CD20/CD22 Bispecific Antibodies with Peptide Linkers
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Solution Overview
Problem
Current antibody-based immunooncology therapies face challenges such as tumor escape due to antigen loss, differential patient responses, and dose-limiting toxicity, as well as limitations in targeting suitable antigens, particularly in solid tumors where targets may be overexpressed but also present on non-malignant cells, leading to reduced efficacy and increased toxicity.
Innovation Solution
Development of CD20 and CD22 targeting bispecific antigen-binding molecules with three binding domains, including a first domain binding to CD20, a second domain binding to CD22, a third domain binding to the CD3ε chain, and an optional fourth domain for extended half-life, designed to maintain bioactivity and stability through specific peptide linkers, allowing simultaneous targeting of two antigens on the same cell without steric hindrance.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Device complexity
If a single antigen target is used in antibody-based immunooncology therapies, then the therapy is simpler to design and administer, but tumor escape occurs due to antigen loss
Solution Approach 1:
The therapy is segmented into multiple specificities within a single molecule, with each binding domain targeting a different antigen (CD20 and CD22). This segmentation allows the molecule to overcome antigen loss by maintaining binding capability through alternative antigen targets, thereby resolving the contradiction between simple design and reliable efficacy.
Solution Approach 2:
The bispecific molecule performs multiple functions by simultaneously binding to different antigens (CD20 and CD22) on tumor cells. This multi-functionality ensures that if one antigen is lost or downregulated, the molecule can still bind to the other antigen, maintaining therapeutic efficacy and preventing tumor escape.
2Reliability
If dual targeting of CD20 and CD22 is achieved, then tumor escape is prevented and therapeutic efficacy is improved, but molecular structure becomes more complex
Solution Approach 1:
The patent merges multiple binding domains (CD20-specific and CD22-specific) into a single bispecific molecule structure. This combining approach achieves dual targeting capability while maintaining a unified molecular architecture, thereby improving therapeutic efficacy without proportionally increasing structural complexity.
Solution Approach 2:
The molecule utilizes parameter changes in its design, specifically using a flexible peptide linker of optimized length (5-24 amino acids) to connect binding domains. This parameter optimization allows the complex dual-targeting structure to maintain bioactivity and stability, balancing structural complexity with functional performance.
3Reliability
If longer peptide linkers are used to reduce steric hindrance between binding domains, then bioactivity is maintained, but molecular stability decreases due to degradation
Solution Approach 1:
The patent applies parameter changes by optimizing the peptide linker length to a specific range (5-24 amino acids). This optimized parameter length provides sufficient flexibility to reduce steric hindrance between binding domains while maintaining molecular stability and reducing degradation susceptibility, thereby resolving the contradiction between bioactivity and stability.
Solution Approach 2:
The flexible peptide linker introduces local quality changes in the molecular structure, creating a region of controlled flexibility between the rigid binding domains. This local flexibility allows the binding domains to adopt optimal orientations for antigen binding while the overall molecular structure maintains stability through the optimized linker design.
4Adaptability or versatility
If rapid clearance of the molecule occurs, then concentration can be fine-tuned at short notice, but prolonged administration is required to achieve therapeutic effects
Solution Approach 1:
The bispecific molecule incorporates an Fc region from an immunoglobulin, creating a composite structure that combines the rapid clearance characteristics of small molecules with the prolonged circulation characteristics of antibody fragments. This composite design maintains concentration adaptability while reducing the need for prolonged continuous administration.
Data Source
AI summary
The present invention provides CD20 and CD22 targeting antigen-binding molecules characterized by comprising a first and a second domain, binding to CD20 and CD22, respectively, a third domain binding to an extracellular epitope of the human and the Macaca CD3ε chain and optionally a fourth domain, which is a Fc modality. Moreover, the invention provides a polynucleotide, encoding the antigen-binding molecule, a vector comprising this polynucleotide, host cells, expressing the antigen-binding molecule and a pharmaceutical composition comprising the same.