tetano
Editor, Senior Moderator
PNAS Nexus
. 2023 Nov 28;2(12)
gad403.
doi: 10.1093/pnasnexus/pgad403. eCollection 2023 Dec. A pan-SARS-CoV-2-specific soluble angiotensin-converting enzyme 2-albumin fusion engineered for enhanced plasma half-life and needle-free mucosal delivery
Sopisa Benjakul[SUP] 1 2 3 [/SUP], Aina Karen Anthi[SUP] 1 2 3 [/SUP], Anette Kolderup[SUP] 1 2 3 [/SUP], Marina Vaysburd[SUP] 4 [/SUP], Heidrun Elisabeth Lode[SUP] 1 2 5 [/SUP], Donna Mallery[SUP] 4 [/SUP], Even Fossum[SUP] 6 [/SUP], Elisabeth Lea Vikse[SUP] 6 [/SUP], Anna Albecka[SUP] 4 [/SUP], Aleksandr Ianevski[SUP] 7 [/SUP], Denis Kainov[SUP] 7 8 9 [/SUP], Karine Flem Karlsen[SUP] 1 2 [/SUP], Siri Aastedatter Sakya[SUP] 1 2 3 [/SUP], Mari Nyquist-Andersen[SUP] 1 2 3 [/SUP], Torleif Tollefsrud Gjølberg[SUP] 1 2 3 5 [/SUP], Morten C Moe[SUP] 5 [/SUP], Magnar Bjørås[SUP] 6 [/SUP], Inger Sandlie[SUP] 10 [/SUP], Leo C James[SUP] 4 [/SUP], Jan Terje Andersen[SUP] 1 2 3 [/SUP]
Affiliations
Immunocompromised patients often fail to raise protective vaccine-induced immunity against the global emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Although monoclonal antibodies have been authorized for clinical use, most have lost their ability to potently neutralize the evolving Omicron subvariants. Thus, there is an urgent need for treatment strategies that can provide protection against these and emerging SARS-CoV-2 variants to prevent the development of severe coronavirus disease 2019. Here, we report on the design and characterization of a long-acting viral entry-blocking angiotensin-converting enzyme 2 (ACE2) dimeric fusion molecule. Specifically, a soluble truncated human dimeric ACE2 variant, engineered for improved binding to the receptor-binding domain of SARS-CoV-2, was fused with human albumin tailored for favorable engagement of the neonatal fragment crystallizable receptor (FcRn), which resulted in enhanced plasma half-life and allowed for needle-free transmucosal delivery upon nasal administration in human FcRn-expressing transgenic mice. Importantly, the dimeric ACE2-fused albumin demonstrated potent neutralization of SARS-CoV-2 immune escape variants.
Keywords: ACE2; FcRn; SARS-CoV-2; half-life; mucosal delivery.
. 2023 Nov 28;2(12)
gad403.doi: 10.1093/pnasnexus/pgad403. eCollection 2023 Dec. A pan-SARS-CoV-2-specific soluble angiotensin-converting enzyme 2-albumin fusion engineered for enhanced plasma half-life and needle-free mucosal delivery
Sopisa Benjakul[SUP] 1 2 3 [/SUP], Aina Karen Anthi[SUP] 1 2 3 [/SUP], Anette Kolderup[SUP] 1 2 3 [/SUP], Marina Vaysburd[SUP] 4 [/SUP], Heidrun Elisabeth Lode[SUP] 1 2 5 [/SUP], Donna Mallery[SUP] 4 [/SUP], Even Fossum[SUP] 6 [/SUP], Elisabeth Lea Vikse[SUP] 6 [/SUP], Anna Albecka[SUP] 4 [/SUP], Aleksandr Ianevski[SUP] 7 [/SUP], Denis Kainov[SUP] 7 8 9 [/SUP], Karine Flem Karlsen[SUP] 1 2 [/SUP], Siri Aastedatter Sakya[SUP] 1 2 3 [/SUP], Mari Nyquist-Andersen[SUP] 1 2 3 [/SUP], Torleif Tollefsrud Gjølberg[SUP] 1 2 3 5 [/SUP], Morten C Moe[SUP] 5 [/SUP], Magnar Bjørås[SUP] 6 [/SUP], Inger Sandlie[SUP] 10 [/SUP], Leo C James[SUP] 4 [/SUP], Jan Terje Andersen[SUP] 1 2 3 [/SUP]
Affiliations
- PMID: 38077689
- PMCID: PMC10703496
- DOI: 10.1093/pnasnexus/pgad403
Immunocompromised patients often fail to raise protective vaccine-induced immunity against the global emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Although monoclonal antibodies have been authorized for clinical use, most have lost their ability to potently neutralize the evolving Omicron subvariants. Thus, there is an urgent need for treatment strategies that can provide protection against these and emerging SARS-CoV-2 variants to prevent the development of severe coronavirus disease 2019. Here, we report on the design and characterization of a long-acting viral entry-blocking angiotensin-converting enzyme 2 (ACE2) dimeric fusion molecule. Specifically, a soluble truncated human dimeric ACE2 variant, engineered for improved binding to the receptor-binding domain of SARS-CoV-2, was fused with human albumin tailored for favorable engagement of the neonatal fragment crystallizable receptor (FcRn), which resulted in enhanced plasma half-life and allowed for needle-free transmucosal delivery upon nasal administration in human FcRn-expressing transgenic mice. Importantly, the dimeric ACE2-fused albumin demonstrated potent neutralization of SARS-CoV-2 immune escape variants.
Keywords: ACE2; FcRn; SARS-CoV-2; half-life; mucosal delivery.