A therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein

Abstract

Vaccines and therapeutics are urgently needed for the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we screen human monoclonal antibodies (mAb) targeting the receptor binding domain (RBD) of the viral spike protein via antibody library constructed from peripheral blood mononuclear cells of a convalescent patient. The CT-P59 mAb potently neutralizes SARS-CoV-2 isolates including the D614G variant without antibody-dependent enhancement effect. Complex crystal structure of CT-P59 Fab/RBD shows that CT-P59 blocks interaction regions of RBD for angiotensin converting enzyme 2 (ACE2) receptor with an orientation that is notably different from previously reported RBD-targeting mAbs. Furthermore, therapeutic effects of CT-P59 are evaluated in three animal models (ferret, hamster, and rhesus monkey), demonstrating a substantial reduction in viral titer along with alleviation of clinical symptoms. Therefore, CT-P59 may be a promising therapeutic candidate for COVID-19.

Therapeutic effect of CT-P59 against SARS-CoV-2 South African variant

“…It was reported that SARS-CoV-2 preferentially replicates in the upper respiratory tract of ferrets, thus the relatively lower virus titer in the lower respiratory tract is likely in line with mild symptoms with SARS-CoV-2, which means it could represent of patients with asymptomatic to mild symptoms [ 22 , 23 ]. Such findings were consistent with the previous literature [ 16 ], thereby, the current study employed ferrets for the disease model, taking the intended indication of CT-P59 for treating patients with the mild symptoms into account. As expected, ferrets showed the lower virus titer in the lower airway than the upper airway, for the wild type virus.…”

“…Unlike LY-CoV555, CT-P59 was able to bind to RBD of B.1.351and neutralized B.1.351, albeit with reduced K D and IC 50 values. This is a suggestion that CT-P59 showed high barrier to resistant viruses since CT-P59 has relatively conserved residues for RBD binding although K417 and E484 are part of the epitope of CT-P59 [ 16 ].…”

“…The viral loads in nasal washes and lungs were determined via qRT-PCR and TCID 50 as previously described [ 16 ]. Briefly, Viral RNA was extracted and cDNAs were generated.…”

“…We have developed a COVID-19 therapeutic antibody, CT-P59 which binds to RBD of SARS-CoV-2, interfering with binding to ACE2 (Angiotensin-Converting Enzyme 2), the cellular receptor for viral entry. Also, we have demonstrated that CT-P59 has high potency against the original variant in in vitro and in vivo studies [ 16 ]. Here, we evaluated the efficacy of CT-P59 against SA variant via both in vitro binding and neutralization assay with live and pseudoviruses and in vivo challenge experiment in ferrets.…”

SARS-CoV-2 cell entry and targeted antiviral development

“…Meanwhile, early signals of efficacy from convalescent plasma therapy have encouraged isolation of multiple neutralizing SARS-CoV-2 mAbs 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 . Up to date, several single and combination mAb therapeutics have received emergency use authorization (EUA) 71 , 72 , 73 , including CT-P59 (granted in South Korea) 74 , LY-CoV555 alone or its cocktail with LY-CoV016 (granted in USA) 71 , 75 , 76 , and REGN-COV2 cocktail (granted in USA) 77 , 78 . Although the EUA of LY-CoV555 alone has been revoked by the US Food and Drug Administration (FDA) due to the sustained increase of resistant SARS-CoV-2 viral variants 79 , there are more candidates in the pipeline 80 .…”