An IFN-<i>β</i>-Albumin Fusion Protein That Displays Improved Pharmacokinetic and Pharmacodynamic Properties in Nonhuman Primates

Sung, Cynthia; Nardelli, Bernardetta; LaFleur, David W.; Blatter, Erich E.; Corcoran, Marta L.; Olsen, Henrik S.; Birse, Charles E.; Pickeral, Oxana K.; Zhang, Junli; Shah, Devanshi S.; Moody, Gordon; Gentz, Solange; Beebe, Lisa E.; Moore, Paul A.

doi:10.1089/10799900360520423

Cited by 66 publications

(39 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…cDNA microarrays. The effect of treatment on gene expression was assayed using cDNA array hybridization technology as previously described (12). In these experiments, human primary adipocytes (ZenBio) were starved overnight in low glucose media (DMEM), before treatment with insulin or Albulin at a concentration corresponding to the half-maximal concentration (EC 50 ) and 10ϫ EC 50 as determined using the glucose uptake assay described above.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Development of a Long-Acting Insulin Analog Using Albumin Fusion Technology

et al. 2005

Self Cite

View full text Add to dashboard Cite

The primary therapeutic goal for the treatment of diabetes is maintenance of a long-term, near-normoglycemic condition and prevention of the onset or progression of the complications associated with the disease. Although several analogs of human insulin have been developed, the currently prescribed long-acting insulin analogs do not provide a stable basal glycemia for more than a few hours. Here, we report the development of Albulin, a long-acting insulin analog obtained by direct gene fusion of a singlechain human insulin to human serum albumin. Albulin showed an elimination t 1/2 of ϳ7 h in normoglycemic mice. In vitro pharmacodynamic profiles for Albulin characterized by receptor binding, inhibition of gluconeogenesis, induction of glucose uptake, and global regulation of gene expression in relevant cell types showed that Albulin produced similar activity profiles compared with that of recombinant human insulin. A single Albulin administration in vivo normalized blood glucose level in diabetic mice in a relatively peakless and sustained (24-h) fashion. A further reduction in glucose levels was achieved by administering a recombinant human insulin a few hours after Albulin injection in mice, indicating the potential for Albulin therapy in combination with available fast-acting insulin derivatives. In summary, Albulin displays characteristics of a potent long-acting insulin analog that can be evaluated for use as a novel insulin therapy for patients with insulin-dependent diabetes. Diabetes 54:251-258, 2005

show abstract

Section: Methodsmentioning

confidence: 99%

“…Proteins resulting from HSA gene fusions have the long circulating life of albumin while retaining their biological and therapeutic properties (11,12). Here we report the development of Albulin, a biologically active recombinant analog of human insulin fused to HSA, and compare the relative biological activities of Albulin and insulin in vitro and in vivo.…”

mentioning

confidence: 99%

Development of a Long-Acting Insulin Analog Using Albumin Fusion Technology

et al. 2005

Self Cite

View full text Add to dashboard Cite

show abstract

“…Moreover, HSA has also been successfully used to generate fusion proteins, e.g. with hormones (insulin, human growth hormone) (25,26) and cytokines (interferon-␣, interferon-␤, IL-2) (27)(28)(29), to reduce immunogenicity and modulate the pharmacokinetic properties, thus improving therapeutic efficacy of these molecules. Improved pharmacokinetic properties have also been described for a scFv-HSA fusion protein as well as for F(abЈ) and F(abЈ) 2 conjugated to rat serum albumin (RSA) for the targeting of human tumor necrosis factor (20).…”

mentioning

confidence: 99%

Improved Pharmacokinetics of Recombinant Bispecific Antibody Molecules by Fusion to Human Serum Albumin

Müller

Karle²,

Meißburger

et al. 2007

Journal of Biological Chemistry

204

126

View full text Add to dashboard Cite

Recombinant bispecific antibodies such as tandem scFv molecules (taFv), diabodies (Db), or single chain diabodies (scDb) have shown to be able to retarget T lymphocytes to tumor cells, leading to their destruction. However, therapeutic efficacy is hampered by a short serum half-life of these small molecules having molecule masses of 50 -60 kDa. Thus, improvement of the pharmacokinetic properties of small bispecific antibody formats is required to enhance efficacy in vivo. In this study, we generated several recombinant bispecific antibody-albumin fusion proteins and analyzed these molecules for biological activity and pharmacokinetic properties. Three recombinant antibody formats were produced by fusing two different scFv molecules, bispecific scDb or taFv molecules, respectively, to human serum albumin (HSA). These constructs (scFv 2 -HSA, scDb-HSA, taFv-HSA), directed against the tumor antigen carcinoembryonic antigen (CEA) and the T cell receptor complex molecule CD3, retained full binding capacity to both antigens compared with unfused scFv, scDb, and taFv molecules. Tumor antigen-specific retargeting and activation of T cells as monitored by interleukin-2 release was observed for scDb, scDb-HSA, taFv-HSA, and to a lesser extent for scFv 2 -HSA. T cell activation could be further enhanced by a target cell-specific costimulatory signal provided by a B7-DbCEA fusion protein.Furthermore, we could demonstrate that fusion to serum albumin strongly increases circulation time of recombinant bispecific antibodies. In addition, our comparative study indicates that single chain diabody-albumin fusion proteins seem to be the most promising format for further studying cytotoxic activities in vitro and in vivo.Bispecific antibodies are designed to target two different antigens simultaneously (1). In the context of a tumor therapy they can be applied to selectively recruit potent effector cells of the immune system such as cytotoxic T lymphocytes to tumor cells (2). This is achieved by binding on the one side to a tumorassociated antigen and on the other side to a trigger molecule on the effector cell, leading to the activation of the effector cell and tumor cell destruction. To reduce potential side effects elicited by the Fc part of antibodies (3) small recombinant bispecific antibody formats composed only of the variable regions, which define the binding unit of an antibody, have been developed (1, 4). These formats include bispecific diabodies (Db), 4 single chain diabodies (scDb), and tandem scFv (taFv) molecules, which have been applied successfully in vitro and also in vivo for the retargeting of cytotoxic T lymphocytes (via T-cell receptor molecule CD3) to tumor cells (e.g. recognizing CEA, EpCAM, or CD19) (5-8).However, these small bispecific antibody molecules with molecular masses between 50 and 60 kDa are rapidly cleared from circulation with an initial half-life of less than 30 min (9, 10). This puts some obstacles on therapeutic applications, e.g. requirement of high doses and repeated injections or infusion...

show abstract

“…3 Recently, Saunthararajah et al devised a method based on a logistical regression model to predict which patients classified as having MDS are most likely to respond to ATG. 4 Important positive predictive factors in this analysis are younger age, shorter duration of red cell transfusion dependence, and HLA-DR15 (DR2) positivity. These surrogate markers for immune-mediated marrow failure will need to be validated in a prospectively treated cohort of MDS patients, and we can expect refinement of the model as experience with the drug accumulates.…”

Section: Responsementioning

confidence: 93%