PMID- 15592670
OWN - NLM
STAT- MEDLINE
DCOM- 20050602
LR  - 20240426
IS  - 0340-7004 (Print)
IS  - 1432-0851 (Electronic)
IS  - 0340-7004 (Linking)
VI  - 54
IP  - 6
DP  - 2005 Jun
TI  - Pharmacokinetics and in vitro and in vivo anti-tumor response of an 
      interleukin-2-human serum albumin fusion protein in mice.
PG  - 535-47
AB  - PURPOSE: Albuleukin fusion protein is a recombinant human interleukin-2 (rIL-2) 
      genetically fused to recombinant human serum albumin (rHSA). The pharmacokinetics 
      and pharmacologic activity of Albuleukin were examined in mice to determine 
      whether the fusion protein had the immunomodulatory and anti-tumor properties of 
      rIL-2 as well as a prolonged serum half-life due to the rHSA. METHODS: The effect 
      of Albuleukin on lymphocyte proliferation, IL-2 receptor binding, and release of 
      IFN-gamma from human NK cells were examined in vitro. For the pharmacokinetic 
      analysis, Albuleukin and rIL-2 were administered intravenously (i.v.) and 
      subcutaneously (s.c.) to BALB/c mice, both at a single dose of 500 microg/kg. The 
      anti-tumor properties of Albuleukin were evaluated in a Renca tumor model in 
      BALB/c mice and in a metastatic liver model of B16F10 melanoma in C57B1/6 mice. 
      In the Renca tumor model, BALB/c mice were dosed intraperitoneally (i.p.) and 
      s.c. with Albuleukin on days 12, 14, 16, 19, 21, and 23 and i.p. with rIL-2 daily 
      for two periods of 5 days (days 10-14 and 17-21). In the B16 melanoma model, 
      C57B1/6 mice were dosed s.c. with rIL-2 twice daily or Albuleukin every 48 h for 
      14 days. RESULTS: In vitro, Albuleukin induced the proliferation of primary human 
      and mouse T cells and B cells and primary human NK cells, competed with rIL-2 for 
      binding to the IL-2 receptors, and induced the production of IFN-gamma from 
      primary human NK cells. The s.c. bioavailability of Albuleukin was about 45% 
      relative to the i.v. dose. Plasma half-life was prolonged and ranged from 6 to 8 
      h with Albuleukin, compared to 19-57 min with rIL-2. Total clearance of 
      Albuleukin was about 50-fold slower than that of rIL-2 after i.v. dosing. In 
      vivo, Albuleukin suppressed the growth of Renca tumors and induced a dense 
      infiltration of CD4+ and CD8+ T cells. Both Albuleukin and rIL-2 significantly 
      reduced the tumor burden in mice with hepatic B16F10 metastases. Albuleukin 
      significantly reduced the incidence of residual macroscopic hepatic tumors, 
      resulting in improved survival relative to controls and rIL-2. CONCLUSION: 
      Results from these studies suggest that the therapeutic efficacy of rIL-2 is 
      improved in mice by prolonging its in vivo half-life through genetic fusion to 
      albumin. Albuleukin, the fusion protein, had pronounced anti-tumor effects in 
      Renca and hepatic melanoma tumor models without an increase in mortality. On the 
      basis of its preclinical effects, Albuleukin was brought to the clinic to assess 
      its therapeutic benefit in a variety of cancers.
FAU - Melder, Robert J
AU  - Melder RJ
AD  - Medtronic Vascular, Santa Rosa, CA, 95403, USA.
FAU - Osborn, Blaire L
AU  - Osborn BL
FAU - Riccobene, Todd
AU  - Riccobene T
FAU - Kanakaraj, Palanisamy
AU  - Kanakaraj P
FAU - Wei, Ping
AU  - Wei P
FAU - Chen, Guoxian
AU  - Chen G
FAU - Stolow, David
AU  - Stolow D
FAU - Halpern, Wendy Green
AU  - Halpern WG
FAU - Migone, Thi-Sau
AU  - Migone TS
FAU - Wang, Qi
AU  - Wang Q
FAU - Grzegorzewski, Krzysztof J
AU  - Grzegorzewski KJ
FAU - Gallant, Gilles
AU  - Gallant G
LA  - eng
PT  - Journal Article
DEP - 20041208
PL  - Germany
TA  - Cancer Immunol Immunother
JT  - Cancer immunology, immunotherapy : CII
JID - 8605732
RN  - 0 (Interleukin-2)
RN  - 0 (Receptors, Interleukin-2)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Serum Albumin)
SB  - IM
MH  - Animals
MH  - Female
MH  - Half-Life
MH  - Humans
MH  - Interleukin-2/pharmacokinetics/*pharmacology
MH  - Liver Neoplasms, Experimental/prevention & control/secondary
MH  - Lymphocyte Activation/drug effects
MH  - Male
MH  - Melanoma, Experimental/drug therapy
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Neoplasms, Experimental/*drug therapy
MH  - Receptors, Interleukin-2/metabolism
MH  - Recombinant Fusion Proteins/pharmacokinetics/*pharmacology
MH  - Serum Albumin/pharmacokinetics/*pharmacology
PMC - PMC11034298
EDAT- 2004/12/14 09:00
MHDA- 2005/06/03 09:00
PMCR- 2004/12/08
CRDT- 2004/12/14 09:00
PHST- 2004/07/29 00:00 [received]
PHST- 2004/09/21 00:00 [accepted]
PHST- 2004/12/14 09:00 [pubmed]
PHST- 2005/06/03 09:00 [medline]
PHST- 2004/12/14 09:00 [entrez]
PHST- 2004/12/08 00:00 [pmc-release]
AID - 624 [pii]
AID - 10.1007/s00262-004-0624-7 [doi]
PST - ppublish
SO  - Cancer Immunol Immunother. 2005 Jun;54(6):535-47. doi: 10.1007/s00262-004-0624-7. 
      Epub 2004 Dec 8.