Recombinant Polyclonal Antibodies for Consistent SARS-CoV-2 Neutralization
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Solution Overview
Problem
Plasma-derived antibody therapeutics face challenges such as supply shortages, impurities, allergic reactions, batch-to-batch variation, and difficulty in engineering Fc sequences, limiting their effectiveness against emerging pathogens like SARS-CoV-2.
Innovation Solution
Development of recombinant polyclonal proteins (RPPs) derived from peripheral blood B cells or plasmablasts, specifically mobilized by SARS-CoV-2 infection, which are engineered to bind SARS-CoV-2 antigens, offering a diverse mixture of antibodies with enhanced specificity and efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If plasma-derived antibody therapeutics are used, then immediate therapeutic effect is achieved, but supply shortages and batch-to-batch variation occur
Solution Approach 1:
The patent creates recombinant copies of natural polyclonal antibodies by isolating B cells from immunized donors, extracting their antibody genes, and expressing them in recombinant cell lines. This copying process produces identical antibody sequences that can be manufactured at scale without relying on plasma donations, thereby ensuring both supply availability and batch-to-batch consistency
Solution Approach 2:
The patent transforms the production parameters from plasma collection (donor-dependent, variable) to recombinant expression (cell-line-dependent, controllable). By changing the production system from biological plasma donation to controlled recombinant manufacturing, the patent achieves consistent antibody production with scalable supply while maintaining the therapeutic efficacy of polyclonal antibodies
2Speed
If plasma-derived antibodies are used, then rapid response to emerging pathogens is possible, but impurities and allergic reactions occur
Solution Approach 1:
The patent extracts only the essential therapeutic component (antibody variable regions) from the complex plasma matrix by isolating B cells and sequencing their immunoglobulin genes. This extraction eliminates unwanted plasma components such as clotting factors, infectious viruses, and other proteins that cause impurities and adverse reactions, while preserving the neutralizing antibody activity
Solution Approach 2:
The patent uses transient transfection of B cell sequences into host cells to produce antibodies, rather than relying on long-term plasma collection. This approach allows rapid production of disposable antibody batches that can be quickly updated for emerging variants, reducing the risk of transmitting plasma-borne pathogens while maintaining rapid response capability
3Adaptability or versatility
If plasma-derived therapeutics are used, then polyclonal diversity is achieved, but engineering Fc sequences is difficult
Solution Approach 1:
The patent segments the antibody molecule into separate functional domains: the variable regions (VH and VL) are isolated from B cell sequences to maintain polyclonal diversity, while the constant Fc regions are replaced with engineered sequences. This segmentation allows independent optimization of each domain - preserving natural antibody diversity in the binding regions while incorporating engineered Fc properties for enhanced effector functions and pharmacokinetics
Solution Approach 2:
The patent creates composite antibody molecules combining natural variable regions from diverse B cell clones with engineered Fc regions. This composite structure merges the advantages of polyclonal diversity (from natural sequences) with the benefits of Fc engineering (enhanced ADCC, ADCP, half-life extension), achieving both adaptability and ease of manufacture
4Speed
If animal-derived hyperimmune globulins are used, then rapid pathogen response is achieved, but immunogenicity and suboptimal effector properties occur
Solution Approach 1:
The patent creates humanized copies of animal-derived antibody sequences by isolating B cells from human donors immunized with the pathogen, sequencing their immunoglobulin genes, and expressing them in human cell lines. This copying process produces human-compatible antibodies that eliminate immunogenicity issues while maintaining the rapid response capability of hyperimmune globulins
Solution Approach 2:
The patent changes the species origin parameter from animal to human by using human B cell sequences. This parameter change eliminates the immunogenicity difference between animal and human proteins while preserving the hyperimmune characteristics. Additionally, the Fc region parameters are optimized for human effector functions, ensuring suboptimal effector properties are corrected
Data Source
AI summary
Provided herein are compositions comprising recombinant polyclonal proteins (RPPs) derived from mammalian plasma cells and plasmablasts. Also provided are methods of using the RPPs.