VNAR Antibodies Access Buried Spike Epitopes
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Solution Overview
Problem
Current COVID-19 therapies, including vaccines and antibodies, face challenges in providing long-term protection against emerging variants and are less effective in older populations and immunocompromised individuals, with conventional antibodies often generating responses to glycans on the spike protein, leading to immunodominance and limited epitope coverage, making them prone to viral escape mutations.
Innovation Solution
Development of Type II VNAR antibodies that target the SARS-CoV-2 spike protein, specifically binding to the S1 fragment and neutralizing the virus by accessing buried epitopes beneath the glycan shield, with a formula comprising specific CDR1, HV2, HV4, and CDR3 sequences, and optionally fused with a human Fc domain to form bispecific antibodies for enhanced efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antibodies are used to target the spike protein, then neutralization activity is achieved, but immunodominance occurs directing response to viral epitopes more tolerant of mutations
Solution Approach 1:
The invention segments the antibody response by using VNARs with exceptionally long CDR3 loops that can independently access and bind to multiple distinct epitopes on the spike protein, including conserved regions beneath the glycan shield, thereby avoiding immunodominance and providing broader epitope coverage
Solution Approach 2:
The invention adds a new dimension to antibody structure by utilizing the exceptionally long CDR3 loop of VNARs, which extends beyond the typical antibody structure to reach buried epitopes beneath the glycan shield that conventional antibodies cannot access, thereby expanding epitope coverage to previously inaccessible regions
2Reliability
If antibodies target surface-exposed epitopes, then binding is achieved, but viral escape mutations can occur more easily
Solution Approach 1:
The invention uses the long CDR3 loop to nestle into and access buried epitopes beneath the glycan shield, targeting conserved regions that are essential for viral function and less tolerant of mutations, thereby reducing the risk of viral escape
3Reliability
If B cell cloning is used to generate antibodies, then neutralizing antibodies are produced, but many antibodies are generated to glycans on the spike protein which impede recognition of neutralizing epitopes
Solution Approach 1:
The invention uses VNARs as an intermediary approach that does not rely on B cell cloning and glycan recognition, instead using the long CDR3 loop to directly access and bind to neutralizing epitopes beneath the glycan shield, thereby avoiding the problem of glycan interference entirely
4Reliability
If conventional antibodies are used, then immune response is generated, but protection is less effective in older populations and immunocompromised individuals
Solution Approach 1:
The invention changes the fundamental parameters of the antibody structure by using VNARs with exceptionally long CDR3 loops and different domain architecture, creating a novel therapeutic approach that may be more effective in populations with compromised immune responses by directly providing high-affinity neutralizing antibodies rather than relying on endogenous immune responses
Data Source
AI summary
The present disclosure provides coronavirus S1-fragment specific binding moieties comprising Type II VNAR domains, VNAR antibodies, methods of using those moieties and antibodies to treat COVID-19. In some embodiments, a VNAR antibody, originally selected from a phage display library as a VNAR clone using S1fragments from the SARS-CoV-2 Wuhan strain, are also effective at specifically binding to and/or neutralizing SARS-CoV-2 and certain SARS-CoV-2 mutants.