AlbuFlex™ – Albumin-Binding VHH Antibody Platform

What is AlbuFlex™

AlbuFlex™ is our proprietary VHH antibody platform designed to exploit the natural half-life extension and biodistribution properties of serum albumin. By integrating an albumin-binding VHH antibody into MultiDome™ constructs, we can tune the pharmacokinetics of therapeutic VHH antibodies 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. By binding to defined epitopes on albumin, AlbuFlex™ VHH antibodies enable therapeutic constructs to circulate longer and distribute more effectively across tissues. It is important to consider, however, that such interactions should preferably not interfere with the normal physiological functions of albumin.

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.

Figure: Design elements of the AlbuFlex™ platform.

Advantages of AlbuFlex™

• Tunable half-life extension through modular albumin-binding design.

• Potential to modulate biodistribution and competition with endogenous ligands.

• Compatibility with multiple therapeutic formats, including bi- and multi-specific VHH antibody constructs.

• Direct integration into the MultiDome™ 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. Together with partners, we identify the design that best balances PK, stability, and potency for the intended clinical use. AlbuFlex™ 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.