PMID- 20346868
OWN - NLM
STAT- MEDLINE
DCOM- 20100830
LR  - 20191210
IS  - 1872-9614 (Electronic)
IS  - 0969-8051 (Linking)
VI  - 37
IP  - 3
DP  - 2010 Apr
TI  - Site-specifically 89Zr-labeled monoclonal antibodies for ImmunoPET.
PG  - 289-97
LID - 10.1016/j.nucmedbio.2009.11.010 [doi]
AB  - Three thiol reactive reagents were developed for the chemoselective conjugation 
      of desferrioxamine (Df) to a monoclonal antibody via engineered cysteine residues 
      (thio-trastuzumab). The in vitro stability and in vivo imaging properties of 
      site-specifically radiolabeled (89)Zr-Df-thio-trastuzumab conjugates were 
      investigated. METHODS: The amino group of desferrioxamine B was acylated by 
      bromoacetyl bromide, N-hydroxysuccinimidyl iodoacetate, or N-hydroxysuccinimidyl 
      4-[N-maleimidomethyl]cyclohexane-1-carboxylate to obtain thiol reactive reagents 
      bromoacetyl-desferrioxamine (Df-Bac), iodoacetyl-desferrioxamine (Df-Iac) and 
      maleimidocyclohexyl-desferrioxamine (Df-Chx-Mal), respectively. Df-Bac and Df-Iac 
      alkylated the free thiol groups of thio-trastuzumab by nucleophilic substitution 
      forming Df-Ac-thio-trastuzumab, while the maleimide reagent Df-Chx-Mal reacted 
      via Michael addition to provide Df-Chx-Mal-thio-trastuzumab. The conjugates were 
      radiolabeled with (89)Zr and evaluated for serum stability, and their positron 
      emission tomography (PET) imaging properties were investigated in a BT474M1 
      (HER2-positive) breast tumor mouse model. RESULTS: The chemoselective reagents 
      were obtained in 14% (Df-Bac), 53% (Df-Iac) and 45% (Df-Chx-Mal) yields. 
      Site-specific conjugation of Df-Chx-Mal to thio-trastuzumab was complete within 1 
      h at pH 7.5, while Df-Iac and Df-Bac respectively required 2 and 5 h at pH 9. 
      Each Df modified thio-trastuzumab was chelated with (89)Zr in yields exceeding 
      75%. (89)Zr-Df-Ac-thio-trastuzumab and (89)Zr-Df-Chx-Mal-thio-trastuzumab were 
      stable in mouse serum and exhibited comparable PET imaging capabilities in a 
      BT474M1 (HER2-positive) breast cancer model reaching 20-25 %ID/g of tumor uptake 
      and a tumor to blood ratio of 6.1-7.1. CONCLUSIONS: The new reagents demonstrated 
      good reactivity with engineered thiol groups of trastuzumab and very good 
      chelation properties with (89)Zr. The site-specifically (89)Zr-labeled 
      thio-antibodies were stable in serum and showed PET imaging properties comparable 
      to lysine conjugates.
CI  - Copyright 2010 Elsevier Inc. All rights reserved.
FAU - Tinianow, Jeff N
AU  - Tinianow JN
AD  - Genentech Research and Early Development, Genentech Inc., South San Francisco, CA 
      94080, USA.
FAU - Gill, Herman S
AU  - Gill HS
FAU - Ogasawara, Annie
AU  - Ogasawara A
FAU - Flores, Judith E
AU  - Flores JE
FAU - Vanderbilt, Alexander N
AU  - Vanderbilt AN
FAU - Luis, Elizabeth
AU  - Luis E
FAU - Vandlen, Richard
AU  - Vandlen R
FAU - Darwish, Martine
AU  - Darwish M
FAU - Junutula, Jagath R
AU  - Junutula JR
FAU - Williams, Simon-P
AU  - Williams SP
FAU - Marik, Jan
AU  - Marik J
LA  - eng
PT  - Evaluation Study
PT  - Journal Article
DEP - 20100210
PL  - United States
TA  - Nucl Med Biol
JT  - Nuclear medicine and biology
JID - 9304420
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Radioisotopes)
RN  - 0 (Radiopharmaceuticals)
RN  - C6V6S92N3C (Zirconium)
SB  - IM
MH  - Animals
MH  - *Antibodies, Monoclonal/chemistry/immunology
MH  - Breast Neoplasms/*diagnostic imaging/immunology
MH  - Female
MH  - Humans
MH  - Metabolic Clearance Rate
MH  - Mice
MH  - Mice, Nude
MH  - Organ Specificity
MH  - Positron-Emission Tomography/*methods
MH  - Radioimmunodetection/*methods
MH  - *Radioisotopes/immunology
MH  - Radiopharmaceuticals/chemical synthesis/immunology
MH  - Tissue Distribution
MH  - *Zirconium/immunology
EDAT- 2010/03/30 06:00
MHDA- 2010/08/31 06:00
CRDT- 2010/03/30 06:00
PHST- 2009/10/10 00:00 [received]
PHST- 2009/11/25 00:00 [revised]
PHST- 2009/11/27 00:00 [accepted]
PHST- 2010/03/30 06:00 [entrez]
PHST- 2010/03/30 06:00 [pubmed]
PHST- 2010/08/31 06:00 [medline]
AID - S0969-8051(09)00291-1 [pii]
AID - 10.1016/j.nucmedbio.2009.11.010 [doi]
PST - ppublish
SO  - Nucl Med Biol. 2010 Apr;37(3):289-97. doi: 10.1016/j.nucmedbio.2009.11.010. Epub 
      2010 Feb 10.