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Halpern, Wendy; Riccobene, Todd; Agostini, Heidi; Baker, Kevin C.; Stolow, D T; Gu, Mili; Hirsch, Jonathan; Mahoney, Angela; Carrell, Jeffrey A.; Boyd, Ernest; Grzegorzewski, Krzysztof

doi:10.1023/a:1020917732218

Cited by 81 publications

(18 citation statements)

References 11 publications

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“…2b), the fusion protein exhibited a comparable myelopoietic effect to that of G-CSF when administered s.c. in mice. This elevated in vivo effectiveness may be due to a prolonged plasma half-life and a decrease of clearance as previously described in a recombinant G-CSF-albumin fusion protein (17). Conceivably, G-CSF-Tf may have a clearance rate similar to Tf, but not to G-CSF.…”

Section: Discussionmentioning

confidence: 72%

“…The G-CSF activity of the fusion protein was measured by NFS-60 proliferation assay (17,18). NFS-60 cells were washed three times with RPMI medium 1640͞10% FBS and aliquoted to 96-well microtiter plates at a density of 1 ϫ 10 5 cells per ml.…”

Section: Methodsmentioning

confidence: 99%

“…The mice were allowed to acclimate for 5 days. BDF1 mice were chosen for their stimulatory response to human G-CSF (17). Animal experiments were compliant with Principles of Laboratory Animal Care (National Institutes of Health Publication 85-23) and approved by the Institutional Animal Care and Utilization Committee of the University of Southern California.…”

Section: Methodsmentioning

confidence: 99%

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Recombinant granulocyte colony-stimulating factor-transferrin fusion protein as an oral myelopoietic agent

Bai

Ann

Shen

2005

Proc. Natl. Acad. Sci. U.S.A.

116

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An expression construct harboring granulocyte colony-stimulating factor (G-CSF)-transferrin (Tf) fusion protein (G-CSF-Tf) was engineered by fusing human cDNAs encoding G-CSF and Tf to explore the feasibility of using Tf as a carrier moiety for oral delivery of therapeutic proteins. The recombinant protein, G-CSF-Tf, was harvested from protein-free, conditioned medium of transfected HEK293 cells. The in vitro studies demonstrated that the purified G-CSF-Tf fusion protein possesses the activity of both Tf receptor (TfR) binding in Caco-2 cells and G-CSF-dependent stimulation of NFS-60 cell proliferation. Subcutaneous administration of G-CSF-Tf fusion protein to BDF1 mice demonstrated a pharmacological effect comparable to the commercial G-CSF on the increase of absolute neutrophil counts (ANC). However, the fusion protein elicited a significant increase in ANC upon oral administration to BDF1 mice, whereas G-CSF had no effect. This study also showed that orally administered G-CSF-Tf elicits a sustained myelopoietic effect up to 3 days, whereas the s.c. administered G-CSF or G-CSF-Tf lasts only 1 day. Furthermore, coadministration of free Tf abolished the increase of ANC by orally delivered G-CSF-Tf, suggesting that the recombinant protein is absorbed via a TfR-mediated process in the gastrointestinal tract. Taken together, we conclude that the Tf-based recombinant fusion protein technology represents a promising approach for future development of orally effective peptide and protein drugs. myelopoiesis ͉ oral delivery ͉ protein drug

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Section: Discussionmentioning

confidence: 72%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Recombinant granulocyte colony-stimulating factor-transferrin fusion protein as an oral myelopoietic agent

Bai

Ann

Shen

2005

Proc. Natl. Acad. Sci. U.S.A.

116

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“…These include increasing the molecular size by chemical modifications such as conjugation with polyethylene glycol (5,6) or genetic fusion to human serum albumin (HSA) 2 (7)(8)(9) or the Fc portion of human IgG (hIgG) (10). In addition, noncovalent association with albumin or IgG has been explored as an alternative to direct fusion.…”

mentioning

confidence: 99%

Extending Half-life by Indirect Targeting of the Neonatal Fc Receptor (FcRn) Using a Minimal Albumin Binding Domain

Andersen

Pehrson

Tolmachev

et al. 2011

Journal of Biological Chemistry

153

115

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The therapeutic and diagnostic efficiency of engineered small proteins, peptides, and chemical drug candidates is hampered by short in vivo serum half-life. Thus, strategies to tailor their biodistribution and serum persistence are highly needed. An attractive approach is to take advantage of the exceptionally long circulation half-life of serum albumin or IgG, which is attributed to a pH-dependent interaction with the neonatal Fc receptor (FcRn) rescuing these proteins from intracellular degradation. Here, we present molecular evidence that a minimal albumin binding domain (ABD) derived from streptococcal protein G can be used for efficient half-life extension by indirect targeting of FcRn. We show that ABD, and ABD recombinantly fused to an Affibody molecule, in complex with albumin does not interfere with the strictly pH-dependent FcRn-albumin binding kinetics. The same result was obtained in the presence of IgG. An in vivo study performed in rat confirmed that the clinically relevant human epidermal growth factor 2 (HER2)-targeting Affibody molecule fused to ABD has a similar half-life and biodistribution profile as serum albumin. The proof-of-concept described may be broadly applicable to extend the in vivo half-life of short lived biological or chemical drugs ultimately resulting in enhanced therapeutic or diagnostic efficiency, a more favorable dosing regimen, and improved patient compliance.

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“…tevapharm.com), a recombinant protein composed of human serum albumin and human G-CSF produced through recombinant DNA technology in Saccharomyces cereviseae [19]. The albumin domain prolongs the circulating half-life of balugrastim compared with G-CSFs, allowing once-per-cycle, fixed-dose, s.c. administration [20].…”

Section: Introductionmentioning

confidence: 99%

A Phase III Study of Balugrastim Versus Pegfilgrastim in Breast Cancer Patients Receiving Chemotherapy With Doxorubicin and Docetaxel

et al. 2015

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Objectives. This study aimed to evaluate the efficacy and safety of once-per-cycle balugrastim versus pegfilgrastim for neutrophil support in breast cancer patients receiving myelosuppressive chemotherapy. Methods. Breast cancer patients (n 5 256) were randomized to 40 or 50 mg of subcutaneous balugrastim or 6 mg of pegfilgrastim 24 hours after chemotherapy (60 mg/m 2 doxorubicin and 75 mg/m 2 docetaxel, every 21 days for up to 4 cycles). The primary efficacy parameter was the duration of severe neutropenia (DSN) in cycle 1. Secondary parameters included DSN (cycles 2-4), absolute neutrophil count (ANC) nadir, febrile neutropenia rates, and time to ANC recovery (cycles 1-4). Safety, pharmacokinetics, and immunogenicity were assessed.Results. Mean cycle 1 DSN was 1.0 day with 40 mg of balugrastim, 1.3with50mgofbalugrastim,and1.2withpegfilgrastim(upperlimit of 95% confidence intervals for between-group DSN differences was ,1.0 day for both balugrastim doses versus pegfilgrastim). Between-group efficacy parameters were comparable except for time to ANC recovery in cycle 1 (40 mg of balugrastim, 2.0 days; 50 mg of balugrastim, 2.1; pegfilgrastim, 2.6). Median terminal elimination half-life was 37 hours for 40 mg of balugrastim, 36 for 50 mg of balugrastim, and 45 for pegfilgrastim. Antibody response to balugrastim was low and transient, with no neutralizing effect. Conclusion. Once-per-cycle balugrastim is not inferior to pegfilgrastim in reducing cycle 1 DSN in breast cancer patients receiving chemotherapy; both drugs have comparable safety profiles. The Oncologist 2016;21:7-15 Implications for Practice: This paper provides efficacy and safety data for a new, once-per-cycle granulocyte colony-stimulating factor, balugrastim, for the prevention of chemotherapy-induced neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy. In this phase III trial, balugrastim was shown to be not inferior to pegfilgrastim in the duration of severe neutropenia in cycle 1 of doxorubicin/docetaxel chemotherapy, and the safety profiles of the two agents were similar. Once-per-cycle balugrastim is a safe and effective alternative to pegfilgrastim for hematopoietic support in patients with breast cancer receiving myelosuppressive chemotherapy associated with a greater than 20% risk of developing febrile neutropenia.

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Abstract: The sustained activity of Albugranin in mice and monkeys demonstrated in these studies suggests that this agent could be given less frequently than Filgrastim to achieve similar therapeutic effects in patients.

Cited by 81 publications

References 11 publications

Recombinant granulocyte colony-stimulating factor-transferrin fusion protein as an oral myelopoietic agent

Recombinant granulocyte colony-stimulating factor-transferrin fusion protein as an oral myelopoietic agent

Extending Half-life by Indirect Targeting of the Neonatal Fc Receptor (FcRn) Using a Minimal Albumin Binding Domain

A Phase III Study of Balugrastim Versus Pegfilgrastim in Breast Cancer Patients Receiving Chemotherapy With Doxorubicin and Docetaxel

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