Design of yeast-secreted albumin derivatives for human therapy: biological and antiviral properties of a serum albumin-CD4 genetic conjugate.
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.
Yeh
P
P
Rhône-Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, Vitry, France.
Landais
D
D
Lemaître
M
M
Maury
I
I
Crenne
J Y
JY
Becquart
J
J
Murry-Brelier
A
A
Boucher
F
F
Montay
G
G
Fleer
R
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001483:Base Sequence; D001667:Binding, Competitive; D015704:CD4 Antigens / Q000737:chemistry / Q000378:metabolism*; D005822:Genetic Vectors; D006678:HIV / Q000254:growth & development / Q000378:metabolism; D007716:Kluyveromyces / Q000235:genetics; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D011817:Rabbits; D011991:Receptors, Virus / Q000737:chemistry / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics*; D012709:Serum Albumin / Q000737:chemistry / Q000493:pharmacokinetics*; D012995:Solubility; D014779:Virus Replication
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D009838:Oligodeoxyribonucleotides; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin