Recombinant Polyclonal Proteins for Scalable 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 limited engineering capabilities, which are not addressed by conventional recombinant DNA technology due to technical hurdles in isolating and pairing heavy and light chain immunoglobulins.
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 mixture of antibodies with diverse sequences and improved 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 antibodies by isolating B cell sequences and expressing them in mammalian cells. This copying approach produces identical antibody sequences that can be manufactured at scale without relying on donor plasma availability, thereby ensuring both supply consistency and therapeutic reliability
Solution Approach 2:
The patent performs preliminary isolation and characterization of high-affinity B cell sequences from immunized donors before manufacturing. By pre-selecting and validating antibody sequences upfront, the system ensures that subsequent recombinant production yields consistent, high-quality therapeutics with predictable efficacy, eliminating batch-to-batch variation
2Reliability
If plasma-derived hyperimmune globulins are used, then high potency is achieved, but impurities and allergic reactions occur
Solution Approach 1:
The patent extracts only the essential therapeutic component (antibody sequences) from B cells through PCR amplification, leaving behind all harmful plasma components such as viruses, clotting factors, and other impurities. The recombinant expression system then produces purified antibodies without contaminants, eliminating the source of allergic reactions and adverse events while preserving therapeutic potency
Solution Approach 2:
The patent uses transient transfection of mammalian cells with plasmid DNA to produce antibodies, rather than maintaining permanent cell lines. This disposable approach allows each production batch to be independently controlled and purified, ensuring high product quality without the risk of contamination from long-term cell culture, thereby reducing adverse reactions
3Speed
If animal-derived hyperimmune globulins are used, then rapid response to emerging pathogens is achieved, but immunogenicity and suboptimal effector properties occur
Solution Approach 1:
The patent applies local quality by using human or humanized antibody sequences with human Fc regions, ensuring that the effector functions and immune compatibility are optimized for human patients. The variable regions are derived from human B cells to maintain pathogen-specific binding, while the constant regions are humanized to eliminate immunogenicity, achieving both rapid response and immune compatibility
4Ease of manufacture
If conventional recombinant DNA technology is used, then manufacturing control is improved, but technical hurdles in heavy and light chain pairing occur
Solution Approach 1:
The patent merges heavy and light chain sequences into a single B cell-derived pair through co-expression in the same mammalian cell. This merging strategy ensures that the heavy and light chains are produced in stoichiometric proportions and properly assembled into functional antibodies, eliminating the pairing complexity that arises from separate production while maintaining manufacturing control
5Adaptability or versatility
If plasma-derived antibodies are used, then natural diversity is preserved, but engineering capabilities are limited
Solution Approach 1:
The patent creates a dynamic system where the initial B cell sequences provide natural diversity, but the recombinant expression platform enables subsequent engineering modifications. The modular plasmid design allows easy introduction of mutations, fusion proteins, or other modifications while maintaining the core natural antibody sequences, thus achieving both natural variability and engineering flexibility
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.