A potent bispecific nanobody protects hACE2 mice against SARS-CoV-2 infection via intranasal administration

Wu, Xilin; Cheng, Lin; Fu, Ming; Huang, Boxian; Zhu, Liqiang; Xu, Shiqi; Shi, Hailong; Zhang, Doudou; Yuan, Huanyun; Nawaz, Waqas; Yang, Ping; Hu, Qinxue; Liu, Yalan; Wu, Zhiwei

doi:10.1016/j.celrep.2021.109869

Cited by 78 publications

(77 citation statements)

References 42 publications

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“…In addition, Nb-based neutralizing antibodies had been proven to provide effective protection for both prophylactic and therapeutic purposes against SARS-CoV-2 infection in hACE2 transgenic mice. 43 As for the immunogenicity of camelid-derived nanobodies, there has not been much in-depth research, but Nbs need to be routinely humanized during development. 44…”

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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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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“… 146 Humanized sdAbs targeting the RBD exhibit potent neutralization activity against both pseudotyped and authentic SARS-CoV-2, and fusion of the human IgG1 Fc to sdAbs further improves their neutralization activity by up to 10 times. 148 Reformatting sdAbs into multivalent constructs 149 or a bispecific format 150 makes them more potent to broadly neutralize SARS-CoV-2 variants. In this regard, sdAb represents a promising therapeutic agent for passive immunization against SARS-CoV-2.…”

Section: Challenges and Future Perspectivesmentioning

confidence: 99%

Therapeutic antibodies for COVID-19: is a new age of IgM, IgA and bispecific antibodies coming?

Zhang

Sun

2022

mAbs

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Early humoral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are dominated by IgM and IgA antibodies, which greatly contribute to virus neutralization at mucosal sites. Given the essential roles of IgM and IgA in the control and elimination of SARS-CoV-2 infection, the mucosal immunity could be exploited for therapeutic and prophylactic purposes. However, almost all neutralizing antibodies that are authorized for emergency use and under clinical development are IgG antibodies, and no vaccine has been developed to boost mucosal immunity for SARS-CoV-2 infection. In addition to IgM and IgA, bispecific antibodies (bsAbs) combine specificities of two antibodies in one molecule, representing an important alternative to monoclonal antibody cocktails. Here, we summarize the latest advances in studies on IgM, IgA and bsAbs against SARS-CoV-2. The current challenges and future directions in vaccine design and antibody-based therapeutics are also discussed.

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“…Bi-specific antibodies have also been developed against SARS-CoV-2. The majority of these bi-specific antibodies target two different epitopes within the RBD ( 91 – 95 ). One example of an assymetric RBD-targeting bi-specific antibody is CoV-X2, which neutralizes the ancestral strain with a comparable potency of imdevimab or Evusheld (IC 50 of 5.8 ng/ml) ( Tabel 1 ) ( 91 ).…”

Section: Introductionmentioning

confidence: 99%

“…In summary, the current SARS-CoV-2 bi-specific antibodies are at least as potent as the clinical approved monoclonal antibody therapies in neutralizing the ancestral SARS-CoV-2 strain, and may therefore render an interesting candidate for future antibody therapies to combat VOCs ( 91 , 95 , 96 ). However, as no bi-specific antibodies against SARS-CoV-2 are yet in human clinical trial, it is unlikely that bi-specific antibodies will soon become a treatment option against COVID-19.…”

Section: Introductionmentioning

confidence: 99%

“…In addition to the two IgG-like bi-specific SARS-CoV-2 antibodies that we described in the previous paragraph, there are also bi-specific and multivalent antibodies developed against SARS-CoV-2 which lack the Fc domain ( 94 , 95 , 97 ). The Fc domain of an antibody is important for its solubility, stability and increases the antibody half-life.…”

Section: Introductionmentioning

confidence: 99%

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Optimization of Anti-SARS-CoV-2 Neutralizing Antibody Therapies: Roadmap to Improve Clinical Effectiveness and Implementation

Straten

Gils

Taeye

et al. 2022

Front. Med. Technol.

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One of the major breakthroughs to combat the current Coronavirus Disease 2019 (COVID-19) pandemic has been the development of highly effective vaccines against the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Still, alternatives are needed for individuals who are at high risk of developing severe COVID-19 and are not protected by vaccination. Monoclonal antibodies against the spike protein of SARS-CoV-2 have been shown to be effective as prophylaxis and treatment against COVID-19. However, the emergence of variants of concern (VOCs) challenges the efficacy of antibody therapies. This review describes the neutralization resistance of the clinically-approved monoclonal antibody therapies against the Alpha (B.1.1.7), Beta (B.1.351), Gamma (P1), Delta (B.1.617.2), and the Omicron (B.1.1.529) variants. To guide the development of monoclonal antibody therapies and to anticipate on the continuous evolution of SARS-CoV-2, we highlight different strategies to broaden the antibody activity by targeting more conserved epitopes and/or simultaneously targeting multiple sites of vulnerability of the virus. This review further describes the contribution of antibody Fc effector functions to optimize the antibody efficacy. In addition, the main route of SARS-CoV-2 antibody administration is currently intravenously and dictates a monthly injection when used as prophylactic. Therefore, we discusses the concept of long-acting antibodies (LAABs) and non-intravenously routes of antibody administration in order to broaden the clinical applicability of antibody therapies.

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A potent bispecific nanobody protects hACE2 mice against SARS-CoV-2 infection via intranasal administration

Cited by 78 publications

References 42 publications

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

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

Therapeutic antibodies for COVID-19: is a new age of IgM, IgA and bispecific antibodies coming?

Optimization of Anti-SARS-CoV-2 Neutralizing Antibody Therapies: Roadmap to Improve Clinical Effectiveness and Implementation

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