ADE and recombinant antibody interventions
The discovery of mAbs against the SARS-CoV-2 S protein is progressing rapidly. Recent advances in B-cell screening and antibody discovery have enabled the rapid isolation of potent SARS-CoV-2 neutralizing antibodies from convalescent human donors76,77 and immunized animal models78, and through re-engineering previously identified SARS-CoV antibodies79. Many more potently neutralizing antibodies will be identified in the coming weeks and months, and several human clinical trials are ongoing in July 2020. Human trials will comprise both prophylactic and therapeutic uses, both for single mAbs and cocktails. Some human clinical trials are also incorporating FcR knockout mutations to further reduce ADE risks80. Preclinical data suggest a low risk of ADE for potently neutralizing mAbs at doses substantially above the threshold for neutralization, which protected mice and Syrian hamsters against SARS-CoV-2 challenge without enhancement of infection or disease81,82. ADE risks could increase in the time period where mAb concentrations have waned below a threshold for protection (which is analogous to the historical mother–infant data that provided important clinical evidence for ADE in dengue83). The sub-protective concentration range will likely occur several weeks or months following mAb administration, when much of the initial drug dose has cleared the body. Notably, Syrian hamsters given low doses of an RBD-specific neutralizing mAb prior to challenge with SARS-CoV-2 showed a trend for greater weight loss than control animals82, though differences were not statistically significant and the low-dose animals had lower viral loads in the lung compared to control animals. Non-neutralizing mAbs against SARS-CoV-2 could also be administered before or after infection in a hamster model to determine whether non-neutralizing antibodies enhance disease. Passive transfer of mAbs at various time points after infection (for example, in the presence of high viral loads during peak infection) could also address the question of whether immune complex formation and deposition results in the enhancement of disease and lung immunopathology. If ADE of neutralizing or non-neutralizing mAbs is a concern, the Fc portion of these antibodies could be engineered with mutations that abrogate FcR binding80. Animal studies can help to inform whether Fc-mediated effector functions are crucial in preventing, treating or worsening SARS-CoV-2 infection, in a similar way to previous studies of influenza A and B infection in mice84,85 and simian-HIV infection in macaques86,87. An important caveat for testing human mAbs in animal models is that human antibody Fc regions may not interact with animal FcRs in the same way as human FcRs88. Whenever possible, antibodies used for preclinical ADE studies will require species-matched Fc regions to appropriately model Fc effector function.
https://www.nature.com/articles/s41564-020-00789-5