A multi-specific, multi-affinity antibody platform neutralizes sarbecoviruses and confers protection against SARS-CoV-2 in vivo

Aschner, Clare Burn; Muthuraman, Krithika; Kucharska, Iga; Cui, Hong; Prieto, Katherine; Nair, Manoj S.; Wang, Maple; Huang, Yaoxing; Christie-Holmes, Natasha; Poon, Betty; Lam, Jessica; Sultana, Azmiri; Kozak, Robert; Mubareka, Samira; Rubinstein, John L.; Rujas, Edurne; Treanor, Bebhinn; Ho, David D.; Jetha, Arif; Julien, Jean-Philippe

doi:10.1126/scitranslmed.adf4549

Cited by 5 publications

(3 citation statements)

References 85 publications

(92 reference statements)

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“…Furthermore, in addition to biparatopic Abs, the incorporation of natural trimeric motifs such as human type III procollagen or foldon (Fd) protein can facilitate the design of tri-specific VHH Ab 28 , 29 . This approach has the potentials to further improve the pharmaceutical effect of the Ab drugs, which represents a direction for future research 30 , 31 .…”

Section: Discussionmentioning

confidence: 99%

Biparatopic anti-PCSK9 antibody enhances the LDL-uptake in HepG2 cells

Li,

Zhang,

Shu

et al. 2024

Sci Rep

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target to reduce lipids. In 2020, we reported a chimeric camelid-human heavy chain antibody VHH-B11-Fc targeting PCSK9. Recently, it was verified that VHH-B11 binds one linear epitope in the PCSK9 hinge region. To enhance its druggability, we have developed a novel biparatopic B11-H2-Fc Ab herein. Thereinto, surface plasmon resonance (SPR) confirmed the epitope differences in binding-PCSK9 among VHH-B11, VHH-H2 and the approved Repatha. Additionally, SPR revealed the B11-H2-Fc exhibits an avidity of approximately 0.036 nM for PCSK9, representing a considerable increase compared to VHH-B11-Fc (~ 0.69 nM). Moreover, we found the Repatha and B11-H2-Fc exhibited > 95% PCSK9 inhibition efficiency compared to approximately 48% for the VHH-Fc at 7.4 nM (P < 0.0005). Further, we verified its biological activity using the human hepatoma cells G2 model, where the B11-H2-Fc exhibited almost 100% efficiency in PCSK9 inhibition at only 0.75 μM. The immunoblotting results of low-density lipoprotein cholesterol (LDL-c) uptake assay also demonstrated the excellent performance of B11-H2-Fc on recovering the LDL-c receptor (LDLR), as strong as the Repatha (P > 0.05). These findings provide the first evidence of the efficacy of a novel Ab targeting PCSK9 in the field of lipid-lowering drugs.

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Section: Discussionmentioning

confidence: 99%

Biparatopic anti-PCSK9 antibody enhances the LDL-uptake in HepG2 cells

Li,

Zhang,

Shu

et al. 2024

Sci Rep

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“…In general, avidity can be influenced by affinity, the valences of the antibody and the antigen, and the geometry of the interaction between the antigen and antibody. Although efficient neutralization fundamentally depends on strong affinity, recent studies provide compelling evidence for additional avidity mechanisms that optimize pathogen recognition 149‐151 . The risks of developing vaccine escape variants are less in comparison to therapeutics.…”

Section: Probable Mechanism Of Immune Escape Against Sars‐cov‐2 Variantsmentioning

confidence: 99%

Lessons from COVID‐19: Aspects of prevention, therapeutics, and diagnostics against SARS‐CoV‐2 with special focus on JN.1 and XBB sublineages

Jaishwal,

Gyaneshwari,

Jha

et al. 2024

MedComm – Future Medicine

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The end of second decade in the 21st century witnessed a prominent disease outbreak caused by the novel coronavirus SARS‐CoV‐2 (including most diverse omicron subvariants), where the death toll crossed the boundary of 6.9 million across the globe by December 19, 2023. All spheres of central dogma of molecular biology and host‒pathogen interaction was explored to find ways in diagnostics, isolation, curtailment, and therapy. Above all, diagnostics and therapeutics against COVID‐19 took an enormous jump, which needs to be evaluated for accuracy and feasibility and requires serious compilation for current and future generations. With the same objective, this review encompasses the diverse ways including prevention practiced and proposed during the handling of this pandemic across the globe. It involves the role of mutations in viruses and subsequent epitope mapping with potential immune escape mechanisms of SARS‐CoV‐2 variants including the conservancy of T‐cell epitopes has also been highlighted. The efficacy in antigen/antibody‐based diagnostics, RT‒PCR‐ and NGS‐based confirmation of pathogen presence, and imaging (X‐ray/CT‐scan) for symptoms and damage assessment has been thoroughly filtered. The possibility of errors in diagnostics and their cause and consequences have also been presented for the ease of readers and further improvisers.

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“…Additionally, mono-specific Multabodies potently neutralize SARS-CoV-2 variants of concern because of their augmented avidity, and tri-specific Multabodies expand the neutralization breadth beyond SARS-CoV-2 to other sarbecoviruses. Therefore, combining avidity and multi-specificity can confer protection and resilience against viral diversity, exceeding those provided by traditional monoclonal antibody therapies ( Burn Aschner et al., 2023 ; Table 1 ).…”

mentioning

confidence: 99%