The COVID-19 Textbook

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CHAPTER 8 • Antibodies in COVID-19

Modifications on both the Fab and the Fc-domains have been proposed to improve the breadth, potency, and antiviral capacity of next-generation mAbs. On the Fab, computational modeling of mAb/RBD binding and escape by VOCs allows for in silico artificial intelligence–based design of next-generation antibodies that maintain contacts with mutationally resistant amino acids and less contact dependence on mutationally variable amino acids. As RBD mutational analyses show that many evasive mutations in VOCs were largely predictable, 194 this strategy provides an opportunity to define optimal Fab sequences that provide ideal coverage of current and future VOCs. Using syn thetic yeast and phage display tools (scanning tools), which are able to present thousands of mutated versions of the RBD and other Spike segments, computationally designed mAbs can be rapidly tested to select for the most potent, high-affinity mAbs. This type of screening strategy can allow for the downselection of more resilient, flexible Fabs that can bind to viral variants as they evolve. These novel Fabs can be coupled to new Fc-formats. IgGs can be Fc-enhanced to have longer half-life and/or customized functionality to leverage NK cells, complement, or other key immuno logic functions. 195 Multimerization-inducing mutants can further improve the affinity/avidity of the mAb. Antibody engineering can bring together multiple distinct Fabs into a single mAb format, creating antibodies that are bispecific to two antigens, or trispecific to three, to enhance the breadth of binding on a single molecule across the S protein, key to resilience against VOCs. 196-199 Finally, the use of non-IgG isotypes, such as IgM or IgA, can utilize each isotype’s unique functionality alongside potentially enhanced function at mucosal barriers. 200,201 Newer Gene Delivery Strategies In addition to mAb engineering, new strategies for mAb delivery have emerged, including vector-based delivery, such as adeno-associated viral (AAV) vectors, 202 which are able to deliver mAbs for extended periods of time to provide protection against infection or to attenuate disease. 202 Novel CRISPR-based BCR replacement, which uses CRISPR to insert a specific mAb into a B cell, leads to long-lived antibody production in vivo, 203 generating highly protective mAbs for prevention or treatment of disease. Transient production of mAbs can be achieved using mRNA. 202,203 Collectively, these strategies offer a means to leverage the body’s own protein manufacturing capacity to make mAbs with high therapeutic efficacy, obviating the need for long drug infusions. CONCLUSION Antibodies represent the primary correlate of immunity following all clinically approved vaccines and following natural infection. The past three decades has taught us that antibodies play a key part in many aspects of the response to infection from neutralization to regulators of the cellular immune response. We now have the capacity to harness both ends of the antibody to maximize success in vac cine and therapeutic design. Although vaccine and therapeutic development evolved independently at a furious pace over the COVID-19 pandemic, the two research communities faced similar chal lenges with an evolving pathogen, highlighting the need for cross-pollination across vaccine and ther apeutic development. By working together to understand and utilize the incredible power of these Y-shaped proteins, we can successfully combat COVID-19 and prepare to face future pandemics. REFERENCES 1. Behring EV. Studies on the development of diphtheria immunity in animals. Ger Med Wkly . 1890;16:1145-1148. 2. Behring EV, Kitasato, S. On the development of diphtheria immunity and tetanus immunity in animals. Ger Med Wkly . 1890;16:1113-1114. 3. Pauling L. A theory of the structure and process of formation of antibodies. J Am Chem Soc . 1940;62:2643-2657. 4. Porter RR. The hydrolysis of rabbit y-globulin and antibodies with crystalline papain. Biochem J . 1959;73:119-126. 5. Edelman GM, Benacerraf B, Ovary Z, Poulik MD. Structural differences among antibodies of different specificities. Proc Natl Acad Sci U S A . 1961;47:1751–1758. 6. Burnet FM. A modification of Jerne’s theory of antibody production using the concept of clonal selection. CA Cancer J Clin . 1976;26:119-121. 7. Nossal GJ, Lederberg J. Antibody production by single cells. Nature . 1958;181:1419-1420. 8. Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature . 1975;256:495-497. 9. Mullard A. FDA approves 100th monoclonal antibody product. Nat Rev Drug Discov . 2021;20:491-495. 10. Halliday A. The therapeutic antibody revolution. Biopharma. 2020. https://www.technologynetworks.com/biopharma/articles/the-therapeutic- antibody-revolution-330615 11. Poljak RJ, Amzel LM, Avey HP, Chen BL, Phizackerley RP, Saul F . Three-dimensional structure of the Fab’ fragment of a human immunoglobulin at 2,8-A resolution. Proc Natl Acad Sci U S A. 1973;70:3305-3310.

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