PMID- 15661270
OWN - NLM
STAT- MEDLINE
DCOM- 20050323
LR  - 20171116
IS  - 0145-2126 (Print)
IS  - 0145-2126 (Linking)
VI  - 29
IP  - 3
DP  - 2005 Mar
TI  - Molecular modification of a recombinant, bivalent anti-human CD3 immunotoxin 
      (Bic3) results in reduced in vivo toxicity in mice.
PG  - 331-41
AB  - A novel bivalent single chain fusion protein, Bic3, was assembled consisting of 
      the catalytic and translocation domains of diphtheria toxin (DT(390)) fused to 
      two repeating sFv molecules recognizing human CD3 epsilon of the human T-cell 
      receptor. Historically, problems with these constructs include low yield, 
      toxicity, and reduced efficacy. Instead of using conventional Gly(4)Ser linkers 
      to connect heavy/light chains, aggregation reducing linkers (ARL) were used which 
      when combined with a new SLS-based refolding method reduced aggregation and 
      enhanced the yield of final product. Toxicity was reduced at least 25-fold by 
      repeating the two sFv molecules and adding a portion of the hinge-CH2-CH3 human 
      constant regions. The resulting Bic3 was just as cytotoxic to HPB-MLT.UM T 
      leukemia cells in vitro (IC(50)=4 pmol) as a monovalent construct made with the 
      same DT and sFv. In vivo, Bic3 was effective in a new and aggressive therapy 
      model in which it significantly prolonged survival of scid mice with established 
      human T-cell leukemia (p<0.0001 compared to controls). Importantly, no toxicity 
      measured by weight loss, enzyme function, or histology was observed at the 
      highest dose of Bic3 tested (2000 ug/kg). Bic3 warrants investigation as a new 
      drug for treating T-cell malignancy and other T-cell related disorders.
FAU - Vallera, Daniel A
AU  - Vallera DA
AD  - Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota 
      Cancer Center, Section on Molecular Cancer Therapeutics, MMC: 367, Minneapolis, 
      MN 55455, USA. valle001@umn.edu
FAU - Todhunter, Deborah
AU  - Todhunter D
FAU - Kuroki, David W
AU  - Kuroki DW
FAU - Shu, Yanqun
AU  - Shu Y
FAU - Sicheneder, Andy
AU  - Sicheneder A
FAU - Panoskaltsis-Mortari, Angela
AU  - Panoskaltsis-Mortari A
FAU - Vallera, Vincent D
AU  - Vallera VD
FAU - Chen, Hua
AU  - Chen H
LA  - eng
GR  - R01-CA36725/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Leuk Res
JT  - Leukemia research
JID - 7706787
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (CD3 Complex)
RN  - 0 (Immunoglobulin G)
RN  - 0 (Immunotoxins)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 0 (Recombinant Fusion Proteins)
SB  - IM
CIN - Leuk Res. 2005 Mar;29(3):249-51. PMID: 15661259
MH  - Animals
MH  - Antibodies, Monoclonal
MH  - CD3 Complex/immunology
MH  - Disease Models, Animal
MH  - Humans
MH  - Immunoglobulin G
MH  - Immunotoxins/*adverse effects/*chemistry
MH  - Kidney/pathology
MH  - Leukemia, T-Cell/*drug therapy
MH  - Mice
MH  - Mice, SCID
MH  - Receptors, Antigen, T-Cell
MH  - Recombinant Fusion Proteins/*adverse effects/*chemical synthesis/chemistry
MH  - T-Lymphocytes/drug effects
EDAT- 2005/01/22 09:00
MHDA- 2005/03/24 09:00
CRDT- 2005/01/22 09:00
PHST- 2004/04/30 00:00 [received]
PHST- 2004/08/17 00:00 [accepted]
PHST- 2005/01/22 09:00 [pubmed]
PHST- 2005/03/24 09:00 [medline]
PHST- 2005/01/22 09:00 [entrez]
AID - S0145-2126(04)00294-2 [pii]
AID - 10.1016/j.leukres.2004.08.006 [doi]
PST - ppublish
SO  - Leuk Res. 2005 Mar;29(3):331-41. doi: 10.1016/j.leukres.2004.08.006.