Bispecific Fab Antibody Architecture for Longer-Acting VEGF-A and ANG2 Binding
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Solution Overview
Problem
Existing bispecific antibodies targeting VEGF and ANG2 for ocular vascular diseases have limitations in efficacy, duration of action, and require frequent intravitreal injections, increasing patient burden.
Innovation Solution
Development of a bispecific anti-VEGF-A/anti-ANG2 antibody with specific CDR sequences in VH and VL domains, exhibiting high affinity and stability, allowing for independent binding to both antigens, even in Fab fragment form, and suitable for high-concentration formulations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If existing bispecific antibodies are used for treatment, then VEGF and ANG2 are targeted, but the duration of action is insufficient and injection frequency is high
Solution Approach 1:
The patent applies parameter changes by optimizing the CDR sequences of the antibody to achieve higher affinity binding to both VEGF and ANG2. Specifically, the VEGF-paratope uses CDR-H2, CDR-L1, and CDR-L3, while the ANG2-paratope uses CDR-H1, CDR-H3, and CDR-L2, with specific amino acid sequences that enhance binding strength and prolong duration of action
Solution Approach 2:
The patent creates a composite binding structure within a single VH/VL pair that simultaneously recognizes both VEGF and ANG2 antigens. This biparatopic design combines two distinct paratopes in one antibody domain pair, allowing dual antigen targeting with a single molecule, thereby extending duration of action and reducing injection frequency
2Reliability
If existing bispecific antibodies are used, then dual antigen binding is achieved, but binding affinity and stability are insufficient
Solution Approach 1:
The patent optimizes binding affinity by carefully selecting and designing the CDR sequences. The VEGF-paratope comprises specific amino acid residues from CDR-H2, CDR-L1, and CDR-L3, while the ANG2-paratope comprises residues from CDR-H1, CDR-H3, and CDR-L2. These parameter optimizations ensure high-affinity binding to both antigens while maintaining structural stability
Solution Approach 2:
The patent inverts the conventional approach by placing both paratopes within a single VH/VL pair rather than distributing them across separate domains. This unconventional arrangement allows the antibody to bind both antigens with high affinity and stability while maintaining the integrity of the antigen-binding sites
3Quantity of substance
If standard antibody structures are used, then dual binding capability is achieved, but the number of binding sites per dose is limited
Solution Approach 1:
The patent segments the antibody structure by creating distinct paratopes within the VH and VL domains. The VEGF-paratope is formed by CDR-H2, CDR-L1, and CDR-L3, while the ANG2-paratope is formed by CDR-H1, CDR-H3, and CDR-L2. This segmentation allows independent binding to both antigens while maintaining a relatively simple overall structure
Solution Approach 2:
The patent creates a universal VH/VL pair that performs multiple functions by simultaneously binding to both VEGF and ANG2 antigens. This single antibody structure serves dual purposes, increasing the effective number of binding sites per dose without requiring multiple separate antibody molecules or complex multi-domain constructions
Data Source
AI summary
The present invention relates to anti-VEGF-A/anti-ANG2 antibodies, e.g. in the form of a bispecific Fab fragment, and methods of using the same.