A combination of potently neutralizing monoclonal antibodies isolated from an Indian convalescent donor protects against the SARS-CoV-2 Delta variant

Abstract

Although efficacious vaccines have significantly reduced the morbidity and mortality of COVID-19, there remains an unmet medical need for treatment options, which monoclonal antibodies (mAbs) can potentially fill. This unmet need is exacerbated by the emergence and spread of SARS-CoV-2 variants of concern (VOCs) that have shown some resistance to vaccine responses. Here we report the isolation of five neutralizing mAbs from an Indian convalescent donor, out of which two (THSC20.HVTR04 and THSC20.HVTR26) showed potent neutralization of SARS-CoV-2 VOCs at picomolar concentrations, including the Delta variant (B.1.617.2). One of these (THSC20.HVTR26) also retained activity against the Omicron variant. These two mAbs target non-overlapping epitopes on the receptor-binding domain (RBD) of the spike protein and prevent virus attachment to its host receptor, human angiotensin converting enzyme-2 (hACE2). Furthermore, the mAb cocktail demonstrated protection against the Delta variant at low antibody doses when passively administered in the K18 hACE2 transgenic mice model, highlighting their potential as a cocktail for prophylactic and therapeutic applications. Developing the capacity to rapidly discover and develop mAbs effective against highly transmissible pathogens like coronaviruses at a local level, especially in a low- and middle-income country (LMIC) such as India, will enable prompt responses to future pandemics as an important component of global pandemic preparedness.

Ancestral SARS-CoV-2 driven antibody repertoire diversity in an unvaccinated individual correlates with expanded neutralization breadth

“…In the present study, we report isolation and characterization of two additional mAbs from the same individual: THSC20.HVTR11 and THSC20.HVTR55 (Fig. S1) by RBD-specific single B cell sorting and following same pipeline reported before (7) that differed in their B cell origin. These two new mAbs varied in their ability to neutralize Omicron variants as shown in Fig.…”

“…On the other hand, THSC20.HVTR06 (IGVH7-4-1) could neutralize all the BA.1, BA.2 and BA.4/BA.5 variants but with low potencies, while THSC20.HVTR11 could neutralize BA.1 and BA.2 with comparable potency as THSC20.HVTR04, however failed to neutralize BA.4/BA5. THSC20.HVTR26 mAb that we reported to moderately neutralize BA.1 (7) was included in the experiment for comparison (Table S1). The N440K mutation which is common in Omicron BA.1, BA.2 and BA.4/BA.5 variants did not appear to affect the neutralization potential of THSC20.HVTR04 against BA.2 and BA.4/5, though likely have reduced its potency as noted earlier with SARS-CoV-2 wild type spike.…”

“…Little is known about the antibody responses mounted in individuals previously infected with the ancestral SARS-CoV-2 (Wu-1/CoV2) prior to vaccination and capable of broadly neutralizing evolving VOCs including the currently circulating and rapidly emerging Omicron variants. We previously reported isolation of five RBD-specific neutralizing monoclonal antibodies from an unvaccinated Indian individual (donor C-03-0020) who was infected with ancestral SARS-CoV-2 (7). In the present study, we report isolation and characterization of two additional mAbs from the same individual: THSC20.HVTR11 and THSC20.HVTR55 (Fig.…”

Neutralizing antibodies and their cocktails against SARS-CoV-2 Omicron and other circulating variants

“…1f ) [ 1 , 2 , 11 ]. Most RBD-targeting mAbs, including 55A8, 58G6, S2K146, S2X259, S2H97, THSC20.HVTR04, and THSC20.HVTR26, are in preclinical trials to examine whether they can prevent SARS-CoV-2 infection in cell culture or animal models [ 12 – 14 ]. Other RBD-targeting mAbs, including bamlanivimab (LY-CoV555), etesivimab (LY-CoV016), casirivimab (REGN-10933), imdevimab (REGN-10987), adintrevimab (AGD20), regdanvimab (CT-P59), sotrovimab (VIR-7831), VIR-7832, tixagevimab (AZD8895 or COV2-2196), cilgavimab (AZD1061 or COV2-2130), and bebtelovimab (LY-CoV1404), have progressed to full clinical trials or have received emergency use authorization (EUA) to treat COVID-19 [ 10 , 13 , 15 ].…”

“…Additionally, 55A8 and 58G6 mAb cocktails demonstrated synergetic neutralizing activity in cell culture and protected hamsters from challenge with Omicron (BA.1) [ 14 ]. Notably, cocktails of neutralizing mAbs that target nonoverlapping epitopes on the SARS-CoV-2 S RBD may bind to the domain simultaneously, with synergistic effects for preventing and treating infection by SARS-CoV-2 variants [ 9 , 12 ].…”