The COVID-19 Textbook

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SECTION 3 • Immunology

showed a statistically significant impact on preventing severe disease and death. 167,171-174 CPT was particularly beneficial in individuals with the lowest S-specific antibody titers or opsonophagocytic humoral activity, 175 suggesting that CPT was providing a source of antibodies that was not available in the patient at the time of therapy. However, because of the inherent variability in CPT, with each plasma donation from a different convalescent patient with unique antibody profiles, controlling CPT’s therapeutic impact is not simple. Recombinant nAbs, otherwise known as mAbs, cloned from COVID-19 patients or vaccinees, have exquisite specificity, established use as infectious disease therapies, a well-established safety pro file, and allow for high-speed/high-affinity discovery. Antibody cloning from both SARS-CoV-2 and SARS-CoV-1 individuals 176 has resulted in the generation of diverse sets of antibodies with remarkable neutralization potency. Like CPT, mAbs are particularly effective when administered to high-risk populations early in the disease, prior to the evolution of patient autologous antibodies. Because of concerns of ADE, early mAbs were generated as wild-type IgG1 or with Fc-silencing mutations that avoid FcR engagement and potential enhanced infection. 72,176 However, given the absence of any evidence of ADE in thousands of CPT- and mAb-treated patients, and emerging data that Fc-effector functions may be critical for the resolution of severe disease, 177 newer mAbs have Fc-enhanced IgG1 backbones and extended half-lives to improve the therapeutic impact and benefit All approved mAbs target RBD, 178-180 but they do not bind the same epitope. The epitopes in the RBD are divided into different classes, which are defined by antibody-binding sites 181,182 (Table 8.3). A small fraction of mAbs binds to the NTDs 184-186 or S2. 147,187,188 S2 antibodies may also target sites that are conserved across beta- and alpha-coronaviruses, potentially affording broader protec tion. However, this class typically exhibits lower neutralization potency. 188 Next-Generation Monoclonal Antibodies In many infectious diseases, including influenza, Ebola, and HIV, mAb monotherapy has been quickly followed by mutational escape, necessitating the use of combination therapy consisting of several mAbs and/or drugs. SARS-CoV-2 VOCs accumulate escape mutations in the RBD, and specifically the receptor-binding motif (RBM), 189 where many mAbs bind, driving mutational es cape from current mAbs. 190,191 Combination therapies are resistant to mutational escape, but still show vulnerability to viral evolution. Combinations of RBD epitope–specific targets, or including antibodies targeting the NTD and S2-specific mAbs, could provide enhanced protection against VOCs. 192,193 of these drugs. 136 mAb Targets

TABLE 8.3 Summary of epitope classes and binding sites 88,183

Class Proposed Mechanism Class 1 Up conformation of receptor-binding motif (RBM) Direct ACE2 competition Class 2 Both open and closed conformation of RBD Direct ACE2 competition Class 3 Non-RBM epitopes close to an N-glycan at tached to residue N343, in both up and down conformation of RBDs. Binding Site

Mediate neutralization either by steric hindrance or locking and cross-linking S protein Mediate neutralization either by steric hindrance or locking and cross-linking S protein

Class 4 Highly conserved cryptic epitope that faces the interior of the S protein on “up” RBDs

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ACE, angiotensin-converting enzyme; RBD, receptor-binding domain. Class 5 S2-antibodies may also target sites that are conserved across beta- and alphacoronaviruses, potentially affording broader protection. However, this class typically exhibits lower neutralization potency. 186 From Dacon C, Tucker C, Peng L, et al. Broadly neutralizing antibodies target the coronavirus fusion peptide. Science . 2022;377:728-735.