However, this strategy presents substantial technical hurdles. Many of these problems could be solved by generating multivalent hyperimmune globulins using recombinant DNA technology. Finally, each batch of plasma-derived drug is usually derived from a different cohort of human donors or animals, resulting in batch-to-batch variation 13, 14, 15. Because they are derived from naturally occurring proteins, plasma-derived drugs are not easily engineered for example, it is not possible to modify Fc sequences to improve mechanism of action or drug half-life. Antibody drugs derived from animal plasma occasionally cause allergic reactions 11, lead to antidrug antibodies and have suboptimal effector properties 12. Plasma-derived drugs have suffered from impurities, including infectious viruses and clotting factors, that have resulted in serious adverse events 9, 10. First, demand for normal and convalescent donor plasma often outstrips supply 8. Plasma-derived antibody therapeutics have substantial drawbacks. For rapid response to emerging pathogens with poorly characterized neutralizing epitopes, many groups have developed hyperimmune globulins derived from immunized animal plasma or convalescent human serum, for example, Zika virus hyperimmune globulin 5 or severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) 6, 7. In diseases for which human vaccination is not possible, hyperimmune globulins can be generated by immunizing animals, for example, rabbit-derived thymoglobulin (‘rabbit-ATG’) against human thymocytes for transplant tolerance 4. Polyclonal antibody drugs with higher potency, known as hyperimmune globulins, are often derived from the plasma of recently vaccinated human donors, for example, HepaGam B against hepatitis B virus (HBV) 2 and BabyBIG against infant botulism 3. An established therapeutic modality is multispecific (multivalent) antibodies derived from human or animal plasma, such as intravenous immunoglobulin (IVIG) 1. Many diseases, such as those caused by infectious viruses or bacteria with many variants or serotypes, are best treated by drugs that target multiple epitopes. To address the limitations of rabbit-derived anti-thymocyte globulin, we generated a recombinant human version and demonstrated its efficacy in mice against graft-versus-host disease. Using this approach, we generated hyperimmune globulins with potent neutralizing activity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in under 3 months, Fc-engineered hyperimmune globulins specific for Zika virus that lacked antibody-dependent enhancement of disease, and hyperimmune globulins specific for lung pathogens present in patients with primary immune deficiency. Each hyperimmune globulin product comprised thousands to tens of thousands of antibodies derived from convalescent or vaccinated human donors or from immunized mice. Our method generates of diverse mixtures of thousands of recombinant antibodies, enriched for specificity and activity against therapeutic targets. Here we describe a microfluidics and molecular genomics strategy for capturing diverse mammalian antibody repertoires to create recombinant multivalent hyperimmune globulins. Plasma-derived polyclonal antibody therapeutics, such as intravenous immunoglobulin, have multiple drawbacks, including low potency, impurities, insufficient supply and batch-to-batch variation. Nature Biotechnology volume 39, pages 989–999 ( 2021) Cite this article Generation of recombinant hyperimmune globulins from diverse B-cell repertoires
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