease conditions. The steric shield is not a static block but a dynamic element that can be released under specific disease-activating conditions such as acidic pH or proteolytic enzyme exposure. This dynamic behavior allows the antibody to transition from an inactive, blocked state in normal tissues to an active state at the disease site, maintaining ease of operation and therapeutic efficacy while reducing side effects through preliminary blocking.
Data Source
AI summary
The present application provides activatable antibodies comprising an antibody comprising an antigen-binding domain (ABD), wherein the ABD comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the N-terminus of the VH is fused to a first polypeptide shield moiety (S1), and the N-terminus of the VL is fused to a second polypeptide shield moiety (S2), wherein S1 comprises a first disease-sensing releasable moiety (DS1) and/or S2 comprises a second disease-sensing releasable moiety (DS2), wherein association of S1 with S2 blocks binding of the ABD to its target, and wherein the ABD does not specifically bind to S1, S2, or association thereof. Composition, methods of treatment using the activatable antibodies, and methods of preparation thereof are further provided.