Tetravalent SARS-CoV-2 Neutralizing Antibodies Show Enhanced Potency and Resistance to Escape Mutations

Miersch, Shane; Li, Zhijie; Saberianfar, Reza; Ustav, Mart; Case, James Brett; Blazer, Levi L.; Chen, Chao; Ye, Wei; Pavlenco, Alevtina; Gorelik, Maryna; Perez, Julia Garcia; Subramania, Suryasree; Singh, Serena; Ploder, Lynda; Ganaie, Safder S.; Chen, Rita E.; Leung, Daisy W.; Pandolfi, Pier Paolo; Novelli, Giuseppe; Matusali, Giulia; Colavita, Francesca; Capobianchi, Maria Rosaria; Jain, Suresh; Gupta, Jyoti; Amarasinghe, Gaya K.; Diamond, Michael S.; Rini, James M.; Sidhu, Sachdev S.

doi:10.1016/j.jmb.2021.167177

Cited by 33 publications

(57 citation statements)

References 77 publications

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“…The IgG-(scFv) 2 design outcompetes the CrossMAb design unlikely via stronger blockage of RBD binding to ACE2, but rather via mechanisms including avidity binding and inter-spike crosslinking. In support of our results, previous studies have shown that multivalent antibodies have greater and broader neutralizing activity than bivalent IgG antibodies 23,29 . Similarly, a SARS-CoV-2 tetravalent bsAb (CV1206_521_GS) uses the DVD-Ig design to combine the RBD- and the NTD-specific antibodies, have demonstrated in vitro neutralizing activity that is 100-fold more potent than the cocktail.…”

Section: Discussionsupporting

confidence: 92%

Engineering SARS-CoV-2 cocktail antibodies into a bispecific format improves neutralizing potency and breadth

Xie

Lin

et al. 2022

Preprint

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One major limitation of neutralizing antibody-based COVID-19 therapy is the requirement of costly cocktails to reduce antibody resistance. We engineered two bispecific antibodies (bsAbs) using distinct designs and compared them with parental antibodies and their cocktail. Single molecules of both bsAbs block the two epitopes targeted by parental antibodies on the receptor-binding domain (RBD). However, bsAb with the IgG-(scFv)2 design (14-H-06) but not the CrossMAb design (14-crs-06) increases antigen-binding and virus-neutralizing activities and spectrum against multiple SARS-CoV-2 variants including the Omicron, than the cocktail. X-ray crystallography and computational simulations reveal distinct neutralizing mechanisms for individual cocktail antibodies and suggest higher inter-spike crosslinking potentials by 14-H-06 than 14-crs-06. In mouse models of infections by SARS-CoV-2 and the Beta, Gamma, and Delta variants, 14-H-06 exhibits higher or equivalent therapeutic efficacy than the cocktail. Rationally engineered bsAbs represent a cost-effective alternative to antibody cocktails and a promising strategy to improve potency and breadth.

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Section: Discussionsupporting

confidence: 92%

Engineering SARS-CoV-2 cocktail antibodies into a bispecific format improves neutralizing potency and breadth

Xie

Lin

et al. 2022

Preprint

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“…Multivalent Nbs have been documented for several viruses with much stronger neutralization potency than single Nbs, 28 and multivalent antibodies that bind two epitopes also prevent the emergence of viral escape mutants. 42 It is worth pointing out that the neutralization activity is increased for tens to 2 log fold in the tetravalent Nb1–Nb2–Fc context, which functions as a heavy-chain antibody with a double punch against SARS-CoV-2 in each arm through biepitopic binding. The tetravalent Nb1–Nb2–Fc is evident with high yield in mammalian cells and durable stability at 37 °C, potentiating the application for either an injectable formula or administration by inhalation.…”

Section: Discussionmentioning

confidence: 99%

An ultrapotent RBD-targeted biparatopic nanobody neutralizes broad SARS-CoV-2 variants

Chi

Zhang

Pan

et al. 2022

Sig Transduct Target Ther

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The wide transmission and host adaptation of SARS-CoV-2 have led to the rapid accumulation of mutations, posing significant challenges to the effectiveness of vaccines and therapeutic antibodies. Although several neutralizing antibodies were authorized for emergency clinical use, convalescent patients derived natural antibodies are vulnerable to SARS-CoV-2 Spike mutation. Here, we describe the screen of a panel of SARS-CoV-2 receptor-binding domain (RBD) targeted nanobodies (Nbs) from a synthetic library and the design of a biparatopic Nb, named Nb1–Nb2, with tight affinity and super-wide neutralization breadth against multiple SARS-CoV-2 variants of concern. Deep-mutational scanning experiments identify the potential binding epitopes of the Nbs on the RBD and demonstrate that biparatopic Nb1–Nb2 has a strong escape-resistant feature against more than 60 tested RBD amino acid substitutions. Using pseudovirion-based and trans-complementation SARS-CoV-2 tools, we determine that the Nb1–Nb2 broadly neutralizes multiple SARS-CoV-2 variants at sub-nanomolar levels, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Lambda (C.37), Kappa (B.1.617.1), and Mu (B.1.621). Furthermore, a heavy-chain antibody is constructed by fusing the human IgG1 Fc to Nb1–Nb2 (designated as Nb1–Nb2-Fc) to improve its neutralization potency, yield, stability, and potential half-life extension. For the new Omicron variant (B.1.1.529) that harbors unprecedented multiple RBD mutations, Nb1–Nb2-Fc keeps a firm affinity (KD < 1.0 × 10−12 M) and strong neutralizing activity (IC50 = 1.46 nM for authentic Omicron virus). Together, we developed a tetravalent biparatopic human heavy-chain antibody with ultrapotent and broad-spectrum SARS-CoV-2 neutralization activity which highlights the potential clinical applications.

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“…Antibodies have a lengthy half-life in the blood and are usually free from side effects [ 6 ]. Thus, by adding two additional Fabs to the canonical IgG molecule, we have developed an innovative type of antibody, called tetravalent ultra-high affinity nAbs, exhibiting neutralization potencies higher than those of the bivalent IgG format [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Two Different Therapeutic Approaches for SARS-CoV-2 in hiPSCs-Derived Lung Organoids

Spitalieri

Centofanti

Murdocca

et al. 2022

Cells

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The global health emergency for SARS-CoV-2 (COVID-19) created an urgent need to develop new treatments and therapeutic drugs. In this study, we tested, for the first time on human cells, a new tetravalent neutralizing antibody (15033-7) targeting Spike protein and a synthetic peptide homologous to dipeptidyl peptidase-4 (DPP4) receptor on host cells. Both could represent powerful immunotherapeutic candidates for COVID-19 treatment. The infection begins in the proximal airways, namely the alveolar type 2 (AT2) cells of the distal lung, which express both ACE2 and DPP4 receptors. Thus, to evaluate the efficacy of both approaches, we developed three-dimensional (3D) complex lung organoid structures (hLORGs) derived from human-induced pluripotent stem cells (iPSCs) and resembling the in vivo organ. Afterward, hLORGs were infected by different SARS-CoV-2 S pseudovirus variants and treated by the Ab15033-7 or DPP4 peptide. Using both approaches, we observed a significant reduction of viral entry and a modulation of the expression of genes implicated in innate immunity and inflammatory response. These data demonstrate the efficacy of such approaches in strongly reducing the infection efficiency in vitro and, importantly, provide proof-of-principle evidence that hiPSC-derived hLORGs represent an ideal in vitro system for testing both therapeutic and preventive modalities against COVID-19.

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Tetravalent SARS-CoV-2 Neutralizing Antibodies Show Enhanced Potency and Resistance to Escape Mutations

Cited by 33 publications

References 77 publications

Engineering SARS-CoV-2 cocktail antibodies into a bispecific format improves neutralizing potency and breadth

Engineering SARS-CoV-2 cocktail antibodies into a bispecific format improves neutralizing potency and breadth

An ultrapotent RBD-targeted biparatopic nanobody neutralizes broad SARS-CoV-2 variants

Two Different Therapeutic Approaches for SARS-CoV-2 in hiPSCs-Derived Lung Organoids

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