SARS-CoV-2 spike S2-specific neutralizing antibodies

Li, Chia-Jung; Chang, Shih‐Chung

doi:10.1080/22221751.2023.2220582

Cited by 21 publications

(22 citation statements)

References 82 publications

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“…Hence, it was inferred that the binding mechanism of CvMab-62 differs from that of typical S2 antibodies, primarily because it does not depend on the epitopes commonly required by anti-S2 neutralizing antibodies, and the orientation of residue D1146, which is essential for CvMab-62 binding, is on the opposite side to where S2P6 binds (Figure S5). 34,45 In addition, the bispecific antibody Bis3 did not significantly interfere with the TMPRSS2-dependent spike protein cleavage into the S2 fragment. Therefore, it is presumed that CvMab-62 inhibits the fusion process between the virus and the cell membrane after proteolytic cleavage of the spike protein.…”

Section: Discussionmentioning

confidence: 93%

“…The spike protein of bat Khosta2 differs from SARS-CoV-2 in the corresponding 1070–1162 residue region due to amino acid substitutions such as A1070S, E1072D, D1084K, H1088Y, S1097T, E1111Q, Q1113E, I1114V, D1118E, V1122E, and D1146E (Figure 2I), and additional western blot analyses revealed that mutations A1070S, E1072D, D1084K/H1088Y, QPEV (E1111Q/Q1113E/I1114V), the deletion from 1085–1122, and the deletion from 1149–1162 do not impact CvMab-62 binding, but D1146E mutation disrupts CvMab-62 binding (Figure S1). In addition, the binding of CvMab-62 to the S2 region does not require the presence of residues 1149–1162 (KEELDKYFKNHTSP), a common epitope for most anti-S2 neutralizing antibodies, 34, 45 indicating that the CvMab-62 epitope is novel within the region of residues 1123–1148, with a particular focus on D1146.…”

Section: Resultsmentioning

confidence: 99%

“…Notably, many anti-S2 antibodies targeting SARS-CoV-2 have been reported to exhibit infection inhibitory activity, with several antibodies binding upstream of HR2, the S2 stem helix region within residues 1141-1160 of the spike protein. 34,[36][37][38]40,41,45,79 The alpha helix within residues 1148-1156 (FKEELDKYF) upstream of HR2 is a common epitope for most anti-S2 neutralizing antibodies, and residues F1148, E1151, L1152, D1153, Y1151, and F1156 are directly recognized by the anti-S2 antibody S2P6 complementarity-determining regions (CDRs). 34,45 In particular, as suggested by the S2P6 model, 34 anti-S2 antibodies inhibit the structural conversion of the S2 region necessary for cellular membrane fusion.…”

Section: Discussionmentioning

confidence: 99%

“…34,[36][37][38]40,41,45,79 The alpha helix within residues 1148-1156 (FKEELDKYF) upstream of HR2 is a common epitope for most anti-S2 neutralizing antibodies, and residues F1148, E1151, L1152, D1153, Y1151, and F1156 are directly recognized by the anti-S2 antibody S2P6 complementarity-determining regions (CDRs). 34,45 In particular, as suggested by the S2P6 model, 34 anti-S2 antibodies inhibit the structural conversion of the S2 region necessary for cellular membrane fusion.…”

Section: Discussionmentioning

confidence: 99%

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Overcoming antibody-resistant SARS-CoV-2 variants with bispecific antibodies constructed using non-neutralizing antibodies

Inoue,

Yamamoto,

Sato

et al. 2023

Preprint

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A current challenge is the emergence of SARS-CoV-2 variants, such as BQ.1.1 and XBB.1.5, that can evade immune defenses, thereby limiting antibody drug effectiveness. Emergency-use antibody drugs, including the widely effective bebtelovimab, are losing their benefits. One potential approach to address this issue are bispecific antibodies which combine the targeting abilities of two antibodies with distinct epitopes. We engineered neutralizing bispecific antibodies in the IgG-scFv format from two initially non-neutralizing antibodies, CvMab-6 (which binds to the receptor-binding domain [RBD]) and CvMab-62 (targeting a spike protein S2 subunit epitope adjacent to the known anti-S2 antibody epitope). Furthermore, we created a bispecific antibody by incorporating the scFv of bebtelovimab with our anti-S2 antibody, demonstrating significant restoration of effectiveness against bebtelovimab-resistant BQ.1.1 variants. This study highlights the potential of neutralizing bispecific antibodies, which combine existing less effective anti-RBD antibodies with anti-S2 antibodies, to revive the effectiveness of antibody therapeutics compromised by immune-evading variants.

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Section: Discussionmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Overcoming antibody-resistant SARS-CoV-2 variants with bispecific antibodies constructed using non-neutralizing antibodies

Inoue,

Yamamoto,

Sato

et al. 2023

Preprint

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“…However, the development of SARS-CoV-2 immune escape variants, which frequently have mutations in the S protein, could make present S1 NAbs useless. The S protein S2 has a more conserved component, and S2 targeting NAbs provide a wider neutralizing power against different SARS-CoV-2 variations [ 220 ]. Wang et al discovered the nanobody S102 through an alpaca immune library and demonstrated a high affinity at the sub-picomolar level.…”

Section: Nanobodiesmentioning

confidence: 99%

Aptamers and Nanobodies as New Bioprobes for SARS-CoV-2 Diagnostic and Therapeutic System Applications

Park,

Lee

et al. 2024

Biosensors

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The global challenges posed by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic have underscored the critical importance of innovative and efficient control systems for addressing future pandemics. The most effective way to control the pandemic is to rapidly suppress the spread of the virus through early detection using a rapid, accurate, and easy-to-use diagnostic platform. In biosensors that use bioprobes, the binding affinity of molecular recognition elements (MREs) is the primary factor determining the dynamic range of the sensing platform. Furthermore, the sensitivity relies mainly on bioprobe quality with sufficient functionality. This comprehensive review investigates aptamers and nanobodies recently developed as advanced MREs for SARS-CoV-2 diagnostic and therapeutic applications. These bioprobes might be integrated into organic bioelectronic materials and devices, with promising enhanced sensitivity and specificity. This review offers valuable insights into advancing biosensing technologies for infectious disease diagnosis and treatment using aptamers and nanobodies as new bioprobes.

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Engineered Nanobodies Elicit Durable and Robust Bi‐Therapeutic Efficacy Toward Virus and Tumors

Jia,

Gu,

Shen

et al. 2024

Adv Funct Materials

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Nanobodies (Nbs) are one of the most promising therapeutics for overcoming immune escape in various diseases, including SARS‐CoV‐2 infection and cancers. However, the small sizes of nanobodies make them prone to renal clearance, thus decreasing circulation half‐life and hindering therapeutic efficacy. Traditional modification technologies, i.e., biotinylation and Fc‐fusion, aim to enhance nanobody pharmacokinetics, but they may introduce heterogeneous products with impaired functions and potentially affect binding to the Fc receptor. Here, a versatile nanobody engineering strategy is presented via molecular modification mediated by an intrinsically disordered protein. The engineered nanobody nano‐formulations retain their high‐affinity binding to the spike protein receptor binding domain and possess submicromolar levels of half‐maximal inhibitory concentration (IC50) against the pseudotyped SARS‐CoV‐2 variants, comparable to the unmodified nanobodies. Notably, the nano‐formulations show elongated half‐lives that are up to ≈15 times higher than those of original nanobodies and superior to other reported modified nanobodies. Furthermore, the in vivo therapeutic efficacy of such nano‐formulation toward breast cancer is significantly enhanced. Therefore, this nanobody engineering strategy offers a convenient and broadly applicable solution to address the suboptimal in vivo performance of nanobodies, holding substantial promise for effectively combating treatment‐tolerant cancers and future pandemics.

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SARS-CoV-2 spike S2-specific neutralizing antibodies

Cited by 21 publications

References 82 publications

Overcoming antibody-resistant SARS-CoV-2 variants with bispecific antibodies constructed using non-neutralizing antibodies

Overcoming antibody-resistant SARS-CoV-2 variants with bispecific antibodies constructed using non-neutralizing antibodies

Aptamers and Nanobodies as New Bioprobes for SARS-CoV-2 Diagnostic and Therapeutic System Applications

Engineered Nanobodies Elicit Durable and Robust Bi‐Therapeutic Efficacy Toward Virus and Tumors

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