Broad SARS-CoV-2 Neutralization by Monoclonal and Bispecific Antibodies Derived from a Gamma-infected Individual

Abstract

The worldwide pandemic caused by SARS-CoV-2 has remained a human medical threat due to the continued evolution of multiple variants that acquire resistance to vaccines and prior infection. Therefore, it is imperative to discover monoclonal antibodies (mAbs) that neutralize a broad range of SARS-CoV-2 variants for therapeutic and prophylactic use. A stabilized autologous SARS-CoV-2 spike glycoprotein was used to enrich antigen-specific B cells from an individual with a primary Gamma variant infection. Five mAbs selected from those B cells showed considerable neutralizing potency against multiple variants of concern, with COVA309-35 being the most potent against the autologous virus, as well as against Omicron BA.1 and BA.2. When combining the COVA309 mAbs as cocktails or bispecific antibody formats, the breadth and potency was significantly improved against all tested variants. In addition, the mechanism of cross-neutralization of the COVA309 mAbs was elucidated by structural analysis. Altogether these data indicate that a Gamma-infected individual can develop broadly neutralizing antibodies.

Broadening sarbecovirus neutralization with bispecific antibodies combining distinct conserved targets on the receptor binding domain

“…On the contrary, bsAb combinations containing Fab arms of CR3022 and CV38-142 showed narrower specificities and reduced binding. This was also observed for bsAbs containing mAbs isolated from a Gamma-infected individual; COVA309-22, COVA309-35 and COVA309-38 20 . Binding of Ly-CoV1404 was restricted to Clade 1b viruses, while bsAbs combining Ly-CoV1404 with 10-40 or COVA2-02 could also bind S proteins of sarbecoviruses from other clades (Figure 2).…”

“…Different SARS-CoV-2 targeting bsAbs have been described, which show improved neutralization activity compared to the parental mAbs 18,20,21 . The so far described IgG-like bsAbs are of highly diverse formats, such as the CrossMAb constructs [22][23][24][25][26] , DVD-Ig 24,27 , IgG-(scFv)2 21,24,28,29 , Tandem scFv-Fc 28,30,31 , and VH/Fab IgGs 32,33 , many of which require significant engineering and quality control processes to be efficiently produced.…”

“…We specifically focused on class 3 and 4 mAbs as they are directed towards the more conserved base of the RBD [11][12][13][14][15] . Additionally, we included potent candidates isolated from participants of the COSCA cohort in Amsterdam which showed neutralizing breadth 4,20 . Some of our bsAb candidates demonstrate enhanced breadth and improved potency in neutralization assays against a panel of SARS-CoV-2 variants and other sarbecoviruses.…”

Function and mechanism of bispecific antibodies targeting SARS-CoV-2

“…Learning from Huan Ma's approach of introducing the Y29G mutation to bsAb nanobodies for neutralizing the BA.2.75 variant offers a potential solution ( Ma et al., 2022 ). Another viable strategy involves isolating cross-neutralizing antibodies from patients infected with variants and using them to design bispecific antibodies, further amplifying neutralization potency and broadening the breadth ( Guerra et al., 2023 ).…”