Improving the pharmacokinetic properties of biologics by fusion to an anti-HSA shark VNAR domain

Mischa R Müller, Kenneth Saunders, Christopher Grace, Macy Jin, Nicole Piche-Nicholas, John Steven, Ronan O'Dwyer, Leeying Wu, Lam Khetemenee, Yulia Vugmeyster, Timothy P Hickling, Lioudmila Tchistiakova, Stephane Olland, Davinder Gill, Allan Jensen, Caroline Barelle

Research output: Contribution to journalArticlepeer-review

74 Citations (Scopus)


Advances in recombinant antibody technology and protein engineering have provided the opportunity to reduce antibodies to their smallest binding domain components and have concomitantly driven the requirement for devising strategies to increase serum half-life to optimise drug exposure, thereby increasing therapeutic efficacy. In this study, we adopted an immunization route to raise picomolar affinity shark immunoglobulin new antigen receptors (IgNARs) to target human serum albumin (HSA). From our model shark species, Squalus acanthias, a phage display library encompassing the variable binding domain of IgNAR (VNAR) was constructed, screened against target, and positive clones were characterized for affinity and specificity. N-terminal and C-terminal molecular fusions of our lead hit in complex with a naïve VNAR domain were expressed, purified and exhibited the retention of high affinity binding to HSA, but also cross-selectivity to mouse, rat and monkey serum albumin both in vitro and in vivo. Furthermore, the naïve VNAR had enhanced pharmacokinetic (PK) characteristics in both N- and C-terminal orientations and when tested as a three domain construct with naïve VNAR flanking the HSA binding domain at both the N and C termini. Molecules derived from this platform technology also demonstrated the potential for clinical utility by being available via the subcutaneous route of delivery. This study thus demonstrates the first in vivo functional efficacy of a VNAR binding domain with the ability to enhance PK properties and support delivery of multifunctional therapies.
Original languageEnglish
Pages (from-to)673-685
Number of pages13
Issue number6
Publication statusPublished - 2012


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