Design of yeast-secreted albumin derivatives for human therapy: biological and antiviral properties of a serum albumin-CD4 genetic conjugate.

Abstract

Due to its remarkably long half-life, together with its wide in vivo distribution and its lack of enzymatic or immunological functions, human serum albumin (HSA) represents an optimal carrier for therapeutic peptides/proteins aimed at interacting with cellular or molecular components of the vascular and interstitial compartments. As an example, we designed a genetically engineered HSA-CD4 hybrid aimed at specifically blocking the entry of the human immunodeficiency virus into CD4+ cells. In contrast with CD4, HSA-CD4 is correctly processed and efficiently secreted by Kluyveromyces yeasts. In addition, its CD4 moiety exhibits binding and antiviral in vitro properties similar to those of soluble CD4. Finally, the elimination half-life of HSA-CD4 in a rabbit experimental model is comparable to that of control HSA and 140-fold higher than that of soluble CD4. These results indicate that the genetic fusion of bioactive peptides to HSA is a plausible approach toward the design and recovery of secreted therapeutic HSA derivatives with appropriate pharmacokinetic properties.

Adenovirus-mediated gene transfer of urokinase plasminogen inhibitor inhibits angiogenesis in experimental arthritis

“…HSA was chosen as a pharmacological carrier for the following reasons: (1) it is a long-lasting neutral carrier already used for macromolecular drugs; 21,22 (2) it can escape the vascular compartment allowing access to disease tissue; and (3) it has previously been shown to increase the half-life of a 179-residue peptide in rabbits by 140-fold. 23 Our data showed that mATF-HSA-sustained expression inhibited synovial angiogenesis at the early phase of arthritis since the number of vessels observed in the inflamed paws was significantly decreased in Ad-mATF-HSA-treated animals. Van der Land et al 20 have recently evaluated a similar construct containing ATF gene in a SCID/hu model, where the human synovial cells are isolated and cultured in an inert sponge before implantation in the kidney capsule.…”

Improved tumor targeting of anti–epidermal growth factor receptor Nanobodies through albumin binding: taking advantage of modular Nanobody technology

“…Several strategies have been described in literature to reduce blood clearance of targeting molecules. Most of these strategies focus on the enlargement of the targeting molecule above the critical size for renal clearance (60-70 kDa) by fusion to other proteins like albumin (30) and the Fc portion of an IgG (31) or by glycosylation (32) or pegylation (33). The use of bispecific antibodies as described herein, aiming a noncovalent association with albumin as a means to improve biodistribution and tumor deposition, was pioneered by Dennis et al from the Genentech labs (17).…”

In vivo adenovirus-mediated delivery of a uPA/uPAR antagonist reduces retinal neovascularization in a mouse model of retinopathy

“…HSA was chosen as a pharmacological carrier for the following reasons: it is a long-lasting, neutral carrier that is already used for macromolecular drugs 26,27 and it increases the half-life of a 179-residue rabbit peptide by 140-fold. 28 Apparailly et al 20 used the Ad ATFHSA in a model of arthritis. They found that the systemic injection of Ad ATFHSA decreased the incidence of arthritis and the severity of the disease by inhibiting angiogenesis.…”