Denmark's Novozymes has signed an exclusive worldwide licensing agreement with CSL Behring for albufuse, a proprietary albumin fusion technology that can extend the circulatory half-life of therapeutic proteins through genetic fusion to recombinant human albumin.
No financial details of the agreement were disclosed. Novozymes said CSL Behring, a US-based specialist in plasma protein biotherapeutics, would be using albufuse to research, develop and commercialise novel biotherapeutic products. "We have chosen Novozymes' albufuse as we believe it offers unique product and patient benefits to enhance our current protein therapeutic pipeline," said Val Romberg, senior vice president of R&D at CSL Behring.
There is already evidence to that effect in the form of preclinical data presented by the company at the 49th annual meeting of the American Society of Hematology last December. This proof-of-principle study showed for the first time that it was possible to fuse the coagulant Factor VIIa (FVIIa) genetically to human albumin, prolonging the half-life of the therapeutic protein while retaining its biological activity.
A recombinant VIIa-albumin fusion protein (rVIIa-FP) was generated through genetic engineering, expressed in mammalian cell culture, purified and characterised. In a preclinical rat model, the fusion protein displayed full biological activity and a half-life that was six to nine times that of either the recombinant FVIIa NovoSeven (Novo Nordisk) or a rVIIa control protein, CSL Behring reported. Recombinant Factor VIIa is used to control bleeding episodes in haemophilia patients. As CSL Behring pointed out, this requires multiple injections as rFVIIa has a short half-life of around 2.5 hours - inconvenient for both physicians and patients, particularly during surgical intervention.
Although genetic fusion to albumin is an efficient way to extend the half-life of small proteins, previously it has not been successfully applied in prolonging the half-life of complex proteins, CS Behring noted. "A major unmet need in hematology is improving the pharmacokinetic parameters of coagulation factors, such as half-life, while retaining full haemostatic activity," commented Dr Stefan Schulte, head of preclinical R&D at CSL Behring GmbH in Germany.
"The pharmacological properties of rVIIa-FP seen in our study could one day facilitate a single dosing regimen of one injection per bleeding event, as well as significantly reduce the number of injections haemophilia patients with inhibitors need during surgical interventions." Dr David Mead, business development director in the UK, said the licence agreement with CSL Behring further demonstrated Novozymes' long-term commitment to becoming a strategic partner for the global pharmaceutical industry.
"The applications of albufuse technology are substantial and growing, with one of our licensees initiating a Phase III clinical trial with their interferon-based fusion candidate," he noted. This is the US company Human Genome Sciences (HGS), which last August completed enrollment and initial dosing in ACHIEVE 1, the first of two pivotal Phase III trials evaluating Albuferon (albinterferon alfa-2b) combined with ribavirin in treatment-naive patients with chronic hepatitis C.
Albuferon, for which HGS and Novartis have an exclusive worldwide co-development and commercialisation agreement, is a novel long-acting form of interferon alpha created through the genetic fusion of human albumin and interferon alpha. HGS expects to have Phase III data available by next spring with global marketing applications expected in autumn 2009. Novozymes' albufuse was originally developed by Delta Biotechnology in the UK. The Danish company acquired Delta in July 2006, subsequently incorporating it as Novozymes Biopharma UK. The albufuse technology now belongs to Novozymes' fast-growing biopharmaceutical ingredients (BPI) portfolio.
The fusion technique has already been shown to boost the circulatory half-life of a wide range of therapeutically relevant proteins, increasing bioavailability and cutting administration schedules, dose rates and side-effects, Novozymes said. The combined expression and production process "eliminates the need for additional post-production chemical derivatisation, such as PEGylation, making albufuse technology the natural choice for protein half-life extension", it added.
The technology is a single-step expression solution in which the client's target molecule is genetically fused to albumin at the molecular level, Novozymes explained. The resulting moiety is secreted as a contiguous peptide linked via a peptide bond. The company has extended its capabilities in protein expression by engineering its yeast Saccharomyces cerevisiae to produce albumin fusion proteins in a system free of animal components, it noted.
To date, Novozymes has successfully expressed over 50 albumin fusions, secreted at high levels of up to 5g/L. Proteins characterised to the preclinical stage include growth hormone, cytokines, endostatin, HIV inhibitory peptides, interleukin (IL) 1-receptor antagonists, IL 10 and IL 11.