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Mechanism of Accumulation of ^99mTc-Sulesomab in Inflammation

¹ Department of Nuclear Medicine, Addenbrooke’s Hospital, Cambridge, United Kingdom
² Department of Medicine, Addenbrooke’s and Papworth Hospitals, Cambridge, United Kingdom

^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 ^99mTc-sulesomab and ^99mTc-labeled human serum albumin (HSA), which have similar molecular sizes, in 7 patients with orthopedic infection proven by clearly positive ¹¹¹In-leukocyte scintigraphy. ^99mTc-Sulesomab and ^99mTc-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 ¹¹¹In-leukocytes. ^99mTc-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, 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 0.01). Both values were considerably less than the T/Bkg ratio on the ¹¹¹In-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 ^99mTc-sulesomab in vitro when primed or activated. Conclusion: (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.

Key Words: infection • antibodies, monoclonal • radiopharmaceuticals • granulocytes • tissue distribution

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