title: Mechanism of accumulation of 99mTc-sulesomab in inflammation.
abstract: 99mTc-Sulesomab, the Fab fragment of anti-NCA-90, is used as an in vivo granulocyte labeling agent for imaging inflammation. It is not clear to what extent it targets cells that have already migrated into the interstitial space of an inflammatory lesion as opposed to circulating cells. The contribution to signal of radioprotein diffusion in the setting of increased vascular permeability is also poorly documented.
  
  
  METHODS
  We compared the local kinetics of (99m)Tc-sulesomab and (99m)Tc-labeled human serum albumin (HSA), which have similar molecular sizes, in 7 patients with orthopedic infection proven by clearly positive (111)In-leukocyte scintigraphy. (99m)Tc-Sulesomab and (99m)Tc-HSA were administered in sequence separated by an interval of 2-6 d. Images were obtained 1, 3, 4, and 6 h after injection, and multiple venous blood samples were obtained for blood clearance measurement. Patlak-Rutland (P-R) analysis was performed to measure lesion and control tissue protein clearance. Target-to-background tissue (T/Bkg) ratios were calculated for each radioprotein and compared with the T/Bkg ratio for (111)In-leukocytes. (99m)Tc-Sulesomab binding to granulocytes was measured in vitro and ex vivo and to primed and activated granulocytes in vitro.
  
  
  RESULTS
  After intravenous injection, <5% of the circulating radioactivity was cell bound with both radioproteins so that the P-R curves could therefore be assumed to represent extravascular uptake of free protein. The blood clearance (mean +/- SD) of sulesomab was 23.4 +/- 11.7 mL/min, approximately 5 times greater than that of HSA, for which it was 4.8 +/- 3.1 mL/min. Likewise, clearance into the lesion of sulesomab was consistently higher than that of HSA, on average about 3 times as high. Nevertheless, the T/Bkg ratios for sulesomab and HSA were similar, except at 6 h when that of HSA (2.14 +/- 0.6) was higher than that of sulesomab (1.93 +/- 0.5; P approximately 0.01). Both values were considerably less than the T/Bkg ratio on the (111)In-leukocyte images, which, at 22 h, was 12.3 +/- 5.3. Moderate clearance of sulesomab, but not HSA, was seen in the control tissue. Granulocytes bound significantly more (99m)Tc-sulesomab in vitro when primed or activated.
  
  
  CONCLUSIONS
  (a) Sulesomab does not localize in inflammation as a result of binding to circulating granulocytes; (b) sulesomab is cleared into inflammation nonspecifically via increased vascular permeability; nevertheless, it may be cleared after local binding to primed granulocytes or bind to activated, migrated extravascular granulocytes; and (c) HSA produces a similar or higher T/Bkg ratio than sulesomab because sulesomab is cleared into normal tissues and because image positivity in inflammation is significantly dependent on local blood-pool expansion.
authors.affiliation: Department of Nuclear Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Skehan
authors.forename: Jessica F
authors.initials: JF
authors.lastname: White
authors.forename: John W
authors.initials: JW
authors.lastname: Evans
authors.forename: David R
authors.initials: DR
authors.lastname: Parry-Jones
authors.forename: Chandra K
authors.initials: CK
authors.lastname: Solanki
authors.forename: James R
authors.initials: JR
authors.lastname: Ballinger
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Chilvers
authors.forename: A Michael
authors.initials: AM
authors.lastname: Peters
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics*; D058846:Antibodies, Monoclonal, Murine-Derived; D001850:Bone Diseases, Infectious / Q000097:blood / Q000000981:diagnostic imaging* / Q000378:metabolism*; D004551:Elbow Joint / Q000098:blood supply / Q000000981:diagnostic imaging / Q000378:metabolism; D005260:Female; D033023:Foot Joints / Q000098:blood supply / Q000000981:diagnostic imaging; D006098:Granulocytes / Q000000981:diagnostic imaging*; D006801:Humans; D006811:Humerus / Q000098:blood supply / Q000000981:diagnostic imaging; D066298:In Vitro Techniques; D007205:Indium Radioisotopes; D007249:Inflammation / Q000000981:diagnostic imaging / Q000378:metabolism; D007719:Knee Joint / Q000098:blood supply / Q000000981:diagnostic imaging / Q000378:metabolism; D007962:Leukocytes / Q000000981:diagnostic imaging; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D016459:Prosthesis-Related Infections / Q000000981:diagnostic imaging / Q000378:metabolism; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013668:Technetium Tc 99m Aggregated Albumin / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D007205:Indium Radioisotopes; D019275:Radiopharmaceuticals; D013668:Technetium Tc 99m Aggregated Albumin; C101172:Sulesomab