European Nuclear Medicine Guide
Monoclonal antibodies (MoAbs) are proteins that have been designed to recognise and attach to specific structures (called antigens) that are 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, which is 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, which is 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 chemotactic 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 by two pathways: (a) in-vivo targeting of chemotactically activated granulocytes and (b) non-specific extravasation and retention due to the locally enhanced vascular permeability [361,364,365].
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 mimicking more the biodistribution of radiolabelled autologous white blood cells [361,364,365].
With full size and fragmented radiolabelled anti-granulocyte MoAbs some differences in physiological uptake should always be taken into account. 99mTc-Besilesomab show intense uptake in bone marrow, spleen uptake is higher than liver uptake already 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 to [99mTc]Tc-Besilesomab, with [99mTc]Tc-Sulesomabthere is much less bone marrow uptake, the liver uptake is higher than the spleen uptake, very intense accumulation is seen in the kidneys due to predominantly renal excretion and non-specific bowel activity is already seen 4-6 h after injection due to enzymatic liver degradation of the compound [361,364,365].
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 life. Sulesomab, being a fragment antigen-binding MoAb, does not induce HAMA production and can be re-used several times in the same patient [361,364,365].
Main diagnostic indications of 99mTc-labelled anti-granulocyte MoAbs scintigraphy are:
Evidence-based data support the use of 99mTc-labelled anti-granulocyte MoAbs 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) [361].
A meta-analysis on the use of 99mTc-labelled anti-granulocyte MoAbs scintigraphy for diagnosis of prosthetic joint infections reported a pooled sensitivity and specificity of 83% and 79%, respectively [366]. 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 [367]. For evaluating soft tissue infections this scintigraphic method appear to be less accurate than radiolabelled white blood cells scintigraphy and 18F-FDG PET/CT [361]. In comparison with WBC scan the main advantage of 99mTc-labelled anti-granulocyte MoAbs scintigraphy is that it does not require blood handling [361].
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:
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 radiation dose to the target organ bone is 14.2 mGy and the typical radiation doses to the critical organs, bone marrow, spleen and kidneys are 19.4 mGy, 21.7 mGy, and 16.8 mGy respectively [369].
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 radiation dose to the target organ bone is 6 mGy and the typical radiation doses to the critical organs, urinary bladder, spleen and kidneys are 16.1 mGy, 11.8 mGy, and 33.7 mGy respectively [368].
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) [361].
Visual analysis:
Semi-quantitative analysis:
In equivocal cases at 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 [361].
Possible pitfalls: false positive accumulation of the anti-granulocyte MoAbs due to non-specific inflammatory oedema; false positive results if the scintigraphy is performed within 3 months after surgery; artefacts related to the attenuation over-correction in patients with metallic devices; lesions of size lower than spatial resolution of method causing false negative results; false results in patients with diseases involving neutrophil defects and in patients with haematological malignancies; active substances may inhibit inflammation or affect the haematopoietic system (such as antibiotics and corticosteroids) leading to false negative results [361,364,365].
In order to obtain images of best quality and to reduce the radiation exposure of 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 case-by-case with the referring clinician [361].
Close contact with infants and pregnant women should be restricted during the first 12 hours after the radiopharmaceutical injection [368,369].
It is usual to advise that breast feeding can be restarted when the level in the milk will not result in a radiation dose to the child 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 the administration.
Further information and recommendations are available in the EANM practice guideline on clinical indications, image acquisition and data interpretation for white blood cells and anti-granulocyte monoclonal antibody scintigraphy [361].