CD3-CD137 Bispecific Antibody Linker Design for Reduced Renal Clearance
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Solution Overview
Problem
Current bispecific antibodies targeting CD3 and CD137 face challenges in production efficiency and safety due to high affinity leading to T cell hyperactivation and renal clearance issues, resulting in adverse effects such as liver injury and cytokine storms.
Innovation Solution
A novel multispecific antibody with a lower affinity for CD3 and CD137, designed with peptide linkers to stabilize the protein structure and prevent excessive renal clearance, allowing for effective T cell recruitment while reducing adverse effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If high affinity binding modules are used to enhance T cell recruitment, then T cell activation is improved, but T cell hyperactivation occurs leading to cytokine storms and adverse effects
Solution Approach 1:
The patent applies parameter changes by systematically optimizing the binding affinity of each binding module within a specific range (10^-10 to 10^-6 M). Instead of using high affinity binding, the invention sets the affinity parameters to moderate levels that enable effective T cell recruitment while preventing hyperactivation and cytokine release, thus resolving the contradiction between effectiveness and safety
Solution Approach 2:
The patent employs partial action by using moderate affinity binding modules that provide sufficient but not excessive T cell activation. This partial activation approach achieves the necessary therapeutic effect while avoiding the harmful excessive activation that leads to cytokine storms and adverse events
2Ease of manufacture
If simplified bispecific antibody design is used to ease production, then manufacturing is improved, but renal clearance increases reducing in vivo half-life
Solution Approach 1:
The patent applies composite materials by combining simplified bispecific antibody structures with Fc region extensions or other stabilizing moieties. This composite approach maintains the manufacturing advantages of simplified designs while adding features that reduce renal clearance and extend in vivo half-life, thus resolving the contradiction between ease of manufacture and duration of action
Solution Approach 2:
The patent uses segmentation by dividing the antibody structure into functional modules (binding modules with specific affinities, peptide linkers, and Fc regions) that can be independently optimized. This modular segmentation allows the binding modules to maintain simplified production characteristics while the Fc regions provide extended half-life, resolving the contradiction between manufacturing ease and duration of action
Data Source
AI summary
The present application provides a fusion protein, containing: an anti-CD137 antibody capable of specifically binding to a CD137 molecule or an antigen binding fragment thereof; an anti-CD3 antibody capable of specifically binding to a CD3 molecule or an antigen binding fragment thereof; and a first peptide linker and a second peptide linker. The present application also provides a nucleic acid encoding the fusion protein, an expression vector containing the nucleic acid, a host cell containing the nucleic acid or the expression vector, a method for preparing the fusion protein, a pharmaceutical composition containing the fusion protein, and a use of the fusion protein.