Balancing the pharmacokinetics and pharmacodynamics of interferon-α2b and human serum albumin fusion protein by proteolytic or reductive cleavage increases its in vivo therapeutic efficacy.
Human serum albumin (HSA) fusion (Albufusion) technology has evolved to be a general strategy to increase the in vivo half-lives of therapeutic proteins. However, because of the steric hindrance effect of HSA, conventional Albufusion technology improves the pharmacokinetics (PK) at the cost of pharmacodynamics (PD). To achieve balanced PK and PD of interferon-α2b (IFN-α2b) and HSA fusion protein, protease cleavage sites or disulfide linkage that enabled releasing of intact IFN-α2b with full activity was introduced between these two moieties. Nonreleasable and releasable fusion proteins showed similar cell surface receptor binding affinities; however, releasable fusion proteins exhibited release efficiency proportional increase of in vitro antiviral and antiproliferative activities. The release rate also had a profound impact on the in vivo pharmaceutical properties of fusion proteins. Releasable fusion proteins with intermediate release rate had the most balanced PK and PD, which translated into improved therapeutic efficacy in the HT29 human colon cancer xenograft model. Releasable Albufusion (rAlbufusion) allows tailored design of the PK/PD profile and greatly extends the utility of conventional Albufusion technology.
Department of Microorganism Engineering, Beijing Institute of Biotechnology, 20 Dongdajie Street, Fengtai District, Beijing 100071, People's Republic of China.
Hong Liang
HL
Zhao
Chong
C
Xue
Ji Liang
JL
Du
Min
M
Ren
Shan
S
Xia
Zhi Min
ZM
Liu
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D019073:HT29 Cells; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D012709:Serum Albumin / Q000235:genetics / Q000378:metabolism*; D018116:Vesiculovirus / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D016898:Interferon-alpha; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin