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Elisabeth Fuchs et al. Acta Biomater. 2022 Nov‍

Improving preclinical efficacy and safety studies’ translatability is of utmost importance in drug development, and can certainly be achieved through the generation of more pertinent and reliable preclinical models. Selecting the best formulation of a candidate drug is an important step of drug development, as it must ensure that the drug targets the right tissue, at the right dose, for the right duration. One approach for drug delivery is to use the human serum albumin (HSA) as a molecular cargo.¹ Here again, using an appropriate preclinical model is central to accurately assess HSA and FcRn-binding compounds.

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The HSA/hFcRn model has been successfully used to perform preclinical studies of albumin-based drugs, conventional drugs, and biologics whose action is influenced by reversible binding to endogenous HSA.²

The HSA-based approach has been tested to extend compounds’ half-life for a variety of applications, including the development of COVID-19 antiviral drugs. Indeed, as SARS-CoV-2 viral particles bind the membrane receptor angiotensin converting enzyme 2 (ACE2) to enter cells,³ recombinant ACE2 peptides have been developed to serve as decoy and prevent viral cell entry.⁴ A major shortcoming to this approach turned out to be recombinant ACE2’s short plasma half-life in humans (~10h),⁵ thus limiting the treatment’s efficacy. Different efforts were then focused on increasing these compounds’ half-life using the HSA/FcRn cellular recycling system. Recombinant HSA-ACE2 (rHA-ACE2) genetic fusions were recently developed and tested to assess a potential FcRn-driven half-life extension.⁶ The authors showed an efficient binding of rHA-ACE2 to SARS-CoV-2, and inhibition of cell entry in vitro. These genetic fusions were also tested using a double-humanized HSA/hFcRn model, to assess their in vivo half-time extension, and exhibited a prolonged circulatory half-life when compared to soluble ACE2.

Importantly, one advantage of this approach, using ACE2 as a decoy, is that it should be efficient against all SARS-CoV-2 mutants, present and future, as they all use ACE2 for viral cell entry. Thus, optimized genetic fusions of recombinant ACE2 represent a promising addition to anti-COVID-19 drugs.

Of note, the HSA/hFcRn mouse model described in this publication was generated by, and is available off-the-shelf, at genOway, a designer and provider of numerous physiologically relevant preclinical models in multiple research areas, including immuno-oncology, metabolism, cardiovascular diseases, and neuroscience.

References:

1. Al-Harthi, S. et al. Towards the functional high-resolution coordination chemistry of blood plasma human serum albumin. Journal of Inorganic Biochemistry 198, 110716 (2019).
2. Viuff, D. et al. Generation of a double transgenic humanized neonatal Fc receptor (FcRn)/albumin mouse to study the pharmacokinetics of albumin-linked drugs. Journal of Controlled Release 223, 22–30 (2016).
3. Hoffmann, M. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020 Apr 16;181(2):271-280.e8.
4. Zoufaly, A. et al. Human recombinant soluble ACE2 in severe COVID-19. Lancet Respir Med. 2020 Nov;8(11):1154-1158.
5. Haschke, M. et al. Pharmacokinetics and pharmacodynamics of recombinant human angiotensin-converting enzyme 2 in healthy human subjects. Clin Pharmacokinet. 2013 Sep;52(9):783-92.
6. Fuchs, E. et al. An albumin-angiotensin converting enzyme 2-based SARS-CoV-2 decoy with FcRn-driven half-life extension. Acta Biomater. 2022 Nov;153:411-418.