Darrell Sleep Ph.D. CSO Albumedix
How Today’s Drug Developers Are Utilizing Albumin to Drive a New Generation of Biobetters
Biobetters are new and improved versions of already approved biological drugs. They are being developed to overcome some of the challenges associated with original drugs, which could range from a known in vitro or in vivo chemical or structural instability, product heterogeneity, immunogenicity, through to poor bioavailability, lack of targeting to disease site, and a short half-life leading to a requirement for either high dosing frequency or large volume dosing, which can result in suboptimal safety, efficacy, tolerability, and dosing regimens.
Although working against the same target as an original biological drug and potential biosimilars of that product, biobetters are modified to offer increased effect on the target, fewer side effects, or higher treatment convenience. Modifications may include structural changes by chemical modification, amino acid alteration, or protein fusion as well as improved formulations over the original biological drug. With the development of more effective and/or longer-acting therapeutics, biobetters have the potential to reduce healthcare costs through greater efficacy and/or less frequent dosing.
Given their clinical advantage when compared to the originator product, biobetters can often command a price premium, providing significant commercial advantages over biosimilars and original biologicals. The regulatory authorities treat biobetters as new chemical entities, therefore approval processes can be as long as for a new drug but the development risk is reduced as the mode of action and route to approval is already known. They also often receive patent protection and market exclusivity, as they constitute an improvement over the originator and any biosimilar competitors.
It may come as no surprise then that even though the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved, and are currently evaluating, several biosimilar applications, many drug developers have turned their attention toward the creation of biobetters.
Over the past 30 years, the industry’s understanding of albumin, an ubiquitous protein widely distributed throughout many of the human body’s tissues, has improved immeasurably. As the most abundant plasma protein, binding a range of ligands including metal ions, hormones, bilirubin, haemin, and a range of hydrophobic molecules including fatty acids and some drugs, albumin is a natural carrier for distributing molecules around the body. In addition to albumin’s ability to bind ligands, it has a naturally long circulatory half-life that is partly driven by a receptor-mediated cellular rescue system, and has been shown to accumulate in inflamed tissue and tumors. Together these features of albumin have been exploited in the development of therapeutic drugs, such as Abraxane®, Levemir®, Tanzeum® and Idelvion®, with a range of new and improved albumin-enabled drugs including albenatide, semaglutide, and aldoxorubicin in late-stage clinical development or being considered for approval.
Recently, biobetter developers have exploited albumin’s ability to bind hydrophobic drugs to introduce superior formulations, as exemplified by Celgene’s commercialization of Abraxane. Paclitaxel is a hydrophobic chemotherapeutic drug used in the treatment of a range of cancers; it binds to circulating albumin in the bloodstream and is transported around the body. Because of its low aqueous solubility, paclitaxel can be formulated in a blend of solvents, being diluted in bags before patient administration. However, the solvent cocktail had significant toxic side effects including hypersensitivity reactions, nephrotoxicity, and neurotoxicity that needed to be managed separately by the administrating clinicians. In response to the need for a superior formulation, an albumin-based formulation was developed.
Abraxane is an albumin bound biobetter formulation of paclitaxel composed of water soluble ~130 nm albumin paclitaxel nanoparticles, so avoiding the need for unwanted solvents. After injection, the albumin nanoparticles dissociate and the paclitaxel circulates associated with albumin. It is currently approved for the treatment of breast, pancreatic, and non-small cell lung cancer and is in clinical development for the treatment of melanoma, bladder, and ovarian cancers.
Developers are exploiting albumin’s long half-life (approximately three weeks) in the creation of biobetters by finding novel ways of joining or associating known biological drugs to albumin to extend their circulatory half-life. Not surprisingly given albumin’s known ability to bind and transport a range of ligands, biobetter drug developers have chemically attached these ligands to drugs to allow them to bind to albumin and so extend the circulatory half-life of the drug. One of the most extensively studied group of ligands are fatty acids which have been conjugated to insulin (Levemir) and glucagon like peptides (Victoza® and semaglutide) to significantly extend the circulatory half-life of the peptide, from minutes to hours and then to days, by increasing the affinity of the drug to the endogenous plasma albumin.
Another strategy being adopted by drug developers is to covalently attach the drug to recombinant albumin either by chemical conjugation or by genetic fusion to albumin. This method has been utilized by both GSK and CSL Behring, achieving an extended circulatory half-life of GLP-1 and Factor IX, respectively. By extending circulatory half-life, the burden on patients can be significantly reduced. The use of albumin in the development of biobetters also provides potential for platform purification processes. In most cases, the drug will be considerably smaller than albumin and so, to the advantage of the biobetter drug developer, the biochemical and biophysical properties of the albumin-enabled biobetter will be dominated by those of the albumin component.
The availability of a range of albumin-specific affinity matrices, for example the AlbuPure® matrix developed by ProMetic BioSciences in partnership with Albumedix, provides a highly stable, robust and nontoxic matrix, with high binding capacity, recovery and selectivity for human and animal albumins. This has allowed the development of platform purification processes that effectively use albumin as a purification tag for the drug contained within the biobetter.
A further recent refinement to the use of albumin in the development of biobetters has come from the development of albumin variants created by scientists at Albumedix, the University of Oslo, and Eleven Biotherapeutics, which has arisen from an understanding of the interaction of albumin with the neonatal Fc receptor (FcRn). By increasing the affinity for FcRn, the circulatory half-life of these engineered albumins and the drugs covalently attached to them can be further improved. The availability of engineered albumins further extends the utility of albumin in the development of biobetters.
As an abundant natural protein and a clinically proven platform, albumin offers the flexibility to associate, genetically fuse, or chemically conjugate proteins, peptides, and small molecules to improve the suboptimal performance of the original drug, allowing drug developers to fulfil the potential that biobetters have to offer.
Until now, much attention has been placed on developing new products with improved formulations, greater in vitro or in vivo stability and longer circulatory half-lives. Moving forward, it is likely development will focus on the largely untapped potential of biobetters to deliver enhanced drug performance by increasing the drug delivered to the right anatomical location or target tissue at the right quantities, with the aim of reducing off-target toxicity and adverse events.
1. Strohl, Fusion proteins for half-live extension of biologics as a strategy to make biobetters (2015) BioDrugs 29; 215-239