Effect of albumin fusion on the biodistribution of interleukin-2

Yao, Zhengsheng; Dai, Weili; Perry, James W.; Brechbiel, Martin W.; Sung, Cynthia

doi:10.1007/s00262-003-0454-z

Cited by 53 publications

(22 citation statements)

References 13 publications

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“…Linkers in fusion proteins generally consist of stable peptide sequences, including the glycine-serine linker (GGGGS) n and α-helix-forming peptide linkers, such as A(EAAAK) n A (n=2-5), which can provide structure flexibility, improve protein stability, or increase biological activity (2-5). However, stable peptide linkers do not allow for the separation of the two fusion protein domains in vivo , and have several limitations including steric hindrance between two functional domains, altered biodistribution and metabolism of the protein moieties due to interference with each other, and incorrect folding of the fusion protein (6). …”

Section: Introductionmentioning

confidence: 99%

Design of an in vivo Cleavable Disulfide Linker in Recombinant Fusion Proteins

et al. 2010

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In order to achieve an optimal biological activity and desired pharmacokinetic profiles, a dithiocyclopeptide linker was designed for in vivo release of protein domains from a recombinant fusion protein. This novel in vivo cleavable disulfide linker, based on a dithiocyclopeptide containing a thrombin-sensitive sequence and an intra-molecular disulfide bond, was inserted between transferrin and granulocyte colony-stimulating factor recombinant fusion protein domains. After expression of the fusion protein, G-C-T, from HEK293 cells, thrombin treatment in vitro generated a fusion protein linked via a reversible disulfide bond that was quickly cleaved in vivo, separating the protein domains. After release from the fusion protein, free G-CSF exhibited an improved biological activity in a cell proliferation assay. Although reversible disulfide bonds are commonly used in protein chemical conjugation methods, to our knowledge this report is the first example of the construction of a recombinant fusion protein with a disulfide linkage for the release of the functional domain. This linker design can be adapted to diverse recombinant fusion proteins where in vivo separation of protein domains is required to achieve an improved therapeutic effect, and a desirable pharmacokinetic profile and biodistribution, of the functional domain.

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Section: Introductionmentioning

confidence: 99%

Design of an in vivo Cleavable Disulfide Linker in Recombinant Fusion Proteins

et al. 2010

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“…Several strategies have been used to increase the bioavailability of IL-2. These include changing the injection route (40), using polyethylene glycol-IL-2 (41), an IL-2-IgG fusion protein (42), proteolysis-resistant IL-2 (43), an IL-2-albumin fusion protein (44,45), and gene therapy (46). The present study adds an alternative means to maintain and enhance IL-2 efficacy in vivo by combined treatment with the anti-IL-2 mAb and IL-2 plasmid DNA.…”

Section: And Ref 13) a Recent Report By Fontenot Et Al (4)mentioning

confidence: 99%

IL-2 In Vivo Activities and Antitumor Efficacy Enhanced by an Anti-IL-2 mAb

Kamimura

Sawa

Sato

et al. 2006

The Journal of Immunology

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IL-2 is a potent immunostimulant and has been tested for clinical use, including in immunotherapy for cancers and HIV infection. Here we show that a widely used neutralizing anti-murine IL-2 mAb (S4B6) exhibits unexpected activities that enhance the treatment effects of IL-2 in vivo. Coinjection of the anti-IL-2 mAb with a plasmid carrying murine IL-2 cDNA significantly increased the serum IL-2 levels and induced a substantial increase in the division of CD8+ T and NK1.1high cells in vivo. Injection of the mAb premixed with recombinant murine IL-2 showed the same enhanced effect. A 5-day treatment with the anti-IL-2 mAb alone gradually increased the CD44highCD8+ population, and the increased population was maintained for >300 days, suggesting that the mAb can gradually maintain and potentially enhance the bioactivity of endogenous IL-2 for extended periods. Furthermore, combined treatment with the anti-IL-2 mAb plus the IL-2 plasmid markedly enhanced Ag-specific CTL activity in vivo and partially protected mice from tumor metastasis to the lungs, compared with the anti-IL-2 mAb or IL-2 plasmid alone. These results demonstrated IL-2-enhancing effects of the anti-IL-2 mAb in vivo and suggest that combining a neutralizing anti-IL-2 Ab with IL-2 gene delivery might be used effectively to enhance IL-2 functions in clinical applications.

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“…The immunoconjugate accumulated in lymphoid tissues instead. This was possibly due to the affinity of IL-2 to its receptors that were plentiful on lymphocytes in these tissues [Yao et al, 2004;Foss, 2001]. Therefore, targeting by molecular fusion to antibody (or antibody fragments) would likely work best where the endogenous antigens are not widely distributed.…”

Section: Molecular Targeting Approachmentioning

confidence: 96%

Immuno-Isolation in Cancer Gene Therapy

Cirone

Potter²,

Hirte³

et al. 2006

CGT

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The implantation of genetically-modified non-autologous cells in immuno-protected microcapsules is an alternative to ex vivo gene therapy. Such cells delivering a recombinant therapeutic product are isolated from the host's immune system by being encapsulated within permselective microcapsules. This approach has been successful in pre-clinical animal studies involving delivery of hormone or enzymes to treat dwarfism, lysosomal storage disease, or hemophilia B. Recently, this platform technology has shown promise in the treatment for more complex diseases such as cancer. One of the earliest strategy was to augment the chemotherapeutic effect of a prodrug by implanting encapsulated cells that can metabolise prodrugs into cytotoxic products in close proximity to the cancer cells. More recent approaches include enhancing tumor cell death through immunotherapy, or suppressing tumor cell proliferation through anti-angiogenesis. These can be achieved by delivering single molecules of cytokines or angiostatin, respectively, by implanting microencapsulated cells engineered to secrete these recombinant products. Recent refinements of these approaches include genetic fusion of cytokines or angiostatin to additional functional groups with tumor targeting or tumor cell killing properties, thus enhancing the potency of the recombinant products. Furthermore, a COMBO strategy of implanting microencapsulated cells to deliver multiple products targeted to diverse pathways in tumor suppression also showed much promise. This review will summarise the application of microencapsulation of genetically-modified cells to cancer treatment in animal models, the efficacy of such approaches, and how these studies have led to better understanding of the biology of cancer treatment. The flexibility of this modular system involving molecular engineering, cellular genetic modification, and polymer chemistry provides potentially a huge range of application modalities, and a tremendous multi-disciplinary challenge for the future.

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Effect of albumin fusion on the biodistribution of interleukin-2

Cited by 53 publications

References 13 publications

Design of an in vivo Cleavable Disulfide Linker in Recombinant Fusion Proteins

Design of an in vivo Cleavable Disulfide Linker in Recombinant Fusion Proteins

IL-2 In Vivo Activities and Antitumor Efficacy Enhanced by an Anti-IL-2 mAb

Immuno-Isolation in Cancer Gene Therapy

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