REGEN-COV protects against viral escape in preclinical and human studies

Abstract

Monoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. As rapidly emerging virus mutants are becoming the next major concern in the fight against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of minor virus variants in SARS-COV-2 isolates found in nature or identified from preclinical in vitro and in vivo studies and in the clinic. This study demonstrates that a combination of non-competing antibodies not only provides full coverage against currently circulating variants but also protects against emergence of new such variants and their potential seeding into the population in a clinical setting.

Global Prevalence of Adaptive and Prolonged Infections’ Mutations in the Receptor-Binding Domain of the SARS-CoV-2 Spike Protein

“…On 31 May 2021, the WHO named these variants from alpha to kappa (https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/) (accessed on 31 May 2021). These variants have been shown to exhibit reduced susceptibility to some of the mAbs that are under clinical trials, to convalescent plasma and plasma from vaccinated people [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39]. Table 1 shows mutations and their level of resistance to mAbs that are in different stages of clinical trials currently.…”

“…This mutation was found in greater proportions in sequences isolated from nearly 41 countries. Some of the adaptive mutations that we have studied here have been shown by others to have a moderate to a very high level of resistance (≥100-fold) towards some of the mAbs that are currently either in emergency use in patients or different stages of clinical trials, to convalescent plasma and plasma from vaccinated individuals (Table 1) [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39]. € = Europe excluding Switzerland and the UK; ‡ = North America excluding the USA; empty cell = 4 or more decimal places or 0%.…”

“…The emergence of new SARS-CoV-2 variants acts as a hurdle to mAb therapy as well as vaccine protection. Similar to the vaccines that target the S protein, some SARS-CoV-2 mutations can also resist neutralization by mAbs currently in clinical trials, to convalescent plasma and plasma from vaccinated individuals [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39]. Table 1 shows mAbs that are in different stages of clinical trials and their effectiveness against different mutations.…”

SARS-CoV-2 Antiviral Therapy

“…Bamlanivimab plus etesevimab retains activity against the VOC B.1.1.7 but displays an approximately 5- to 10-fold reduced susceptibility against B.1.617 and B.1.427/9 and has little if any residual activity against B.1.351 and P.1 ( 191 – 193 ) ( https://www.fda.gov/media/145802/download ). The combination of casirivimab plus imdevimab appears to retain full susceptibility against each of the VOCs ( 192 , 194 ) ( https://www.fda.gov/media/145611/download ) likely because casirivimab binds to the RBD receptor binding motif, while imdevimab binds to the more conserved RBD core. Sotrovimab, which binds to the RBD core, also appears to be fully active against B.1.1.7, B.1.351, P.1, and B.1.427/9 ( 191 , 192 , 195 , 196 ) ( https://www.fda.gov/media/149534/download ).…”

Multivalent designed proteins protect against SARS-CoV-2 variants of concern

“…To overcome this limitation, it is common practice to prepare a cocktail of different mAbs targeting different epitopes. However, two circulating SARS-CoV-2 variants, B.1.351 (Beta) and P.1 (Gamma), disrupt binding of both mAbs in the authorized bamlanivimab and etesevimab cocktail as well as casirivimab in the authorized REGN-COV cocktail (3)(4)(5)(6).…”