European Nuclear Medicine Guide
[99mTc]Tc-Besilesomab
[99mTc]Tc-Sulesomab
Monoclonal antibodies (MoAbs) are proteins that have been designed to recognise and attach to specific structures (called antigens) found in the body.
Besilesomab is a full-size anti-granulocyte MoAb produced in murine cells and designed to attach to an antigen called NCA-95 found on the surface of granulocytes, a type of white blood cells involved in inflammation and fighting infection.
Sulesomab is a fragment antigen-binding MoAb designed to target an antigen called NCA-90, present on the surface of granulocytes.
Both MoAbs (Besilesomab and Sulesomab) can be radiolabelled with (99mTc). When these radiopharmaceuticals are intravenously injected into the patient, the MoAb carries the radioactivity to the target antigens present on the granulocytes. Radiolabelled anti-granulocyte MoAbs allow rapid and safe delineation of infectious foci by efficient accumulation on the surface of chemotactically activated granulocytes. As large numbers of granulocytes gather at the site of an infection, the radioactivity will accumulate in areas of infection, where it can be detected by scintigraphic methods. Radiolabelled MoAbs bind to granulocytes with high affinity without undesirable expression in non-infected tissues. Anti-granulocyte MoAbs localize in infectious foci via two pathways: (a) in-vivo targeting of chemotactically activated granulocytes and (b) non-specific extravasation and retention due to the locally enhanced vascular permeability [16,19,20].
Both radiolabelled anti-granulocyte MoAbs bind to peripheral neutrophils, but with substantial biodistribution differences. Besilesomab accumulates more than Sulesomab in normal bone marrow, but binds more efficiently to neutrophils in blood and at sites of infection. It has slower plasma clearance than Sulesomab, thus more closely mimicking the biodistribution of radiolabelled autologous white blood cells [16,19,20].
With full size and fragmented radiolabelled anti-granulocyte MoAbs, some differences in physiological uptake should always be taken into account. 99mTc-Besilesomab shows intense uptake in bone marrow, and spleen uptake is higher than liver uptake as early as 1–4 h after injection, whereas both kidneys are shown only slightly. Non-specific bowel activity is regularly seen 20–24 h after injection due to the beginning of radiolabel instability. In contrast, [99mTc]Tc-Sulesomab shows much less bone marrow uptake, hepatic uptake is higher than the splenic, very intense accumulation is seen in the kidneys due to predominant renal excretion, and non-specific bowel activity is already seen 4–6 h after injection due to enzymatic liver degradation of the compound [16,19,20].
Besilesomab, being a full-size murine MoAb, may induce production of human anti-mouse antibodies (HAMA) that must be checked before performing the study and limit its use to one single administration in the patient’s life. Sulesomab, being a fragment antigen-binding MoAb, does not induce HAMA production and can be re-used several times in the same patient [16,19,20].
The main diagnostic indications of 99mTc-labelled anti-granulocyte MoAb scintigraphy are:
Peripheral bone osteomyelitis
Infected joint prosthesis and other orthopaedic hardware
Diabetic foot infection
Pregnancy
Hypersensitivity to MoAbs
Positive screening test for HAMA (for Besilesomab only)
Evidence-based data support the use of 99mTc-labelled anti-granulocyte MoAb scintigraphy in the evaluation of prosthetic joint infections and peripheral bone osteomyelitis, in conjunction with other appropriate imaging modalities (i.e. 3-phase bone scan) [16].
A meta-analysis on the use of 99mTc-labelled anti-granulocyte MoAb scintigraphy for diagnosis of prosthetic joint infections reported a pooled sensitivity and specificity of 83% and 79%, respectively [21]. A meta-analysis on the use of 99mTc-labelled anti-granulocyte MoAb scintigraphy for diagnosis of osteomyelitis reported a pooled sensitivity and specificity of 88% and 71%, respectively [22]. For evaluating soft tissue infections, this scintigraphic method appears to be less accurate than radiolabelled white blood cell scintigraphy and [18F]FDG PET/CT [16]. In comparison with WBC scan, the main advantage of 99mTc-labelled anti-granulocyte MoAb scintigraphy is that it does not require blood handling [16].
Note: Currently, only [99mTc]Tc-Besilesomab is authorised for use in the European Union (6), whereas [99mTc]Tc-Sulesomab in adults has been temporarily withdrawn from use in the European Union [368].
The suggested activities to administer are:
[99mTc]Tc-Besilesomab in adults: 400–800 MBq [24].
[99mTc]Tc-Sulesomab in adults: 740–1110 MBq [23].
The effective dose resulting from the administration of an activity of 800 MBq of [99mTc] Tc-Besilesomab for an adult weighing 70 kg is 6.9 mSv. For an administered activity of 800 MBq, the typical absorbed dose to the target organ bone is 14.2 mGy and the typical absorbed doses to the critical organs, bone marrow, spleen and kidneys are 19.4 mGy, 21.7 mGy, and 16.8 mGy, respectively [24].
The effective dose resulting from the administration of an activity of 750 MBq of [99mTc]Tc-Sulesomab for an adult weighing 70 kg is 6 mSv. For an administered activity of 750 MBq, the typical absorbed dose to the target organ bone is 6 mGy and the typical absorbed doses to the critical organs, urinary bladder, spleen and kidneys are 16.1 mGy, 11.8 mGy, and 33.7 mGy, respectively [23].
Caveat: “Effective Dose” is a protection quantity that provides a dose value related to the probability of health detriment to an adult reference person due to stochastic effects from exposure to low doses of ionizing radiation. It should not be used to quantify the radiation risk for a single individual associated with a particular nuclear medicine examination. It is used to characterize a certain examination in comparison to alternatives, but it should be emphasized that if the actual risk to a certain patient population is to be assessed, it is mandatory to apply risk factors (per mSv) that are appropriate for the gender, the age distribution and the disease state of that population."
Scintigraphic planar (segmental and whole-body) acquisition with [99mTc]Tc-Besilesomab should be performed at 2–4 h and 16–24 h after radiopharmaceutical injection, because a significant increase in sensitivity and specificity will be achieved with late 24 h images due to higher target-to-background ratios (T/B).
Scintigraphic planar (segmental and whole-body) acquisition with [99mTc]Tc-Sulesomab should be performed 1 h and 4–6 h after radiopharmaceutical injection.
Planar images can be acquired using a “time-corrected for isotope decay” protocol. Tomographic acquisition (SPECT or SPECT/CT) increases the diagnostic accuracy (best time point for tomographic acquisition at 4–6 h after injection) [16].
Visual analysis:
Diagnosis of infection is made by comparing planar images at different time points. Images are then classified as:
Negative if there is no radiopharmaceutical uptake, or if there is a significant decrease in uptake in the region of interest from the first to the second time point;
Positive when radiopharmaceutical uptake is seen at both time points, increasing over time in intensity or in size;
Equivocal in all other situations.
Semi-quantitative analysis:
Semi-quantitative evaluation can also be performed following visual assessment, and has added value in equivocal cases as an adjunct for the differentiation between infection and non-specific uptake. Regions of interest (ROIs) are drawn over the area with the highest uptake (target) and copied to presumed normal reference tissue (background: e.g. contra-lateral region). The mean counts per pixel in these ROIs are recorded and used to calculate the target-to-background ratio (T/B) in images performed at both time points. For diagnosis of infection, images are then classified as:
Negative when the T/B decreases over time;
Positive when the T/B increases over time by at least 10%;
Equivocal in all other situations.
In equivocal cases in both visual and semi-quantitative analysis, bone marrow imaging using 99mTc-labelled sulphur colloids should be used. Radiolabelled colloids and anti-granulocyte MoAbs accumulate in healthy and displaced bone marrow, whereas radiolabelled colloids do not accumulate in infection sites [16].
Possible pitfalls: False-positive accumulation of the anti-granulocyte MoAbs due to non-specific inflammatory oedema; false-positive results if scintigraphy is performed within 3 months after surgery; artefacts related to attenuation over-correction in patients with metallic devices; lesions of size lower than scanner spatial resolution causing false- negative results; false results in patients with diseases involving neutrophil defects or haematological malignancies; active substances inhibiting inflammation or affecting the haematopoietic system (such as antibiotics and corticosteroids) leading to false-negative results [16,19, 20].
In order to obtain images of best quality and to reduce the radiation exposure to the bladder, patients should be encouraged to drink sufficient amounts of water and to empty their bladder prior to and after the scintigraphic examination.
An interval of at least 2 days must be observed between any previous scintigraphy with other 99mTc-labelled agents and administration of 99mTc-labelled anti-granulocyte MoAbs.
The potential interference of antibiotics has to be considered. However, patients receiving antibiotic treatment should not be excluded “a priori”. The decision whether to perform or cancel the study depends entirely on the clinical setting and must be discussed with the referring clinician on a case-by-case basis [16].
Close contact with infants and pregnant women should be restricted during the first 12 hours after the radiopharmaceutical injection [23, 24].
It is routine to advise that breastfeeding can be restarted when the level in the milk will not result in a radiation dose to the child of greater than 1 mSv. Due to the half-life of 99mTc, a dose of less than 1 mSv in mother’s milk can be expected 24 hours after administration.
Further information and recommendations are available in the EANM practice guideline on clinical indications, image acquisition and data interpretation for white blood cell and anti-granulocyte monoclonal antibody scintigraphy [16].