Albumin-VHH Platform

AlbuFlex™ – Albumin-Binding VHH Nanobody Platform

What is AlbuFlex™

AlbuFlex™ is our proprietary VHH Nanobody platform designed to exploit the natural half-life extension and biodistribution properties of serum albumin. Built on the same FC8TM scaffold framework as every Cortalix VHH, AlbuFlexTM binders are humanized and stable by design. By integrating an albumin-binding FC8TM VHH into MultiDomeTM constructs, we can tune the pharmacokinetics of therapeutic VHH Nanobodies and optimize their in vivo performance.

How it Works

Serum albumin is the most abundant protein in plasma, with a half-life of approximately 20 days. This unusually long half-life is driven by the neonatal Fc receptor (FcRn). Albumin taken up into vascular endothelial cells by pinocytosis encounters FcRn within acidified endosomes, where the low pH allows FcRn to bind albumin with high affinity and divert it away from lysosomal degradation. The FcRn-albumin complex is then recycled back to the cell surface, where the neutral pH of the bloodstream triggers release of albumin back into circulation. Proteins that fail to engage FcRn are not rescued by this shuttle and are degraded instead. AlbuFlexTM VHH antibodies are designed to bind defined epitopes on albumin that hitch a ride on this same FcRn recycling pathway, extending the circulation time of any construct they are fused to and enabling therapeutic constructs to distribute more effectively across tissues. It is important to consider, however, that these binding epitopes are chosen to leave albumin’s FcRn-binding region undisturbed: interactions that block FcRn engagement would disrupt the recycling mechanism itself and should preferably not interfere with the normal physiological functions of albumin.
AlbuFlex platform albumin-binding VHH antibody design elements

Figure: Graphical representation of distinct VHH Nanobodies selected for binding to specific regions of the serum albumin molecule.

Design Variations Within AlbuFlex™

  • Number and position of albumin binders
    AlbuFlex™ offers the flexibility to engage one or multiple VHHs with distinct domains of serum albumin. This allows fine-tuning of pharmacokinetics (PK) and the possibility to modulate how other plasma proteins interact with albumin at those sites.
  • Spacer architecture
    The albumin-binding VHH can be connected to other target-specific VHHs via different spacers. These spacers can be positioned N-terminally, centrally, or C-terminally in the construct. Spacer design influences folding, accessibility, and functional synergy between the albumin-binding and target-binding domains. Since these effects are highly context-dependent, optimal designs are established empirically during development.
AlbuFlex platform albumin-binding VHH antibody framework design

Figure: Design elements of the AlbuFlex™ platform.

Advantages of AlbuFlex™

  • Tunable half-life extension through modular albumin-binding design.
  • Built on the humanized, aggregation-free FC8TM framework for translation-ready constructs.
  • Potential to modulate biodistribution and competition with endogenous ligands.
  • Compatibility with multiple therapeutic formats, including bi- and multi-specific VHH Nanobody constructs.
  • Direct integration into the MultiDomeTM platform for oncology, radiopharma, and inflammatory applications.

Applications

  • Oncology: improved tumor uptake when combined with tumor-targeting VHHs.
  • Radiopharmaceuticals: optimized tracer circulation and tumor-to-background ratios.
  • Inflammatory diseases: sustained systemic activity with reduced dosing frequency.

Our Approach

At Cortalix, we systematically explore combinations of albumin-binding valency, domain positioning, and spacer configurations. Every albumin-binding and target-binding VHH originates from our FC8TM Discovery Platform, ribosomal display and phage display, or immune libraries, ensuring consistent quality across the construct. Together with partners, we identify the design that best balances PK, stability, and potency for the intended clinical use. AlbuFlexTM thus serves as a versatile platform for engineering next-generation VHH antibody therapeutics

Select Source

  • Hoefman S, Ottevaere I, Baumeister J, Sargentini-Maier ML. Pre-Clinical Intravenous Serum Pharmacokinetics of Albumin Binding and Non-Half-Life Extended Nanobodies. Antibodies. 2015;4(3):141-156.
  • Song W, Wang J, Mei H, Limaye A, Samanta A, Braddock M, et al. Albumin binding improves nanobody pharmacokinetics for tumor targeting. 2023.
  • Van Lith SAM, et al. Novel VHH-Based Tracers with Variable Plasma Half-Lives for Imaging. Molecular Pharmaceutics. 2022;19(7):…
  • Harmsen MM, Ackerschott B, de Smit H, et al. Serum immunoglobulin or albumin binding single-domain antibodies that enable tailored half-life extension of biologics in multiple animal species. Frontiers in Immunology. 2024.
  • Glassman PM, Balthasar JP. Molecularly Engineered Nanobodies for Tunable Half-Lives by Albumin Binding. 2020.
  • Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007;7(9):715-725.