Bispecific ISVD Binders Targeting Conserved Spike Epitopes
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Solution Overview
Problem
Current therapeutic options for COVID-19, particularly against SARS-COV-2, face challenges due to emerging variants that reduce the efficacy of monoclonal antibodies and vaccines, necessitating the development of pan-specific antibodies that bind conserved epitopes on the Spike protein to prevent viral escape mutations.
Innovation Solution
Development of bispecific or multispecific binding agents comprising immunoglobulin single variable domains (ISVDs) that target non-overlapping epitopes on the Spike protein's Receptor Binding Domain (RBD), specifically binding to amino acid residues Y369, F377, K378, T393, N394, V395, and Y396, which are conserved across sarbecoviruses, thereby neutralizing SARS-COV-1 and SARS-COV-2 viruses effectively.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If monoclonal antibodies targeting the RBM region are used, then neutralization potency against SARS-COV-2 is achieved, but viral escape mutations reduce efficacy
Solution Approach 1:
The patent applies universality by designing binding agents that simultaneously target multiple conserved epitopes across different sarbecovirus clades. The binding agents comprise polyclonal, multispecific, or bispecific antibodies that can bind to at least two different epitopes on the Spike protein, providing broad-spectrum neutralization activity against SARS-CoV-1, SARS-CoV-2, and emerging variants. This multi-functional approach ensures reliable neutralization while adapting to viral diversity.
Solution Approach 2:
The patent applies segmentation by dividing the binding agent into multiple specificities, where each antibody component targets a distinct conserved epitope region on the Spike protein. This segmentation allows the binding agent to engage multiple sites simultaneously, preventing viral escape through single-point mutations and maintaining neutralization potency across variants.
2Adaptability or versatility
If binding agents target conserved epitopes, then broad-spectrum neutralization is achieved, but binding site accessibility may be limited
Solution Approach 1:
The patent applies dimensionality change by utilizing the three-dimensional structure of the Spike protein to identify and target conserved epitopes that are spatially distinct and accessible. The binding agents are designed to access epitopes in different conformational states of the Spike protein, including both RBD-up and RBD-down states, thereby achieving broad-spectrum neutralization while maintaining binding site accessibility through multi-dimensional targeting strategies.
3Reliability
If polyclonal or multispecific binding agents are used, then viral escape is reduced, but manufacturing complexity increases
Solution Approach 1:
The patent applies merging by combining multiple monoclonal antibody specificities into single bispecific or multispecific binding agents. These merged molecules simultaneously engage multiple conserved epitopes on the Spike protein, providing the viral escape resistance of polyclonal sera while maintaining the manufacturing advantages of defined monoclonal antibody structures. This approach simplifies production compared to traditional polyclonal antibody preparations.
Data Source
AI summary
Compositions and binding agents specifically binding the Spike protein of Corona viruses via at least two different binding sites and potently neutralizing coronaviruses, in particular sarbecoviruses, such as SARS-COV-1 and SARS-COV-2. The compositions or agents specifically bind to epitopes of the Receptor binding domain (RBD) of the Spike protein wherein both epitopes are conserved over multiple clades of the sarbecoviruses, providing broadly neutralizing pan-specific antibody-based compositions, thereby reducing viral escape. Application and uses of these agents and compositions are disclosed.