PMID- 15297722
OWN - NLM
STAT- MEDLINE
DCOM- 20040928
LR  - 20190724
IS  - 0031-6903 (Print)
IS  - 0031-6903 (Linking)
VI  - 124
IP  - 8
DP  - 2004 Aug
TI  - [Creation of functional muteins using phage libraries for pharmacoproteomic-based 
      drug discovery and development of DDS].
PG  - 531-9
AB  - Tumor necrosis factor-alpha (TNF-alpha) has been expected to be a promising new 
      antitumor agent, but toxic side effects by the systemic administration of 
      TNF-alpha limit its clinical application. In this study, we attempted to improve 
      the therapeutic potency of TNF-alpha by using our protein-drug innovation 
      systems. Among phage libraries displaying various mutant TNF-alphas, we isolated 
      some lysine-deficient super mutant TNF-alphas, typified by mTNF-alpha-K90R, with 
      higher TNF-receptor affinities and stronger bioactivity in vitro, in spite of the 
      importance of lysine residues for trimer formation and receptor binding. 
      mTNF-alpha-K90R showed more than 10 times stronger in vivo antitumor effects and 
      1.3 times less toxicity than wild-type TNF-alpha (wTNF-alpha). Site-specifically 
      mono-PEGylated mTNF-alpha-K90R (sp-PEG-mTNF-alpha-K90R) at N-terminus showed 
      higher in vitro bioactivity than unmodified wTNF-alpha, whereas randomly 
      mono-PEGylated wTNF-alpha at a lysine residue (ran-PEG-wTNF-alpha) had less than 
      6% of the bioactivity of wTNF-alpha. The antitumor therapeutic window of 
      sp-PEG-mTNF-alpha-K90R was extended by about 5 times, 60 times and 18 times 
      compared with those of mTNF-alpha-K90R, wTNF-alpha and ran-PEG-wTNF-alpha, 
      respectively. sp-PEG-mTNF-alpha-K90R may, thus, be a potential systemic 
      anti-tumor therapeutic agent. These data suggested that our fusion protein-drug 
      innovation system composed of a creation system of functional mutant proteins 
      based on phage display technique and a site-specific PEGylation system may open 
      up a new avenue to the optimal protein therapy.
FAU - Yoshioka, Yasuo
AU  - Yoshioka Y
AD  - Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka 
      University, Yamadaoka, Suita, Japan. y-yoshioka@nihs.go.jp
LA  - jpn
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - Japan
TA  - Yakugaku Zasshi
JT  - Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan
JID - 0413613
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Peptide Library)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - K3Z4F929H6 (Lysine)
SB  - IM
MH  - Animals
MH  - *Antineoplastic Agents
MH  - *Bacteriophages
MH  - *Drug Delivery Systems
MH  - Drug Design
MH  - Humans
MH  - Lysine
MH  - *Peptide Library
MH  - Polyethylene Glycols
MH  - Proteomics/methods
MH  - *Tumor Necrosis Factor-alpha
RF  - 25
EDAT- 2004/08/07 05:00
MHDA- 2004/09/29 05:00
CRDT- 2004/08/07 05:00
PHST- 2004/08/07 05:00 [pubmed]
PHST- 2004/09/29 05:00 [medline]
PHST- 2004/08/07 05:00 [entrez]
AID - JST.JSTAGE/yakushi/124.531 [pii]
AID - 10.1248/yakushi.124.531 [doi]
PST - ppublish
SO  - Yakugaku Zasshi. 2004 Aug;124(8):531-9. doi: 10.1248/yakushi.124.531.