Use of a metastable technetium-99 radionuclide-comprising radioimmunoconjugate for dosimetry

Abstract

The present invention concerns dosimetry-related uses and methods that rely on a metastable technetium-99 (99mTc) radionuclide-comprising (dosimetric) radioimmunoconjugate (RIC) to evaluate or establish therapeutic doses of yttrium-90 (90Y) radionuclide-comprising (therapeutic) radioimmunoconjugates, both RICs targeting the same molecular target. More specifically, radioimmunoconjugates that comprise a CD66-binding component are used. Another aspect of the invention relates to Single Time Point dosimetry procedures replacing the need for traditionally used Multiple Time Point dosimetry procedures for yttrium-90 (90Y) radionuclide-comprising radioimmunoconjugates.

Description

[0001] USE OF A METASTABLE TECHNETIUM-99 RADIONUCLIDE-COMPRISING RADIOIMMUNOCONJUGATE FOR DOSIMETRY

[0002] FIELD OF THE INVENTION

[0003] The present invention broadly relates to the field of radioimmunotherapy and radiopharmaceuticals. More particularly, the invention relates to a new and innovative use of a metastable technetium-99 (99mTc) radionuclidecomprising radioimmunoconjugate as alternative for indium-ill (U1ln) -comprising radioimmunoconjugates for dosimetry purposes. The use of the metastable technetium-99 (99mTc) radionuclide-comprising radioimmunoconjugate is of particular interest for all aspects dosimetry related of yttrium-90 (90Y)-comprising radioimmunoconjugates.

[0004] BACKGROUND OF THE INVENTION

[0005] Haematopoietic stem cell transplantation (HSCT) is a medical treatment procedure applied to patients suffering from various haematological malignancies, severe autoimmune diseases, monogenetic diseases and patients in need for gene- or cell therapies. More than 100 000 HSCT procedures are performed worldwide preferentially in countries with high income (USA, EU). HSCT can be performed using autologous or allogeneic stem cells depending on the respective disease and stage of the disease.

[0006] The standard HSCT procedure consists of 1: Stem cell harvest and storage, 2: Conditioning, and 3: Stem cell transplantation. This procedure is associated with a significant treatment related mortality mainly due to the deleterious effects of the conditioning step which is essential to eliminate the diseased cells as well as the haematopoietic cells of the bone marrow e.g. through chemotherapy or irradiation allowing the transplanted stem cells to repopulate the bone marrow and rebuild an intact haematological system.

[0007] The standard conditioning agent used during the last 30 years is melphalan. However, melphalan also induces deleterious side effects such as mucositis, fever, chills, sepsis, nausea, vomiting in a high percentage of patients etc. Therefore, patients need intensive care to survive the conditioning procedure with high-dose (HD) melphalan followed by the haematopoietic stem cell transplant.

[0008] WO 2018 / 134430 Al describes a conditioning procedure that is better tolerated than conditioning using high-dose melphalan. This conditioning procedure uses antibody targeted bone marrow irradiation to eliminate diseased cells and haematopoietic bone marrow cells before haematopoietic stem cells are transplanted. In said conditioning procedure,90Y-DTPA-Besilesomab (anti-CD66 antibody) is administered and delivers high dose radiation to the active bone marrow, eradicating disease whilst limiting the radiation dose to normal organs and tissue (as also reported by e.g. Orchard et al., Nature Bone Marrow Transplantation, 2024). However, the radioisotope90Y is a pure beta ( ) photon emitter and cannot be readily imaged.

[0009] In order to confirm suitability for treatment, by estimating the treatment dose received by the bone marrow and limiting the dose received by the organs at risk, including liver and kidneys, patient specific dosimetry is to date carried out using DTPA-Besilesomab radiolabelled withU1ln as a surrogate for90Y. The radioisotopeU1ln emits gamma (y) photons that can be measured by single photon emission computed tomography (SPECT) or gamma scintigraphy. Therefore, the images acquired afterluIn-DTPA-besilesomab administration enable the absorbed doses of90Y-DTPA-besilesomab biodistribution to be inferred via calculation.

[0010] However, the dosimetry approach outlined above is far from optimal at least due to reliance on Multiple Time Point (MTP) dosimetry, which requires MTP imaging coupled with blood sampling spanning multiple days, hence imposing a burden on imaging facilities and general hospital facilities. In addition,U1ln is produced by complex and costly procedures wherein cyclotrons are used to bombard natural cadmium with protons. Cyclotron facilities are not as widespread as other radioisotope production methods. This limited production infrastructure results in less frequent and geographically constrained availability ofH1In. Because of these production challenges, it is more difficult to maintain a steady and affordable supply of1HIn, especially in locations without easy access to cyclotron facilities, causing delays in experiments or and causing supply chain bottlenecks. For a commercial anti CD66 antibody basedU1ln dosimetry agent, theU1ln labelled antibody chelate has to be manufactured centrally and distributed upon request to the nuclear medical facility of a transplant center to perform dosimetry. This is a logistically difficult and expensive process which is limiting the use of theU1ln labelled pretherapeutic dosimetry agent in routine transplantation procedures.

[0011] There is thus an unmet need for improved dosimetry protocols to optimize and facilitate treatment with90Y- comprising radioimmunoconjugates such as the aforementioned90Y-DTPA-Besilesomab. Both improvements to the dosimetry protocols as such and providing improved alternatives toU1ln would greatly benefit patients and the healthcare system in general.

[0012] SUMMARY OF THE INVENTION

[0013] By extensive experimentation, the inventors have unexpectedly found that radioimmunoconjugates comprising as radionuclide (99mTc) offer several advantages when compared to radioimmunoconjugates comprising as radionuclide (inIn) for the purpose of dosimetry experiments to obtain subject-specific treatment dose information for yttrium-90 (90Y) radionuclide-comprising radioimmunoconjugates, for examples those used for (90Y) anti- CD66 radioimmunotherapy. Using99mTc instead ofU1ln is beneficial since concerns regarding costs, on-site preparation, supply and availability that exist withU1ln are not present.

[0014] One example in the context of anti-CD66 radioimmunotherapy is the scintimun kit which is commercially available, contains besilesomab, and is now exclusively used for inflammation detection. The anti-CD66 antibody besilesomab of said kit can readily be radiolabeled with sodium pertechnetate to allow scintigraphy. The present work demonstrates that "mTc anti-CD66 antibody besilesomab (e.g. available in kits such as scintimun) performs similarly in dosimetry as the usually applied111In-CHX-A”-DTPA besilesomab and can therefore be used for dosimetry purposes in (90Y) anti-CD66 radioimmunotherapy. Hence, a99mTc anti-CD66 antibody (e.g. as available in the scintimun kit) can, upon radiolabeling, act as an off-the-shelf means for dosimetry of90Y-DTPA- Besilesomab.

[0015] Moreover, the inventors have found that upon use of such a radioimmunoconjugate comprising as radionuclide (99mTc) the routinely used albeit time and resource consuming MTP dosimetry protocol using radioimmunoconjugates comprising as radionuclide (U1ln) can be replaced by a more convenient Single Time Point (STP) approach. Notably, for the STP a planar scintigram of the subject that was administered the radioimmunoconjugate suffices.

[0016] Unexpectedly, it was found that a prima facie indication regarding suitability of a certain dose can already be deducted by a so-called "rib-ovcr-livcr" evaluation, whereby visibility of the ribs eclipsing the liver on the scintigram provides a first indication thereto. A rib is considered visible if the bone marrow in the rib is distinctly displayed in the scintigram, i.e. the signal of the liver in the scintigram does not cover the entire signal of the bone marrow in the rib. For a thorough evaluation of the dose, a rational decision tree was developed that provides detailed information regarding suitability of a certain dose (e.g. 45 MBq / kg lean body weight (lbw)) for any given subject.

[0017] The present invention hence enables the replacement ofU1ln radiolabelled dosimetric radioimmunoconjugates (RICs), which are expensive, short in supply and difficult to use on-site (e.g. in the clinic), with99mTc radiolabelled RICs that are much cheaper, easier to use on-site and easier to supply, while retaining the same dosimetric assessment quality (i.e., both have a highly similar blood clearance and organ uptake). Furthermore, the present invention shows that instead of multiple time point dosimetry, single time point dosimetry is sufficient for obtaining good results, when using99mTc radiolabelled RICs.

[0018] The invention therefore provides in the following numbered aspects:

[0019] Aspect 1. Use of a first (dosimetric) radioimmunoconjugate (RIC) comprising as radionuclide metastable technetium-99 (99mTc) for subject specific dosimetry of an effective amount of a second (therapeutic) RIC comprising yttrium-90 (90Y) as radionuclide.

[0020] Aspect 2. A method of determining subject specific dosimetry of an effective amount of a second (therapeutic) RIC comprising yttrium-90 (90Y) as radionuclide, comprising:

[0021] - administration to said subject of a first (dosimetric) RIC, said first RIC comprising as imaging radionuclide metastable technetium-99 (99mTc);

[0022] - recording a planar (whole body or thorax) scintigram of the subject; and

[0023] - determining the relative signal intensity of the liver and the relative signal intensity of one or more ribs of the thorax based on said planar scintigram.

[0024] Aspect 3. The method according to aspect 2, wherein the subject specific dosimetry is determined by comparing the signal intensity of the liver and the signal intensity of one or more ribs of the thorax, preferably wherein a safe dose for the subject results in a higher signal intensity of the one or more ribs of the thorax when compared to the signal intensity of the liver, more preferably wherein a suitable dose results in at least a 1,5: 1 rib to liver signal intensity, most preferably at least a 2: 1 rib to liver signal intensity.

[0025] Aspect 4. Use of a first (dosimetric) RIC comprising as radionuclide metastable technetium-99 (99mTc) for identifying by dosimetry subjects eligible for safe and effective exposure to an effective amount of a second (therapeutic) RIC comprising yttrium-90 (90Y) as radionuclide. Aspect 5. A method of identifying by dosimetry subjects eligible for safe and effective exposure to an effective amount of a second (therapeutic) RIC comprising yttrium-90 (90Y) as radionuclide, comprising:

[0026] - administration to said subject of a first RIC, said first (dosimetric) RIC comprising as imaging radionuclide metastable technetium-99 (99mTc);

[0027] - recording a planar (whole body or thorax) scintigram of the subject; and

[0028] - determining the relative signal intensity of the liver and the relative signal intensity of one or more ribs of the thorax based on said planar scintigram.

[0029] Aspect 6. The method according to aspect 5, wherein the eligibility of the subject for safe and effective exposure to an effective amount of a second radioimmunoconjugate (RIC) is determined by comparing the signal intensity of the liver and the signal intensity of one or more ribs of the thorax, preferably wherein the subject is considered eligible upon a higher signal intensity of the one or more ribs of the thorax when compared to the signal intensity of the liver, more preferably wherein the subject is considered eligible upon at least a 1,5: 1 rib to liver signal intensity, most preferably at least a 2: 1 rib to liver signal intensity.

[0030] Aspect 7. Use of a first (dosimetric) RIC comprising as radionuclide metastable technetium-99 (99mTc) for determining by dosimetry the inclusion of a subject in a treatment plan, said treatment plan comprising the administration of an effective amount of a second (therapeutic) RIC comprising yttrium-90 (90Y) as radionuclide.

[0031] Aspect 8. A method of determining the inclusion of a subject in a treatment plan, said treatment plan comprising the administration of an effective amount of second (therapeutic) RIC comprising yttrium-90 (90Y) as radionuclide, comprising:

[0032] - administration to said subject of a first RIC, said first (dosimetric) RIC comprising as imaging radionuclide metastable technetium-99 (99mTc);

[0033] - recording a planar (whole body or thorax) scintigram of the subject; and

[0034] - determining the relative signal intensity of the liver and the relative signal intensity of one or more ribs of the thorax based on said planar scintigram.

[0035] Aspect 9. The method according to aspect 8, wherein the inclusion of the subject in the treatment plan is determined by comparing the signal intensity of the liver and the signal intensity of one or more ribs of the thorax, preferably wherein in a subject suited for inclusion in the treatment plan a higher signal intensity of the one or more ribs of the thorax when compared to the signal intensity of the liver is observed, more preferably wherein the subject is included in the treatment plan upon at least a 1,5:1 rib to liver signal intensity, most preferably at least a 2:1 rib to liver signal intensity.

[0036] Aspect 10. The use or method according any one of the preceding aspects, wherein the effective amount of the RIC comprising yttrium-90 (90Y) as radionuclide is 45 MBq / kg lean body weight (lbw).

[0037] Aspect 11. The use or method according any one of the preceding aspects, wherein 45 MBq / kg lean body weight (lbw) of the second RIC comprising yttrium-90 (90Y) as radionuclide is administered as a single dose. Aspect 12. The use or method according to aspect 11, wherein the single dose administration is intravenous single dose administration.

[0038] Aspect 13. The use or method according to any one of the preceding aspects, wherein said use or method further comprises a step of determining safety and effectiveness of a treatment plan with a yttrium-90 (90Y)- comprising radioimmunoconjugate (RIC) in said subject calculated from (i.e. based on) a scintigram of said subject after receiving a single dose of between 400-800 MBq / patient metastable technetium-99 (99mTc) radionuclide-comprising RIC, wherein:

[0039] Upon a calculated90Y liver absorption dose of >15Gy, or a calculated90Y kidney absorption dose of >13Gy, or a calculated90Y bone marrow absorption dose of >35Gy arrived at by measuring the99mTc absorption doses and wherein a 20% reduction of RIC does not result in a lowering of said calculated 90Y liver absorption dose to 15Gy or less, said calculated90Y kidney absorption dose to 13Gy or less, and said calculated90Y bone marrow absorption dose to 35Gy or less, the subject is excluded from treatment;

[0040] Upon a calculated90Y liver absorption dose of >15Gy, or a calculated90Y kidney absorption dose of >13Gy, ora calculated90Ybone marrow absorption dose of >35Gy arrived at by measuring the99mTc absorption doses, and wherein a 20% reduction of RIC does result in a lowering of said calculated 90Y liver absorption dose to 15Gy or less, said calculated90Y kidney absorption dose to 13Gy or less, and said calculated90Ybone marrow absorption dose to 35Gy or less, subject specific treatment dose is recalculated based on the reduction of RIC;

[0041] Upon a calculated90Y liver absorption dose of <15Gy, a calculated90Y kidney absorption dose of <13Gy, and a calculated90Y bone marrow absorption dose of <35Gy arrived at by measuring the 99mTc absorption doses, and wherein the calculated90Y bone marrow absorption dose is higher than the calculated90Y liver absorption dose, the subject is eligible for being treated with 45 MBq / kg lean body weight (lbw) yttrium-90 (90Y)-comprising RIC;

[0042] Upon a calculated90Y liver absorption dose of <15Gy, a90Y kidney absorption dose of <13Gy, a90Y bone marrow absorption dose of <10Gy arrived at by measuring the99mTc absorption doses, and wherein the bone marrow absorption dose is lower than the liver absorption dose, the subject is excluded from treatment.

[0043] Aspect 14. The use or method according to any one of the preceding aspects, wherein in the planar scintigram the relative signal intensity in the area of the liver and the relative signal intensity of one or more ribs are quantified, preferably by computerised means.

[0044] Aspect 15. The use or method according to any one of the preceding aspects, wherein the dosimetry is obtained by using SPECT / CT imaging.

[0045] Aspect 16. The use or method according to any one of the preceding aspects, wherein the dosimetry is Single Time Point (STP) dosimetry.

[0046] Aspect 17. A method of subject specific Single Time Point (STP) dosimetry for an yttrium-90 (90Y)- comprising (therapeutic) RIC, comprising - administration to said subject of a metastable technetium-99 (99mTc)-comprising (dosimetric) RIC;

[0047] - recording a planar (whole body or thorax) scintigram of said subject at a single point in time; and

[0048] - determining the relative signal intensity in the area of the liver and the relative signal intensity in the area of at least part of the bone marrow in the thorax based on said planar scintigram.

[0049] Aspect 18. A metastable technetium-99 (99mTc)-comprising (dosimetric) RIC, for use in any one of the methods or uses of aspects 1 to 17, more preferably for use in a method of subject-specific Single Time Point (STP) dosimetry for an yttrium-90 (90Y)-comprising (therapeutic) RIC, comprising

[0050] - administration to said subject of a metastable technetium-99 (99mTc)-comprising RIC;

[0051] - recording a planar whole body scintigram of the subject at a single point in time; and

[0052] - determining the relative signal intensity in the area of the liver and the relative signal intensity in the area of at least part of the bone marrow in the thorax.

[0053] Aspect 19. The method according to aspect 17 or the metastable technetium-99 (99mTc)-comprising RIC for use according to aspect 18, wherein the STP dosimetry is obtained by using SPECT / CT imaging.

[0054] Aspect 20. The use, method, or metastable technetium-99 (99mTc)-comprising RIC for use according to any one of aspects 16 to 19, wherein the STP dosimetry is determined between about 0 and about 96 hours, preferably between about 4 hours and about 36 hours, preferably between about 6 hours and about 36 hours, preferably between about 8 hours and about 36 hours, between about 12 and about 36 hours after use or administration, or wherein the STP dosimetry is determined between about 0 hours and about 24 hours, preferably between 3 hours and about 6 hours, or between about 6 hours and about 8 hours after administration of the99mTc -comprising RIC.

[0055] Aspect 21. The use, method, or metastable technetium-99 (99mTc)-comprising RIC for use according to aspect 20, wherein the STP dosimetry is determined between 20 and 27 hours, such as at about 24 hours after injection of the RIC comprising as imaging radionuclide metastable technetium-99 (99mTc).

[0056] Aspect 22. The use, method, or metastable technetium-99 (99mTc)-comprising RIC for use according to any one of the preceding aspects, wherein the STP dosimetry is determined at about 24 hours after injection of the RIC comprising as imaging radionuclide metastable technetium-99 (99mTc).

[0057] Aspect 23. The use, method, or metastable technetium-99 (99mTc)-comprising RIC for use according to any one of aspects 16 to 22, wherein the accuracy of the STP dosimetry is within 20% of the Multiple Time Point (MTP) dose, preferably within 20% of the MTP for bone marrow and / or liver.

[0058] Aspect 24. Use of a radioimmunoconjugate (RIC) comprising a metastable technetium-99 (99mTc) radionuclide as a dosimetry agent for an yttrium-90 (90Y)-comprising RIC.

[0059] Aspect 25. Use of a metastable technetium-99 (99mTc) radionuclide-comprising radioimmunoconjugate (RIC) as pretherapeutic dosimetric patient selection agent for an yttrium-90 (90Y)-comprising RIC.

[0060] Aspect 26. A computer-implemented method for determining subject specific treatment conditions of a yttrium-90 (90Y)-comprising radioimmunoconjugate (RIC), the method comprising: A step of receiving input from either a user or the imaging device used for obtaining a planar scintigram of the thorax of said subject "mTc absorption doses for liver, kidney, and bone marrow after said subject received a single dose of 400-800 MBq / patient metastable technetium-99 (99mTc) radionuclide-comprising RIC;

[0061] A step of calculating from (i.e. based on) the99mTc absorption doses the90Y absorption doses for liver, kidney, and bone marrow;

[0062] A decision making step, said decision making step adhering to the following logic: o Upon a calculated90Y liver absorption dose of >15Gy, or a calculated90Y kidney absorption dose of >13Gy, or a calculated90Y bone marrow absorption dose of >35Gy arrived at by measuring the "mTc absorption doses and wherein a 20% reduction of RIC does not result in a lowering of said calculated90Y liver absorption dose to 15Gy or less, said calculated 90Y kidney absorption dose to 13Gy or less, and said calculated90Ybone marrow absorption dose to 35Gy or less, the subject is excluded from treatment; o Upon a calculated90Y liver absorption dose of >15Gy, or a calculated90Y kidney absorption dose of >13Gy, or a calculated90Y bone marrow absorption dose of >35Gy arrived at by measuring the99mTc absorption doses, and wherein a 20% reduction of RIC does result in a lowering of said calculated90Y liver absorption dose to 15Gy or less, said calculated90Y kidney absorption dose to 13Gy or less, and said calculated90Y bone marrow absorption dose to 35Gy or less, subject specific treatment dose is recalculated based on the reduction of RIC; o Upon a calculated90Y liver absorption dose of <15Gy, a calculated90Y kidney absorption dose of <13Gy, and a calculated90Y bone marrow absorption dose of <35Gy arrived at by measuring the "mTc absorption doses, and wherein the calculated90Y bone marrow absorption dose is higher than the calculated90Y liver absorption dose, the subject is eligible for being treated with 45 MBq / kg lean body weight (lbw) yttrium-90 (90Y)-comprising RIC; o Upon a calculated90Y liver absorption dose of <15Gy, a90Y kidney absorption dose of <13Gy, and a90Y bone marrow absorption dose of <10Gy arrived at by measuring the99mTc absorption doses, and wherein the bone marrow absorption dose is lower than the liver absorption dose, the subject is excluded from treatment;

[0063] A step of providing output wherein the decision is provided to a user or stored on a computer- readable storage medium.

[0064] Aspect 27. The computer-implemented method according to aspect 26, comprising a further step wherein a user applies the decision to a subject.

[0065] Aspect 28. A computer system configured to perform the method of aspect 26.

[0066] Aspect 29. A computer program product comprising instructions which when the program is executed by a computer, cause the computer to carry out the steps of the method of aspect 26.

[0067] Aspect 30. A computer-readable storage medium, comprising a data storage material encoded with computer readable data wherein said data comprises one or more planar scintigrams of the thorax of a subject after receiving a single dose of 400-800 MBq metastable technetium-99 (99mTc) radionuclide-comprising RIC configured to perform the method of aspect 26.

[0068] Aspect 31. The computer-readable storage medium according to aspect 30, further comprising computer readable data wherein said data comprises quantified signal intensities of the liver, kidney, and bone marrow of the subject.

[0069] Aspect 32. The computer system according to aspect 28, the computer program product according to aspect 29, or the computer-readable storage medium according to aspect 30 or 31, further comprising a database containing scintigrams or information on scintigrams of one or more other subjects.

[0070] Aspect 33. A computer-implemented method of determining a sub-population of subjects that can be safely and effectively treated for a disease or disorder by 45 MBq / kg lean body weight (lbw) of a yttrium-90 (90Y)- comprising radioimmunoconjugate (RIC), said method comprising:

[0071] A step of receiving input from either a user or the imaging device used for obtaining a planar scintigram of the thorax of said subjects99mTc absorption doses for liver, kidney, and bone marrow after said subject received a single dose of 400-800 MBq / patient metastable technetium-99 (99mTc) radionuclide-comprising RIC;

[0072] A step of calculating from (i.e. based on) the99mTc absorption doses the90Y absorption doses for liver, kidney, and bone marrow;

[0073] A decision making step wherein subjects are considered to be safely and effectively treated are characterised upon a calculated90Y liver absorption dose of <15Gy, a calculated90Y kidney absorption dose of <13Gy, a calculated90Ybone marrow absorption dose of <35Gy is obtained, and wherein the bone marrow absorption dose is higher than the liver absorption dose; and

[0074] A step of providing output wherein the decision is provided to a user or stored on a computer- readable storage medium.

[0075] Aspect 34. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding aspects, wherein the RIC comprises a CD66-binding component or the first and second RIC comprise a CD66-binding component, preferably wherein both the first and the second RIC comprise the same CD66-binding component.

[0076] Aspect 35. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding aspects, wherein both RIC’s are identical except for the radionuclide and chelating agent.

[0077] Aspect 36. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding aspects, wherein the CD66-binding component is a polypeptide comprising at least one antibody-binding domain, more preferably an antibody, a chimeric antibody, a humanized antibody or a recombinant antibody, more preferably a single-chain antibody or fragment thereof or a proteolytic antibody fragment such as Fab-, Fab'- or F(ab) 2 -fragment or recombinant antibody fragment such as single-chain Fv-fragments.

[0078] Aspect 37. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding aspects, wherein the CD66-binding component is a monoclonal antibody.

[0079] Aspect 38. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding aspects, wherein the CD66-binding component is an anti-granulocyte monoclonal antibody.

[0080] Aspect 39. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding aspects, wherein the CD66-binding component, preferably an antibody, selectively binds to CD66a, CD66b, CD66c or CD66e, preferably wherein the CD66-binding component, preferably an antibody, selectively binds to CD66b or CD66e.

[0081] Aspect 40. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding aspects, wherein the CD66-binding component is BW 250 / 183 antibody.

[0082] Aspect 41. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding aspects, wherein the metastable technetium-99 (99mTc)-comprising RIC radionuclide is linked to the CD66-binding component by a method comprising using a reduction agent such as ZnCF. a stabilization agent such as PTP, and pertechnetate as99mTc source that is attached to reduced hinge region SH (sulfhydryl) bonds.

[0083] Aspect 42. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to aspect 41, wherein99mTc is bound to hinge region SH (sulfhydryl) bonds without use of a standard chelating agent.

[0084] Aspect 43. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding aspects, wherein the90Y radionuclidecomprising RIC is linked to the CD66-binding component via a structure of the formula

[0085] [(chelating agent)-(R1)p-(R2-R3)n]m-(CD66-binding component) wherein n is 0 or 1, m is 1 to 15, p is 0 or 1,

[0086] R1and R3are independently selected from the group consisting of -NHCSNH-, -NHCONH-, -NHCOCH2S-, -S- S-, -NH-NH-, -NH-, -S-, -CONHNH-, -SCH2CH2COONH-, -SCH2CH2SO2-, -SCH2CH2SO2NH-, -CONH-, -O- CH2CH2O-, -CO-, -COO-, -NH-O-, -CONHO-, -S-(CH2)3C(NH)NH-, -NH-COO-, -O- and , preferably -NH-CS-NH-, and

[0087] R2is selected from the group consisting of C1-C18 alkylen, branched C1-C18, -CEE-CeHio-, -alkylphcnylcnc. -phcnylcnc. / / / -phenylene, -alkyloxyphcnylcnc. naphthylene, -[CH2CH2O]x-, -[CH2CH2SOCH2CH2]X-, - [CH2CH2SO2CH2CH2]X-, or -[NHCHR4CO]y-, wherein x is 1 to 200, y is 1 to 20, and wherein R4 is selected from the group consisting of H-, Me-, HSCH2-, isopropyl, but-2-yl, CH3SCH2CH2-, benzyl, l / Z-indol-3-yl-methyl, HOCH2-, HOOCCH2-, CH3CH(OH)-, HOOCCH2CH2-, 4-hydroxybenzyl, H2NCOCH2-, H2NCOCH2CH2-, 4-aminobut-l-yl, 2-guanidinoethyl, l / / -iinidazol-5-yl-incthyl and 2-methylprop-l-yl.

[0088] Aspect 44. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to aspect 43, wherein the chelating agent is selected from the group consisting of diethylenetriaminepentaacetic acid (DTPA), l,4,7,10-tetraazacyclododecane-N,N',N”,N'”- tetraacetic acid (DOTA), l,4,8,ll-tetraazacyclotetradecane-N,N',N”,N'”-tetraacetic acid (TETA), 1,4,7- triazonane-N,N',N' '-triacetic acid (NOTA), 2,2’-(2-(((lS,2S)-2-(bis(carboxymethyl)amino)cyclohexyl)- (carboxymethyl)amino)ethylazanediyl)diacetic acid (cyclohexano-DTPA), 2,2’-(2-(((lR,2R)-2- (bis(carboxymethyl)amino)cyclohexyl)-(carboxymethyl)amino)ethylazanediyl)diacetic acid, 2,2’-(2-(((lS,2R)-2- (bis(carboxymethyl)amino)cyclohexyl)-(carboxymethyl)amino)ethylazanediyl)diacetic acid, 2,2’-(2-(((lR,2S)-2- (bis(carboxymethyl)amino)cyclohexyl)-(carboxymethyl)amino)ethylazanediyl)diacetic acid, 2,2',2",2'"-(2,2’- ( 1 S,2S)-cyclohexane- 1 ,2-diylbis((carboxymethyl)azanediyl)bis(ethane-2, 1 -diyl))bis(azanetriyl)tetraacetic acid, 2,2',2",2'"-(2,2'-(lS,2R)-cyclohexane-l,2-diylbis((carboxymethyl)azanediyl)bis(ethane-2,l- diyl))bis(azanetriyl)tetraacetic acid, (1R)-1 -benzyl-diethylenetriaminepentaacetic acid, ( IS)- 1 -benzyl- diethylenetriaminepentaacetic acid, (2R)-2-benzyl-diethylenetriaminepentaacetic acid, (2.S')-2-bcnzyl- diethylenetriaminepentaacetic acid, (2R)-2-benzyl-(3R)-3 -methyl -DTPA, (2 / ?)-2-bcnzyl-(3.S')-3 -methyl -DTPA, (2.S')-2-bcnzyl-(3.S')-3-mcthyl-DTPA. (2S -2-benzyl-(3R)-3 -methyl -DTPA, (2R)-2-benzyl-(4R)-4-methyl-DTPA, (2R)-2-benzyl-(4S)-4-methyl-DTPA, (2S)-2-benzyl-(4S)-4-methyl-DTPA, (2S)-2-benzyl-(4R)-4-methyl-DTPA, (lR)-l-benzyl-(3R)-3-methyl-DTPA, (lR)-l-benzyl-(3S)-3-methyl-DTPA, (lS)-l-benzyl-(3S)-3-methyl-DTPA, (lS)-l-benzyl-(3R)-3-methyl-DTPA, (lR)-l-benzyl-(4R)-4-methyl-DTPA, (lR)-l-benzyl-(4S)-4-methyl-DTPA, (lS)-l-benzyl-(4S)-4-methyl-DTPA, (lS)-l-benzyl-(4R)-4-methyl-DTPA, 2,2'-((lR,2R)-2-(((R)-2- (bis(carboxymethyl)amino)-3 -phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2'- ((lS,2S)-2-(((S)-2-(bis(carboxymethyl)amino)-3- phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2'-((lR,2R)-2-(((S)-2- (bis(carboxymethyl)amino)-3 -phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2'- ((lS,2S)-2-(((R)-2-(bis(carboxymethyl)amino)-3- phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2'-((lR,2S)-2-(((R)-2- (bis(carboxymethyl)amino)-3 -phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2'- ((lS,2R)-2-(((S)-2-(bis(carboxymethyl)amino)-3- phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2'-((lS,2R)-2-(((R)-2- (bis(carboxymethyl)amino)-3 -phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2'- ((lR,2S)-2-(((S)-2-(bis(carboxymethyl)amino)-3- phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, (2S)-2-benzyl-l,4,7,10- tetraazacyclododecane-N,N',N' ',N' ' '-tetraacetic acid, (2R)-2-benzyl-l,4,7, 10-tetraazacyclododecane- N,N',N",N" '-tetraacetic acid, 6-benzyl-l,4,8,l l-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid, 2- benzyl-1, 4, 7-triazonane-N,N',N' '-triacetic acid, benzyl-3-methyl-diethylenetriaminepentaacetic acid (2B3M- DTPA), (R)-2-amino-3-(phenyl)propyl)trans-(S, S)-cyclohexane- 1 ,2-diamine-pentaacetic acid) (Bn-CHX-A” - DTPA) and salts and derivatives thereof, particularly (R)-2-amino-3-(phenyl)propyl)trans-(S,S)-cyclohexane-l,2- diamine-pentaacetic acid) (Bn-CHX-A” -DTPA) and salts thereof.

[0089] Aspect 45. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding aspects, wherein the radionuclide is linked to the CD66-binding component via the structure CD66-binding SH-99mTc.

[0090] Aspect 46. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding aspects, wherein the99mTc radionuclide is covalently linked to the CD66-binding component, particularly by reduction / oxidation chemistry, such as using DTT (dithiothreitol) and PTP (propane tetraphosphonate).

[0091] Aspect 47. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding aspects, wherein the subject is a mammalian subject, preferably a human subject.

[0092] Aspect 48. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding aspects, wherein the subject has or is considered to have a bone marrow associated disease.

[0093] Aspect 49. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to aspect 48, wherein the bone marrow associated disease is selected from the group consisting of: haematological malignancies, such as a leukemia, which may be selected from multiple myeloma (MM), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL) and lymphoma, preferably multiple myeloma, autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, scleroderma pigmentosa, systemic lupus erythematodes, colitis ulcerosa, Crohn's disease, and systemic sclerosis, AL-amyloidosis, monogenetic diseases, such as aplastic anemia, pure red cell aplasia, paroxysmal nocturnal hemoglobinuria, fanconi anemia, Thalassemia major, sickle cell anemia, severe combined immunodeficiency, Wiskott-Aldrich syndrome, hemophagocytic lymphohistiocytosis, inborn errors of metabolism, epidermolysis bullosa, severe congenital neutropenia, Schwachman-Diamond syndrome, Diamond-Blackfan anemia, and leucocyte adhesion deficiency, and diseases, which can be treated by ex vivo cellular therapy and gene therapy, such as sickle cell anemia, transthyretin amyloidosis (ATTR), hereditary angio edema, acute myeloid leukemia, transfusion-dependent beta thalassemia (TDT), AMD, Diabetic Retinopathy, bleeding disorders such as Hemophilia A and B, lysosomal storage disease such as Hunter syndrome and Huler syndrome, or peripheral neuropathy (Charcot-Marie-Tooth).

[0094] Aspect 50. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding aspects, wherein the subject is a subject who was treated with induction therapy but had disease progression or had a haematological response.

[0095] Aspect 51. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding aspects, wherein the subject is a subject who was treated with high-dose melphalan followed by stem cell transplantation but had disease progression.

[0096] Aspect 52. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding aspects, wherein the subject is a subject who is ineligible to treatment with high dose (HD) melphalan preceding HSCT

[0097] Aspect 53. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding aspects, wherein the subject is a subject who was treated with a combination of up to 4 dmgs selected from doxombicin, carmustine, cyclophosphamide, dexamethasone, etoposide, melphalan, (methyl)prednisolone, vincristine and idarubicin but had disease progression.

[0098] Aspect 54. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding aspects, wherein the subject is a subject who is ineligible to treatment with a combination of up to 4 drugs selected from doxorubicin, carmustine, cyclophosphamide, dexamethasone, etoposide, melphalan, (methyl)prednisolone, vincristine and idarubicin.

[0099] Aspect 55. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding aspects, wherein the subject is a subject who is eligible for Haematopoietic Stem Cell Transplantation (HSCT).

[0100] Aspect 56. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding aspects, wherein the subject is a subject suffering from AL-amyloidosis, who was treated with Daratumumab and cyclophosphamide, Bortezomib and dexamethasone (Dara-CyBorD) and who did not achieve a complete remission (CR) 6 months after treatment.

[0101] Aspect 57. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding aspects, wherein the subject is a subject suffering from multiple myeloma, who is treatment refractory towards standard care of multiple myeloma including daratumumab and who has cryopreserved haematopoietic stem cells for allowing HSCT following application of the therapeutic RIC. The above and further aspects and preferred embodiments of the invention are described in the following sections and in the appended claims. The subject matter of the appended claims is hereby specifically incorporated in this specification.

[0102] BRIEF DESCRIPTION OF THE FIGURES

[0103] Figure 1. Planar whole body scintigram 24 hours post injection of the imaging RICinIn-DTPA-besilesomab. Left: anterior scintigram. Right: posterior scintigram.

[0104] Figure 2. Planar whole body scintigram 24 hours post injection of the imaging RIC99mTc-besilesomab.

[0105] Figure 3. Planar whole body scintigram 24 hours post injection of the imaging RICluIn-DTPA-besilesomab (5 MBq / kg). Left: anterior scintigram. Right: posterior scintigram. No excessive liver accumulation was detected.

[0106] Figure 4. Planar whole body scintigram 24 hours post injection of the imaging RICluIn-DTPA-besilesomab (5 MBq / kg). Left: anterior scintigram. Right: posterior scintigram. Liver accumulation is clearly visible.

[0107] Figure 5. Planar anterior whole body scintigram 24 hours post injection of the imaging RICluIn-DTPA- besilesomab (185 MBq / subject). Liver accumulation is clearly visible.

[0108] Figure 6. Decision tree for determining safety and effectiveness of a treatment plan with a yttrium-90 (90Y)- comprising radioimmunoconjugate (RIC) in said subject based on a scintigram of said subject after receiving a single dose of 400-800 MBq metastable technetium-99 (99mTc) radionuclide-comprising RIC. From the absorption doses measured after administration of the single dose of 400-800 MBq metastable technetium-99 (99mTc) radionuclide-comprising RIC the90Y absorption doses are calculated. The absorption dose limits recited in the decision tree are90Y absorption dose limits. Bm= Bone marrow. PL Principal investigator.

[0109] Figure 7. Comparison of blood clearance between99mTc-Besilesomab andluIn-DTPA-Besilesomab after administration.

[0110] Figure 8. Comparison of the uptake of99mTc-Besilesomab andluIn-DTPA-Besilesomab in organs immediately after administration. Left condition for each tissue: Tc99m (0.17h); right condition for each tissue: Inlll planar (0.5 h).

[0111] Figure 9. Comparison of the organ uptake of99mTc-Besilesomab at 5h andluIn-DTPA-Besilesomab at 24h. Left condition for each tissue: Tc99m (5h); right condition for each tissue: Ini 11 planar (24 h).

[0112] Figure 10. Comparison of the organ uptake of99mTc-Besilesomab andluIn-DTPA-Besilesomab at 24h. Left condition for each tissue: Tc99m (24h); right condition for each tissue: Ini 11 planar (24 h).

[0113] Figure 11. Proposed method for determining the effective dose "averaging sex" according to ICRP 103.

[0114] Figure 12. Box chart of90Y-DTPA-Besilesomab effective half-life in the liver (left), bone marrow (middle) and kidneys (right) based on MTP data.

[0115] Figure 13. Scatter plot of the association between MTP and STP (24h) in bone marrow (A), liver (B) and kidneys (C). Figure 14. Bar chart comparing absorbed dose per unit administered activity (DpA) between Ringhoffer et al (188Re or90Y-labelled anti-CD66 antibody as part of a dose -reduced conditioning regimen for patients with acute leukaemia or myelodysplastic syndrome over the age of 55: results of a phase I— II study, Br J Haematol, 2005), MTP, and STP (24-96h) in bone marrow, liver, and kidneys. Left bar of each condition: bone marrow; middle bar of each condition: liver; right bar of each condition: kidneys.

[0116] DETAILED DESCRIPTION

[0117] As used herein, the singular forms “a”, “an”, and “the” include both singular and plural referents unless the context clearly dictates otherwise.

[0118] The terms “comprising”, “comprises” and “comprised of’ as used herein are synonymous with “including”, “includes” or “containing”, “contains”, and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps. The terms also encompass “consisting of’ and “consisting essentially of’, which enjoy well-established meanings in patent terminology.

[0119] The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the respective ranges, as well as the recited endpoints. This applies to numerical ranges irrespective of whether they are introduced by the expression “from ... to ...” or the expression “between... and ...” or another expression.

[0120] The terms “about” or “approximately” as used herein when referring to a measurable value such as a parameter, an amount, a temporal duration, and the like, are meant to encompass variations of and from the specified value, such as variations of + / -10% or less, preferably + / -5% or less, more preferably + / -!% or less, and still more preferably + / -0.1% or less of and from the specified value, insofar such variations are appropriate to perform in the disclosed invention. It is to be understood that the value to which the modifier “about” or “approximately” refers is itself also specifically, and preferably, disclosed.

[0121] Whereas the terms “one or more” or “at least one”, such as one or more members or at least one member of a group of members, is clear per se, by means of further exemplification, the term encompasses inter alia a reference to any one of said members, or to any two or more of said members, such as, e.g., any >3, >4, >5, >6 or >7 etc. of said members, and up to all said members. In another example, “one or more” or “at least one” may refer to 1, 2, 3, 4, 5, 6, 7 or more.

[0122] The discussion of the background to the invention herein is included to explain the context of the invention. This is not to be taken as an admission that any of the material referred to was published, known, or part of the common general knowledge in any country as of the priority date of any of the claims.

[0123] Throughout this disclosure, various publications, patents and published patent specifications are referenced by an identifying citation. All documents cited in the present specification are hereby incorporated by reference in their entirety. In particular, the teachings or sections of such documents herein specifically referred to are incorporated by reference.

[0124] Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, term definitions are included to better appreciate the teaching of the invention. When specific terms are defined in connection with a particular aspect of the invention or a particular embodiment of the invention, such connotation or meaning is meant to apply throughout this specification, i.e., also in the context of other aspects or embodiments of the invention, unless otherwise defined. For example, embodiments directed to products are also applicable to corresponding features of methods and uses.

[0125] In the following passages, different aspects or embodiments of the invention are defined in more detail. Each aspect or embodiment so defined may be combined with any other aspect(s) or embodiment(s) unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

[0126] Reference throughout this specification to “one embodiment”, “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to a person skilled in the art from this disclosure, in one or more embodiments. Furthermore, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments, as would be understood by those in the art. For example, in the appended claims, alternative combinations of claimed embodiments are encompassed, as would be understood by those in the art.

[0127] The present invention overcomes multiple problems and difficulties identified and observed in the state of the art and allows for an improved dosimetry approach for a radioimmunoconjugate (RIC) comprising yttrium-90 (90Y) as radionuclide, such as the90Y-DTPA-Besilesomab RIC.

[0128] “Radioimmunoconjugate” and the abbreviation “RIC” as used herein refers to a molecule member of a group of molecules that have been described at numerous occasions throughout the art and a skilled person therefore appreciated the meaning thereof (e.g. in Nasr et al., Life Sciences, 2022). In its broadest interpretation, a radioimmunoconjugate is a complex formed by linking a radioactive isotope (radionuclide) to an affinity agent, such as a monoclonal antibody. The affinity agent specifically binds to an antigen, while the radioactive isotope delivers targeted radiation to moieties in proximity of said antigen. The particulars of this radiation are radionuclide-specific. Illustrative examples of antigens bound by antibodies in the context of the present disclosure are antigens found on the surface of cancer cells. Radioimmunoconjugates are used in both diagnostic imaging and therapeutic applications, particularly in cancer treatment, where they help to localize and destroy tumor cells while minimizing damage to surrounding healthy tissue. One particular strength of using radioimmunoconjugates for e.g. cancer therapy is that these molecules combine the precision of immunotherapy with the effectiveness of radiation therapy.

[0129] The term “metastable technetium-99 (99mTc) radionuclide-comprising radioimmunoconjugate”, interchangeably indicated by “radioimmunoconjugate comprising technetium-99 (99mTc) as radionuclide” throughout the present specification is known to a person of ordinary skill in the art and indicates a type of radioimmunoconjugate that incorporates the radionuclide technetium-99m (99mTc) attached to an affinity agent such as a monoclonal antibody. “Technetium-99m” and the abbreviation (99mTc)” as used herein refers to a metastable nuclear isomer of technetium-99, which in turn is an isotope of technetium.99mTc emits gamma rays with a photon energy of 140 keV The gamma emission half-life of "mTc is 6.0058 hours. This short half-life allows for scanning procedures which collect data rapidly but keep total patient radiation exposure at acceptable low levels.

[0130] “Yttrium-90” and the abbreviation “(90Y)” as used herein refers to a radioactive isotope of yttrium. 90Y emits beta particles and has a half-life of 64.1 hours and a decay energy of 2.28 MeV with an average beta energy of 0.9336 MeV.

[0131] “Indium-111 and the abbreviation “(U1ln)” as used herein is a radioactive isotope of indium (In) that emits gamma photons and has a half-life of 2.8 days.

[0132] The term “scintigram” (i.e. gamma scan) is used as a generic term covering both 2D imaging (planar scintigraphy) or 3D imaging such as through SPECT or SPECT / CT imaging as explained below.

[0133] The term “planar scintigram” as used herein, also known as planar imaging, involves capturing 2D images of the distribution of a radioactive tracer within the body. A gamma camera detects the gamma rays emitted from the radioactive tracer, which has been administered to the patient. The gamma camera remains stationary, and images are taken from different angles. The resulting images are 2D projections, similar to traditional X-rays. This method provides limited spatial resolution and depth information because it does not account for the depth of the tracer within the body. It is mostly as an initial screening tool.

[0134] As indicated in the background section, gamma rays can be readily imaged using Single-Photon Emission Computed Tomography (abbreviated as “SPECT” or “SPET”). SPECT provides detailed three-dimensional images of organs and tissues by detection of gamma rays emitted from a radionuclide introduced to the body. Crucial components of a SPECT system include, without limitation, a gamma camera to detect gamma photons, a collimator comprising holes which limits the direction the gamma rays may come from that reach the detector, filtering unwanted gamma ray and therefore improving image quality. After detection, computer processing is used to reconstruct three-dimensional images of the subject. Compared to other functional imaging techniques like Positron Emission Tomography (PET), SPECT is more widely available and less expensive, making it accessible for a broad range of diagnostic applications. SPECT is used for detailed and specific diagnostics, providing both functional and anatomical information.

[0135] The term “effective amount” or “therapeutic effective amount” as used herein refers to an amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a subject that is being sought by a researcher, veterinarian, medical doctor or other clinician, which may include a reduction or complete removal of the symptoms associated with the disease or condition being treated. Methods to determine pharmaceutically effective amounts are known in the art and are therefore known to a skilled person. In the context of the present disclosure the effective amount of for example a radioimmunoconjugate comprising yttrium-90 as radionuclide is determined by dosimetry experiment using radioimmunoconjugate comprising as radionuclide metastable technetium-99.

[0136] A skilled person is also familiar with the term “dosimetry” and appreciates that this encompasses measuring, calculating, and assessing the amount of radiation absorbed by matter, in the context of the present disclosure, the amount of radiation absorbed by specific tissues of a living subject such as a human. Dosimetry in the field of medicine is primarily used to determine the radiation dose delivered to said subject. Dosimetry aims to optimize radiation exposure to obtain a desired outcome (e.g. effective and safe diagnosis, treatment, or the combination thereof).

[0137] The term “subject”, “patient”, and “subject in need” may be used interchangeably herein and refer to animals, preferably warm-blooded animals, more preferably vertebrates, and even more preferably mammals specifically including humans and non-human mammals. The term “mammals”, or “mammalian subjects” refers to any animal classified as such and hence include, but are not limited to humans, domestic animals, commercial animals, farm animals, zoo animals, sport animals, pet and experimental animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows; primates such as apes, monkeys, orangutans, and chimpanzees; canids such as dogs and wolves; felids such as cats, lions, and tigers; equids such as horses, donkeys, and zebras; food animals such as cows, pigs, and sheep; ungulates such as deer and giraffes; rodents such as mice, rats, hamsters and guinea pigs; and so on. Preferred patients are human subjects. Particularly preferred are human subjects, including both genders and all age categories thereof. Adult subjects, elder subjects, newborn subjects, and foetuses are intended to be covered by the term “subject.

[0138] Therefore, a first aspect of the invention encompasses the use of a first (dosimetric) radioimmunoconjugate (RIC) comprising as radionuclide metastable technetium-99 (99mTc) for subject-specific dosimetry of an effective amount of a second (therapeutic) RIC comprising yttrium-90 (90Y) as radionuclide. In addition to this use, the corresponding method is also provided by the present invention, namely the method of determining subject specific dosimetry of a an effective amount of a second radioimmunoconjugate (RIC) comprising yttrium-90 (90Y) as radionuclide, comprising:

[0139] - administration to said subject of a first RIC, said first RIC comprising as imaging radionuclide99mTc;

[0140] - recording a planar (2D, e.g. whole-body or thorax) scintigram of the subject; and

[0141] - determining the relative signal intensity of the liver and the relative signal intensity of one or more ribs of the thorax based on said planar scintigram.

[0142] It is evident that in the present context, “administration” may be used interchangeably with terms such as “treating”. The terms “treat” or “treatment” encompass both the therapeutic treatment of an already developed disease or condition, such as the therapy of an already developed pulmonary disease, as well as prophylactic or preventive measures, wherein the aim is to prevent or lessen the chances of incidence of an undesired affliction, such as to prevent occurrence, development and progression of a pulmonary infection. Beneficial or desired clinical results may include, without limitation, alleviation of one or more symptoms or one or more biological markers, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and the like. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0143] As used herein, the terms "therapeutic treatment" or "therapy" and the like, refer to treatments wherein the object is to bring a subjects body or an element thereof from an undesired physiological change or disorder, including but not limited to pulmonary infections, to a desired state, such as a less severe or unpleasant state (e.g., amelioration or palliation), or back to its normal, healthy state (e.g., restoring the health, the physical integrity and the physical well-being of a subject), to keep it (i.e., not worsening) at said undesired physiological change or disorder (e.g., stabilization), or to prevent or slow down progression to a more severe or worse state compared to said undesired physiological change or disorder.

[0144] It is to be appreciated that first (dosimetric) radioimmunoconjugate (RIC) is used to calculate the desired dosimetry the patient should receive and / or of the patient is eligible for the treatment, while the second RIC comprising90Y as radionuclide is the therapeutic RIC, i.e. the RIC that upon administration in an effective amount will generally result in a favourable medical effect in the subject receiving the second (i.e. therapeutic RIC). In certain embodiments, the second RIC is administered to the subject after at least 24 hours, preferably at least 48, more preferably at least 72 hours, most preferably at least 96 hours, or more than 96 hours after administration of the first RIC comprising99mTc as radionuclide (i.e. after the diagnostic imaging step). In some embodiments, said first and second RIC comprises as affinity agent an agent targeting the same molecule in the subject. In preferred embodiments, the first and second RIC comprise as affinity agent the same affinity agent. In highly preferred embodiments, said target molecule is CD66 and the affinity agent is a monoclonal anti-CD66 antibody.

[0145] “Relative signal intensity of x” or short “signal intensity of x” in the context of a scintigram refers to the contrast between an organ or tissue (“x”) which is emitting gamma rays due to the presence of the radioimmunoconjugate and an adjacent area of the body wherein no or essentially no radioimmunoconjugate is present. The skilled person knows, which part of a (e.g. planar) scintigram recorded from (at least part of) a thorax of a patient represents the organs such as the liver and the bone marrow such as the bone marrow in the ribs of the patient. The relative signal intensity in the area of the liver is determined in the part of the scintigram representing the liver. Particularly, the relative signal intensity is determined in a predetermined area size, such as but not limited to 1 cm2, within the part of the scintigram representing the liver. Preferably, the mean relative signal intensity in a predetermined area size, such as but not limited to 1 cm2, within the part of the scintigram representing the liver is determined. The relative signal intensity in the area of at least part of the bone marrow, such as at least one rib, is determined in the part of the scintigram representing the at least part of the bone marrow, such as at least one rib. Particularly, the relative signal intensity is determined in a predetermined area size, such as but not limited to 1 cm2, within the part of the scintigram representing at least part of the bone marrow, such as at least one rib. Preferably, the mean relative signal intensity in a predetermined area size, such as but not limited to 1 cm2, within the part of the scintigram representing the at least part of the bone marrow, such as the at least one rib, is determined. The bone marrow in the thorax can comprise, and preferably consists of, the bone marrow in the ribs, in the thoracic vertebrae, and in the sternum.

[0146] A further aspect of the invention is directed to the use of a first (dosimetric) RIC comprising as radionuclide99mTc for identifying subjects eligible for safe and effective exposure to an effective amount of a second (therapeutic) RIC comprising yttrium-9090Y as radionuclide, by using dosimetry with a "mTc radiolabelled affinity agent. The invention also provides in the corresponding method, namely the method of identifying subjects eligible for safe and effective exposure to an effective amount of a second RIC comprising90Y as radionuclide by dosimetry with a "mTc radiolabelled affinity agent, comprising:

[0147] - administration to said subject of a first RIC, said first RIC comprising as imaging radionuclide99mTc; - recording a planar (whole body or thorax) scintigram of the subject; and

[0148] - determining the relative signal intensity of the liver and the relative signal intensity of one or more ribs of the thorax based on said planar scintigram.

[0149] The findings of the inventors allows for stratifying any subject group into at least two groups: a first group which will benefit, or is considered to benefit, in a safe and effective manner from the second (i.e. therapeutic) RIC at a given dose; and a second group which will not benefit, or is considered to not benefit, in a safe and effective manner from the second (i.e. therapeutic) RIC at said given dose. Such a division allows for patient selection in a straightforward manner. It is further envisaged that the use and method may also allow for stratifying any subject group into at least four groups: a first group which will benefit, or is considered to benefit, in a safe and-effective manner from the second (i.e. therapeutic) RIC at a given dose; a second group which will benefit, or is considered to benefit in a safe yet non-effective manner from the second (i.e. therapeutic) RIC at a given dose; a third group which will benefit, or is considered to benefit, in an unsafe yet effective manner from the second (i.e. therapeutic) RIC at a given dose; and finally a fourth group which will react, or is considered to react, in both an unsafe and ineffective manner to the second (i.e. therapeutic) RIC at the given dose normally used for said first group. Treatment of the second, third, and fourth group may nevertheless be initiated after consideration of further parameters of the subject by a medical practitioner, such as but not limited to age, secondary diseases or disorders, disease progression stage, etc. In said second, third, and fourth group a different dose of the second (i.e. therapeutic) RIC may be advisable.

[0150] In a further aspect of the invention the use of a first (dosimetric) RIC comprising as radionuclide metastable99mTc for determining by dosimetry the inclusion of a subject in a treatment plan, said treatment plan comprising the administration of an effective amount of a second (therapeutic) RIC with90Y as radionuclide. The invention also provides in the corresponding method, namely the method of determining the inclusion of a subject in a treatment plan, said treatment plan comprising the administration of an effective amount of a second (therapeutic) RIC comprising90Y as radionuclide, comprising:

[0151] - administration to said subject of a first (dosimetric) RIC, said first RIC comprising as imaging radionuclide metastable99mTc;

[0152] - recording a planar (whole body or thorax) scintigram of the subject; and

[0153] - determining the relative signal intensity of the liver and the relative signal intensity of one or more ribs of the thorax based on said planar scintigram.

[0154] Further particulars of the treatment plan are not limiting for the invention. The treatment plan may hence comprise of a single dose administration of the second (i.e. therapeutic) RIC, or administration of the second RIC at regular time intervals. Optionally, the administration of the second RIC may occur prior to, concomitantly, or after subjecting the subject to another treatment that does not involve a RIC, or even another treatment that does involve a RIC other than the second RIC defined herein. The other treatment may be a surgical procedure. The other treatment may comprise administration of a chemotherapeutic (other than a radioimmunoconjugate). Also not limiting for the invention is the envisaged endpoint of the treatment plan. The treatment plan may thus be a treatment plan having as goal achieving complete remission of a subject but may equally be a treatment plan having as goal prolonging the life span of a subject without the aim of obtaining complete remission.

[0155] Optionally, the amount (or dose) of the therapeutic RIC to be administered to the subject is 45 MBq / kg lean body weight (lbw), although deviation from this amount may occur on a patient-specific basis. Hence, in certain embodiments the amount of the therapeutic RIC to be administered to the subject is more than 45 MBq / kg lean body weight (lbw). Optionally, the amount of the therapeutic RIC to be administered to the subject is between about 37.5 MBq / kg / lbw and about 55 MBq / kg / lbw, preferably between about 45 MBq / kg / lbw and about 50 MBq / kg / lbw.

[0156] In certain embodiments the amount of the therapeutic RIC to be administered to the subject is less than about 45 MBq / kg lean body weight (lbw). Optionally, the amount of the therapeutic RIC to be administered to the subject is between about 30 MBq / kg / lbw and about 37.5 MBq / kg / lbw, preferably between about 33 MBq / kg / lbw and about 37 MBq / kg / lbw.

[0157] These dosages are typical for subjects of the first group as defined herein, i.e. subjects that will benefit from said treatment in a safe and effective manner. For subject of other groups, the dosage may be adapted accordingly.

[0158] For subjects of group 2 for example, subjects that would benefit from the treatment in a safe but non-effective manner, the dosage could be increased with e.g. 20% or up to 55MBq / kg lbw.

[0159] For subjects of group 3 for example, subjects that would benefit from the treatment in a not safe but effective manner, the dosage could be decreased with e.g. 20% or down to 37.5MBq / kg lbw.

[0160] In the aforementioned aspects of the invention, preferably the subject specific dosimetry, the eligibility of the subject for safe and effective exposure to the second (i.e. therapeutic) RIC, or the inclusion of the subject in a treatment plan is determined by comparing the signal intensity of the liver and the signal intensity of one or more ribs of the thorax using a first (dosimetric) RIC targeting the same molecule, preferably wherein a safe dose for the subject results in a higher signal intensity of the one or more ribs of the thorax when compared to the signal intensity of the liver, more preferably wherein a suitable dose results in at least a 1,5: 1 rib to liver signal intensity, most preferably at least a 2:1 rib to liver signal intensity. Typically, said initial dosimetry step is done using a planar (whole body or thorax) scintigraph. A skilled person appreciates that the exact rib to liver signal intensity ratio does not necessary indicates that the targeted bone marrow receives an effective amount of the therapeutic RIC, but that the ratio rather indicates that there will be relatively sufficient accumulation in the bone marrow (as visualised in the rib) without relatively excessive (i.e. unsafe) accumulation in the liver. A ratio of 1: 1 or less than 1 : 1 provides an indication that only relatively sufficient accumulation will be reached in the bone marrow (as visualised in the rib) upon excessive (i.e. unsafe) accumulation in the liver. The therapeutic effectiveness of a certain dose is not directly related to said ratio, but should also be evaluated e.g. on the basis of the bone marrow intensity (as a proxy for the absorbed dose of the bone marrow) as such.

[0161] A preferred method of administration of the first RIC and / or the second RIC, preferably of both the first RIC and the second RIC is intravenous administration. Hence, in certain embodiments described herein the first RIC and second RIC are comprised in a solution optionally including further excipients. Illustrative examples of excipients used for intravenous delivery of the first RIC or second RIC, preferably both the first RIC and the second RIC include sodium dihydrogen phosphate, disodium monohydrogen phosphate, sorbitol, 1, 1, 3, 3-propane tetraphosphonic acid, tetrasodium salt, stannous chloride dihydrate, sodium hydroxide and / or hydrochloric acid. Preferred excipients include sodium dihydrogen phosphate (anhydrous), disodium monohydrogen phosphate (anhydrous), sorbitol E420, 1, 1, 3, 3 -propane tetraphosphonic acid, tetrasodium salt (dihydrate), stannous chloride dihydrate, sodium hydroxide and / or hydrochloric acid. Further suitable excipients include without limitation sodium chloride, lactose, mannitol, polysorbate 80, propylene glycol, benzyl alcohol, citric acid, sodium citrate, glycine, and any combination thereof.

[0162] As a skilled person readily appreciates, different excipients serving different or overlapping functions may be combined in one solution for intravenous administration. Such functional excipient groups include without limitation: Buffering agents: These agents help to maintain the pH of the formulation, which is critical for the stability and activity of the active ingredient. Non-limiting examples include: solubilizing agents, preservatives, stabilizers, viscosity modifiers, tonicity adjusters, complexing agents, antimicrobial preservatives, antioxidants, chelating agents, suspending agents, surfactants, water for injection, solvents, or any combination thereof.

[0163] Optionally, the uses and methods described throughout the present disclosure further comprise a step of determining safety and effectiveness of a treatment plan with90Y-comprising RIC in the subject. Preferably, this determination of safety and effectiveness is based on a scintigram of said subject after receiving a single dose of about 6 to 12 MBq / kg lean body weight (lbw) "mTc radionuclide-comprising RIC (corresponding to between 400 MBq and 800 MBq).

[0164] Preferably, the step comprises the use of a decision tree that is optionally conducted by a computer-implement method. Preferably, the step of determining safety and effectiveness of a treatment plan with90Y-comprising RIC calculated from (i.e. based on) a scintigram of said subject after receiving a single dose of about 400-800 MBq99mTc radionuclide-comprising RIC comprises the following decision tree:

[0165] Upon a calculated90Y liver absorption dose of >15Gy, or a calculated90Y kidney absorption dose of >13 Gy, ora calculated90Y bone marrow absorption dose of >35 Gy arrived at by measuring the99mTc absorption doses and wherein a 20% reduction of RIC does not result in a lowering of said calculated 90Y liver absorption dose to 15Gy or less, said calculated90Y kidney absorption dose to 13Gy or less, and said calculated90Y bone marrow absorption dose to 35Gy or less, the subject is excluded from treatment (these are subjects wherein treatment would not be safe);

[0166] Upon a calculated90Y liver absorption dose of >15Gy, or a calculated90Y kidney absorption dose of >13 Gy, ora calculated90Y bone marrow absorption dose of >35 Gy arrived at by measuring the99mTc absorption doses, and wherein a 20% reduction of RIC does result in a lowering of said calculated 90Y liver absorption dose to 15Gy or less, said calculated90Y kidney absorption dose to 13Gy or less, and said calculated90Y bone marrow absorption dose to 35Gy or less, subject specific treatment dose is recalculated based on the reduction of RIC (these are subjects wherein treatment with 45 MBq / kg / lbw would not be safe, but wherein a safe treatment is achieved by lowering the dose by 20%);

[0167] Upon a calculated90Y liver absorption dose of <15Gy, a calculated90Y kidney absorption dose of <13Gy, and a calculated90Y bone marrow absorption dose of <35Gy arrived at by measuring the99mTc absorption doses, and wherein the calculated90Y bone marrow absorption dose is higher than the calculated90Y liver absorption dose, the subject is eligible for being treated with 45 MBq / kg lean body weight (lbw) yttrium-90 (90Y)-comprising RIC (these are subject wherein treatment is safe and effective);

[0168] Upon a calculated90Y liver absorption dose of <15Gy, a90Y kidney absorption dose of <13Gy, a90Y bone marrow absorption dose of <10Gy arrived at by measuring the99mTc absorption doses, and wherein the bone marrow absorption dose is lower than the liver absorption dose, the subject is excluded from treatment (these are subjects wherein treatment would not be effective and therefore ethically not justifiable);

[0169] Upon a calculated90Y liver absorption dose of about <15Gy, a calculated90Y kidney absorption dose of about <13Gy, a calculated90Y bone marrow absorption dose of between about lOGy and about 15Gy, wherein the calculated90Ybone marrow absorption dose is lower than the calculated90Y liver absorption dose, the subject is further evaluated to determine treatment with about 45 MBq / kg lean body weight (lbw)90Y-comprising RIC.

[0170] Preferably, in the planar scintigram the relative "mTc signal intensity in the area of the liver and the relative signal intensity of one or more ribs are quantified, preferably by computerised means. Preferably, the relative "mTc signal intensity in the area of the liver and the relative99mTc signal intensity of one or more ribs are determined based on the same scintigram. It is preferred that the relative99mTc signal intensity of one or more ribs is quantified from a single scintigram. Alternatively, the relative "mTc signal intensity of one or more ribs may be quantified by averaging the relative intensities from multiple scintigrams. The relative99mTc signal intensity of one or more ribs are preferably those ribs superposing the area of the liver in the thorax. Optionally, the at least one rib can comprise at least one sternal rib, preferably at least one of the first to the 5th sternal rib. The relative "mTc signal intensity of one or more ribs may be the relative99mTc signal intensity of a single rib or the relative "mTc signal intensity of at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24 ribs. Optionally the relative "mTc intensity of the one or more ribs may include the relative99mTc intensity of one or more supernumerary ribs.

[0171] “Computerised means” as used throughout the present disclosure relates to electronic systems, devices, and technologies configured to perform specific tasks, processes, or operations. Optionally, the computerised means used to quantify one or more relative signal intensities is configured to perform additional tasks and processes which may include without limitation data processing, data management, communication means, data presentation means, transaction automation (i.e. the ability to automatically purchase a radioimmunoconjugate upon detecting a particular relative signal intensity or a combination of particular relative signal intensities), automated appoint scheduling, automated decision-making (such as for example by means of artificial intelligence), electronic record keeping, control systems, monitoring systems, and digital authentication.

[0172] A skilled person is aware that the above-mentioned SPECT imaging technique is particularly suited for the uses and methods described herein to assess dosimetry in a subject. A particularly preferred imaging technique is SPECT / CT. SPECT / CT imaging has been described at several occasions throughout the art. SPECT / CT imaging is a hybrid medical imaging technique that combines two imaging techniques: Single Photon Emission Computed Tomography (SPECT) and Computed Tomography (CT). By merging these two technologies, SPECT / CT provides both functional (physiological) and anatomical (structural) information in a single imaging session. The SPECT / CT combination offers several advantages such as a better localisation of the signal due to the addition of the CT image, which is beneficial for deducting precise and accurate teachings from the SPECT data.

[0173] Unless in those uses, methods, or purpose-related99mTc -comprising RICs wherein it is specifically stated or defined otherwise, the uses and methods described throughout the present disclosure may be performed in a context of Multiple Time Point (MTP) dosimetry (such as employing at least 2, at least 3, at least 4, or at least 5 measurements) or Single Time Point (STP) dosimetry. However, STP dosimetry upon use of the herein described RIC comprising99mTc is highly preferred. The terms MTP and STP dosimetry are commonly used in the field of radionuclide imaging and are self-explaining. Amain disadvantage of MTP dosimetry is that it is time and resource consuming since multiple imaging sessions are needed, which is a problem that is overcome in STP dosimetry.

[0174] A further aspect of the invention concerns a method of subject specific STP dosimetry for an90Y-comprising (therapeutic) RIC, comprising

[0175] - administration to said subject of a99mTc -comprising (dosimetric) RIC;

[0176] - recording a planar (whole body or thorax) scintigram of said subject at a single point in time; and

[0177] - determining the relative signal intensity in the area of the liver and the relative signal intensity in the area of at least part of the bone marrow in the thorax based on said planar scintigram.

[0178] Alternatively worded the above aspect evidently also encompasses a99mTc-comprising RIC, for use in a method of subject-specific STP dosimetry for an90Y-comprising RIC, comprising

[0179] - administration to said subject of a99mTc -comprising RIC;

[0180] - recording a planar (whole body or thorax) scintigram of the subject at a single point in time; and

[0181] - determining the relative signal intensity in the area of the liver and the relative signal intensity in the area of at least part of the bone marrow in the thorax based on said planar scintigram.

[0182] The single point in time of recording the scintigram is not particularly limiting for the invention and may be any point in time after injection of the99mTc-comprising RIC wherein activity of said RIC is still visible (i.e. detectable) and preferably can still be quantified. Hence, optionally the scintigram is recorded between about 2 hours and about 48 hours after use or administration, preferably between about 4 hours and about 36 hours, preferably between about 6 hours and about 36 hours, preferably between about 8 hours and 36 hours, preferably between about 10 hours and 36 hours, more preferably between about 12 and about 36 hours after use or administration, more preferably between about 12 and 24 hours after use or administration, most preferably after about 24 hours after use or administration. In a preferred embodiment, the STP dosimetry is determined between about 6 hours and about 8 hours after administration of the99mTc -comprising RIC.

[0183] The scintigrams referred to in the present context, particularly but not limited to those embodiments encompassing STP dosimetry, are preferably planar scintigrams, more preferably anterior or posterior scintigrams, or both an anterior and posterior scintigram. The advantage of using a planar scintigram for the uses and methods described herein is facilitation of data interpretation, such as data interpretation by computerised means, “anterior” and "posterior" in the technical field of medicinal imaging are commonly used terms and refer respectively to a frontal view of the body with the imaging device capturing the body from the from directed towards the thorax and / or face, and a back view of the body with the imaging device capturing the body from the back directed towards the spine.

[0184] The STP methodology developed by the inventors is characterised by a good correlation to MTP approaches for a given RIC. In certain embodiments, the result of the STP dosimetry calculation is within about 20% of the MTP dosimetry calculation, preferably within about 15% of the MTP dosimetry calculation, preferably within about 10% of the MTP dosimetry calculation, preferably within about 5% of the MTP dosimetry calculation. In preferred embodiments, the result of the STP dosimetry calculation is within about 20% of the MTP for bone marrow and / or liver, preferably within about 15% of the MTP for bone marrow and / or liver, preferably within about 10% of the MTP for bone marrow and / or liver, preferably within about 5% of the MTP for bone marrow and / or liver. Unexpectedly, the decision to treat or not to treat a patient is close to 100% if results fromU1ln MTP are compared with those of "mTc STP.

[0185] Yet further aspects of the invention relates to the use of a radioimmunoconjugate (RIC) comprising a99mTc radionuclide as a dosimetry agent for an90Y-comprising RIC and the use of a metastable99mTc radionuclidecomprising RIC as pretherapeutic dosimetric patient selection agent for an90Y-comprising RIC.

[0186] Another aspect of the invention is directed to a computer-implemented method for determining subject specific treatment conditions of a90Y-comprising RIC, the method comprising:

[0187] A step of receiving input from either a user or the imaging device used for obtaining a planar scintigram of the thorax of said subject "mTc absorption doses for liver, kidney, and bone marrow after said subject received a single dose of 400-800 MBq / patient metastable technetium-99 (99mTc) radionuclide-comprising RIC;

[0188] A step of calculating from (i.e. based on) the "mTc absorption doses the 90Y absorption doses for liver, kidney, and bone marrow;

[0189] A decision making step, said decision making step adhering to the following logic: o Upon a calculated90Y liver absorption dose of >15Gy, or a calculated90Y kidney absorption dose of >13Gy, or a calculated90Y bone marrow absorption dose of >35Gy arrived at by measuring the "mTc absorption doses and wherein a 20% reduction of RIC does not result in a lowering of said calculated90Y liver absorption dose to 15Gy or less, said calculated 90Y kidney absorption dose to 13Gy or less, and said calculated90Ybone marrow absorption dose to 35Gy or less, the subject is excluded from treatment; o Upon a calculated90Y liver absorption dose of >15Gy, or a calculated90Y kidney absorption dose of >13Gy, or a calculated90Y bone marrow absorption dose of >35Gy arrived at by measuring the99mTc absorption doses, and wherein a 20% reduction of RIC does result in a lowering of said calculated90Y liver absorption dose to 15Gy or less, said calculated90Y kidney absorption dose to 13Gy or less, and said calculated90Y bone marrow absorption dose to 35Gy or less, subject specific treatment dose is recalculated based on the reduction ofRIC; o Upon a calculated90Y liver absorption dose of <15Gy, a calculated90Y kidney absorption dose of <13Gy, and a calculated90Y bone marrow absorption dose of <35Gy arrived at by measuring the "mTc absorption doses, and wherein the calculated90Y bone marrow absorption dose is higher than the calculated90Y liver absorption dose, the subject is eligible for being treated with 45 MBq / kg lean body weight (lbw) yttrium-90 (90Y)-comprising RIC; o Upon a calculated90Y liver absorption dose of <15Gy, a90Y kidney absorption dose of <13Gy, and a90Y bone marrow absorption dose of <10Gy arrived at by measuring the99mTc absorption doses, and wherein the bone marrow absorption dose is lower than the liver absorption dose, the subject is excluded from treatment;

[0190] A step of providing output wherein the decision is provided to a user or stored on a computer- readable storage medium; and optionally

[0191] A step wherein a user applies the decision to a subject.

[0192] The method described above has as consequence (i.e. effect) that less subjects are treated in an unsafe and / or ineffective manner with 45 MBq / kg lean body weight (lbw) yttrium-90 (90Y)-comprising RIC.

[0193] The particulars of the user recited in the optionally step of the method is not particularly limiting for the invention and may be any person, preferably a healthcare professional such as a medical doctor, a medical assistant, or a nurse.

[0194] As indicated above, the selection criteria may be adapted or optimized for certain sub groups of subject such as but not limited to sub groups defined by age, gender, ethnicity, underlying health problems, disease progression stage, etc.

[0195] In certain embodiments, more relaxed parameters can be used, depending on subject specific parameters including but not limited to disease progression and expected life span without any treatment. For example, upon calculating a90Y liver absorption dose of about >16Gy, about >17Gy, about >18Gy, about >19Gy, about >20Gy, or a90Y kidney absorption dose of about >14Gy, about >15Gy, about >16Gy, about >17Gy, about >18Gy, about >19Gy, about >20Gy, or a90Y bone marrow absorption dose of about >36Gy, about >37Gy, about >38Gy, about >39Gy, about >40Gy, and wherein a 20% reduction of RIC does not result in a lowering of said liver absorption dose to the accepted absorption doses for liver, kidney, and bone marrow, the subject may be excluded from treatment. For example, upon calculating a90Y liver absorption dose of about >16Gy, about >17Gy, about >18Gy, about >19Gy, about >20Gy, or a90Y kidney absorption dose of about >14Gy, about >15Gy, about >16Gy, about >17Gy, about >18Gy, about >19Gy, about >20Gy, or a90Y bone marrow absorption dose of about >36Gy, about >37Gy, about >38Gy, about >39Gy, about >40Gy, and wherein a 20% reduction ofRIC does result in a lowering of said liver absorption dose to accepted absorption doses for liver, kidney, and bone marrow, subject specific treatment dose may be recalculated based on the reduction of RIC. For example, upon calculating a90Y liver absorption dose of about <14Gy, about <13Gy, about <12Gy, about <HGy, about <10Gy, a90Y kidney absorption dose of about <12Gy, about <HGy, about <10Gy, a90Y bone marrow absorption dose of about <9Gy, about <8Gy, about <7Gy, about <6Gy, about <5Gy, and wherein the90Y bone marrow absorption dose is lower than the90Y liver absorption dose, the subject may be excluded from treatment;

[0196] Alternatively or in combination with the above, the method may also employ more stringent parameters depending on subject specific parameters including but not limited to the subject being an infant. For example, upon calculating a90Y liver absorption dose of about <14Gy, about <13Gy, about <12Gy, about <HGy, about <10Gy, a90Y kidney absorption dose of about <12Gy, about <1 IGy, about <10Gy, about <9Gy, about <8Gy, a90Y bone marrow absorption dose of about <34Gy, about <33Gy, about <32Gy, about <3 IGy, about <30Gy, and wherein the90Y bone marrow absorption dose is higher than the90Y liver absorption dose, the subject may be eligible for being treated with about 45 MBq / kg lean body weight (lbw) yttrium-90 (90Y)-comprising RIC.

[0197] Yet alternatively or in combination with the above the limits defining a status wherein further evaluation of the subject is required to determine whether to treat said subject with about 45 MBq / kg lean body weight (lbw)90Y- comprising RIC can be either relaxed or made more stringent. For example, calculating a90Y liver absorption dose of about <14Gy, about <13Gy, about <12Gy, about <HGy, about <10Gy, a90Y kidney absorption dose of about <12Gy, about <HGy, about <10Gy, a90Y bone marrow absorption dose of between about 9Gy and about 14Gy, between about 8Gy and about 13Gy, between about 7Gy and about 12Gy, wherein the90Ybone marrow absorption dose is lower than the90Y liver absorption dose, the subject may be further evaluated to determine treatment with about 45 MBq / kg lean body weight (lbw)90Y-comprising RIC. As an alternative example, calculating a90Y liver absorption dose of about <16Gy, about <17Gy, about <18Gy, about <19Gy, about <20Gy, a90Y kidney absorption dose of about <14Gy, about <15Gy, a90Y bone marrow absorption dose of between about 1 IGy and about 16Gy, between about 12Gy and about 17Gy, between about 13Gy and about 18Gy, between about 14Gy and about 19Gy, between about 15Gy and about 20Gy, wherein the90Y bone marrow absorption dose is lower than the90Y liver absorption dose, the subject may be further evaluated to determine treatment with about 45 MBq / kg lean body weight (lbw)90Y-comprising RIC.

[0198] Further envisaged is a computer system configured for performing, or assisting in performing, any of the herein described uses and methods. Yet further envisaged is a computer program product comprising instructions which when the program is executed by a computer, cause the computer to carry out the herein described uses and methods. It is envisaged that any computer system or any computer-implemented method relying on a computer system described herein may further comprise means of machine learning and / or artificial intelligence of said system to enable and / or improve its functionality. Non-limiting examples of machine learning models, i.e. machine learning algorithms include linear regression, logistic regression, decision trees, support vector machines, naive Bayes, k-nearest neighbors (kNN), k-means, random forest, dimensionality reduction algorithms, and gradient boosting algorithms such as gradient boosting machine (GBM), XGBoost, LightGBM, and CatBoost. The use of artificial intelligence for analysis of scintigrams has been reported in the art and is therefore known to a skilled person (e.g., Hajianfar et al., Zeitschrift fur Medizinische Physik, 2024). Software tools for automatization of analysis have also been described in the art, even for99mTc scintigraphy (e.g., Yoshida et al., Clinical Imaging, 2021). A skilled person is therefore aware of these tools and technologies and appreciates the benefits they may entail. In certain embodiments, the computer readable data is encrypted and requires authentication or authorization credentials from a user or second computer-readable storage system for a computer system to be able to access said data. Hence, the present invention also envisages computer-readable storage media comprising a data storage material encoded with computer readable data wherein said data comprise one or more scintigrams of a subject, or optionally one or more scintigrams of multiple subjects, after receiving a single dose of 400-800 MBq "mTc radionuclide-comprising RIC configured to perform the computer-implemented uses and methods described throughout the present disclosure. In certain embodiments, the computer-readable storage medium is a physical storage medium. In alternative embodiments, the computer-readable storage medium is a non-physical storage medium or a storage medium perceived to be a non-physical storage medium (i.e. a cloud based storage medium). Optionally, the computer readable data comprise information relating to the intensities of certain areas of interest of the one or more scintigrams, such as but not limited to the intensity of liver, bone-marrow, and / or kidneys.

[0199] In another aspect of the invention, a computer-implemented method is envisaged to determine a sub-population of subjects that can be safely and effectively treated for a disease or disorder by 45 MBq / kg lean body weight (lbw) of a yttrium-90 (90Y)-comprising radioimmunoconjugate (RIC), said method comprising:

[0200] A step of receiving input from either a user or the imaging device used for obtaining a planar scintigram of the thorax of said subjects99mTc absorption doses for liver, kidney, and bone marrow after said subject received a single dose of 400-800 MBq / patient metastable technetium-99 (99mTc) radionuclide-comprising RIC;

[0201] A step of calculating from (i.e. based on) the "mTc absorption doses the 90Y absorption doses for liver, kidney, and bone marrow;

[0202] A decision making step wherein subjects are considered to be safely and effectively treated are characterised upon a calculated90Y liver absorption dose of <15Gy, a calculated90Y kidney absorption dose of <13Gy, a calculated90Y bone marrow absorption dose of <35Gy is obtained, and wherein the bone marrow absorption dose is higher than the liver absorption dose; and

[0203] A step of providing output wherein the decision is provided to a user or stored on a computer- readable storage medium; and optionally

[0204] A step wherein a user applies the decision to a subject.

[0205] Optionally, the computer-implemented method is conducted on a database of earlier recorded scintigrams of one or more subjects stored on a computer-readable storage medium. In further embodiments, the computer- implemented method is configured to display, record, print, and / or store the outcome of said determination. In yet further embodiments, for subjects characterized by absorption doses and optional other parameters resulting in an exclusion of said subjects from the subpopulation of subjects that can be safely and effectively treated with 45 MBq / kg lean body weight (lbw) of a90Y-comprising RIC the computer-implement method is configured to display, record, print, and / or store further particulars of the investigated subject or indicate risk factors for the investigated subject.

[0206] In all of the aspects and embodiments described herein, unless defined otherwise, the RIC can comprise as affinity agent a CD66-binding component. In aspects and / or embodiments wherein two different RICs are used, both RICs preferably have a CD66-binding component and more preferably both RICs have the same CD66-binding component. Most preferably, in embodiments wherein both a90Y radionuclide-comprising RIC and a "mTc radionuclide-comprising RIC are referenced said RICs have identical specificity but carry different isotopes (e.g. 9°Y or99mTc).

[0207] “CD66” as used herein refers to a human cluster of differentiation also known as the Carcinoembryonic Antigen- related Cell Adhesion Molecules (“CEACAMs”) family. More particularly, CD66 subtypes include without limitation CD66a (CEACAM1), CD66b (CEACAM8), CD66c (CEACAM6), CD66d (CEACAM3), and CD66e (CEACAM5). As has been described in the art, CD66 proteins are expressed on the surface of certain cell types such as haematopoietic cells, with isoforms of CD66a, CD66b, and CD66c present on cells of myeloid origin from promyelocytes through to mature neutrophils. CD66 proteins are also expressed by leukaemic blasts in a considerable percentage of patients with acute myeloid leukemia and in a high percentage of patients with B cell acute lymphoblastic leukaemia. CD66ais expressed on plasma cells in the majority of cases of myeloma (Orchard et al., Bone Marrow Transplantation, 2024).

[0208] The particular characteristics of the CD66-binding component are not particularly limiting for the invention. Preferably, the CD66-binding component is a protein. The term “protein” as used throughout this specification generally encompasses macromolecules comprising one or more polypeptide chains, i.e., polymeric chains of amino acid residues linked by peptide bonds. As used herein, the term may encompass naturally, recombinantly, semi-synthetically or synthetically produced proteins.

[0209] In preferred embodiments, the CD66-binding component is a polypeptide comprising at least one antibodybinding domain, and may therefore be for example an antibody, a mouse antibody, a chimeric antibody, a humanized antibody, or a recombinant antibody, an antibody fragment, an antibody-like protein scaffold. In alternative embodiments, the CD66-binding component is an antibody mimetic, illustrative examples thereof include without limitation an alphabody, a Designed Ankyrin Repeat Protein (DARPin), a monobody, an affibody, an anticalin, an avimer, a versabody , a duocalin.

[0210] A skilled person appreciates that with the term “CD66-binding component” is intended a component that is characterised by the ability to specifically bind to CD66, and is therefore aware that terms “recognizing” and “targeting” can be interchangeably used with “binding” or “hybridizing to” in this context. The term “specifically” in the context of “binding”, “hybridizing to” or “targeting” implies that the CD66-binding component is developed to bind to or target a CD66 protein without substantially binding or hybridizing to another protein. In highly preferred embodiments, the CD66-binding component is an antibody classified to be an anti-granulocyte monoclonal antibody.

[0211] The term “antibody” is used herein in its broadest interpretation and thus generally refers to any immunologic binding agent, such as a whole antibody or antibody fragments, including without limitation a mouse, chimeric, humanised, human, recombinant, transgenic, grafted and single chain antibody, and the like, or any fusion proteins, conjugates, fragments, or derivatives thereof that contain one or more domains that selectively bind to an antigen of interest. The term antibody thereby includes a whole immunoglobulin molecule, a monoclonal antibody, a chimeric antibody, a humanised antibody, a human antibody, or an immunologically effective fragment of any of these. The term “antibody” is not only inclusive of antibodies generated by methods comprising immunisation, but also includes any polypeptide, e.g. a recombinantly expressed polypeptide, which is made to encompass at least one complementarity -determining region (CDR) capable of specifically binding to an epitope on an antigen of interest, in the context of the present disclosure an epitope of the CD66 target. The term antibody includes antibodies originating from or comprising one or more portions derived from any animal species, preferably vertebrate species, including, e.g. birds and mammals. Without limitation, the antibodies may be chicken, turkey, goose, duck, guinea fowl, quail or pheasant. Also without limitation, the antibodies may be human, murine (e.g. mouse, rat, etc.), porcine, donkey, rabbit, goat, sheep, guinea pig, monkey (e.g. cynomolus monkeys), camel (e.g. Camelus bactrianus and Camelus dromaderius) also including camel heavy-chain antibodies, llama (e.g. Lama paccos, Lama glama or Lama vicugna) also including llama heavy-chain antibodies, or horse.

[0212] Also specifically envisaged herein are “chimeric antibodies” which originate from at least two animal species. More specifically, the term “chimeric antibody” or “chimeric antibodies” refers to antibodies which comprise heavy and light chain variable region sequences from one species and constant region sequences from another species, such as for example antibodies having murine heavy and light chain variable regions linked to human, non-human primate, canine, equine, or feline constant regions. Chimeric antibodies comprise a portion of the heavy and / or light chain that is identical to or homologous with corresponding sequences from antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical to or homologous with corresponding sequences in antibodies from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, exhibiting the desired biological activity (Morrison et al., PNAS USA, 1984).

[0213] A skilled person readily appreciates that a full-length antibody as it exists naturally is an immunoglobulin molecule comprising 2 heavy (H) chains and 2 light (L) chains interconnected by disulfide bonds. The amino terminal portion of each chain includes a variable region of about 100-110 amino acids primarily responsible for antigen recognition via the complementarity determining regions (CDRs) contained therein. Light chains are classified as kappa or lambda, and are characterised by a particular constant region as known in the art is therefore envisaged in the present context. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, and define the isotype of an antibody as IgG, IgM, IgA, IgD, or IgE, respectively. IgG antibodies can be further divided into subclasses, e.g. IgGl, IgG2, IgG3, IgG4. Each heavy chain type is characterised by a particular constant region with a sequence well known in the art and is therefore envisaged in the present context. In certain embodiments, the CD66-binding component is an antibody selected from the group consisting of: IgA, IgD, IgE, IgG and IgM antibodies. In preferred embodiments the anti-CD66 antibody may be a monoclonal antibody or a mixture of monoclonal antibodies. Monoclonal antibodies can target a particular antigen or a particular epitope within an antigen with greater selectivity and reproducibility.

[0214] As used herein, the term “monoclonal antibody” refers to an antibody that is derived from a single copy or clone including, for example, any eukaryotic, prokaryotic, or phage clone, and does not refer to the method by which it is produced. Monoclonal antibodies and antigen-binding fragments thereof of the present invention can be produced, for example, by recombinant technologies, phage display technologies, synthetic technologies, e.g. CDR-grafting, or combinations of such technologies, or other technologies known in the art. By means of example and not limitation, monoclonal antibodies may be made by the hybridoma method (initially described by Kohler et al. Nature, 1975), or may be made by recombinant DNA methods. Monoclonal antibodies may also be made using phage antibody libraries (Clackson et al., Nature, 1991).

[0215] The term “antibody fragment” or “antigen -binding moiety” comprises a portion or region of a full length antibody, generally the antigen binding or variable domain thereof. Examples of antibody fragments include Fab, Fab', F(ab)2, Fv , scFv fragments, single domain (sd)Fv, such as VH domains , VL domains and VHH domains, diabodies, linear antibodies, single-chain antibody molecules, in particular heavy-chain antibodies; and multivalent and / or multispecific antibodies formed from antibody fragment(s), e.g. diabodies, tribodies, and multibodies. The above designations Fab, Fab', F(ab')2, Fv, scFv etc. are intended to have their art-established meaning. The term “antigen-binding portion” or “antigen-binding region” refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen.

[0216] Examples of binding fragments encompassed within the term “antigen-binding portion” of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., Nature, 1989); which comprises a single variable domain; and (vi) an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they may be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv) (Bird et al., Science, 1988). Such single chain antibodies are also intended to be encompassed within the term “antigen-binding portion” of an antibody.

[0217] In certain embodiments wherein the CD66-binding component is an antibody fragment, the CD66-binding component may be a Nanobody. The term “Nanobody” is well-known in the art and as used herein in its broadest sense encompasses an immunological binding agent obtained (1) by isolating the VHH domain of a naturally occurring heavy -chain antibody, preferably a heavy -chain antibody derived from camelids; (2) by expression of a nucleotide sequence encoding a naturally occurring VHH domain; (3) by "humanisation" of a naturally occurring VHH domain or by expression of a nucleic acid encoding a such humanised VHH domain; (4) by "camelisation" of a naturally occurring VH domain from any animal species, and in particular from a mammalian species, such as from a human being, or by expression of a nucleic acid encoding such a camelised VH domain; (5) by "camelisation" of a "domain antibody" or "dAb" as described in the art, or by expression of a nucleic acid encoding such a camelised dAb; (6) by using synthetic or semi-synthetic techniques for preparing proteins, polypeptides or other amino acid sequences known per se; (7) by preparing a nucleic acid encoding a Nanobody using techniques for nucleic acid synthesis known per se, followed by expression of the nucleic acid thus obtained; and / or (8) by any combination of one or more of the foregoing.

[0218] In accordance with the terminology commonly employed in the art, the variable domains present in naturally occurring heavy chain antibodies will also be referred to as “VHH domains”, in order to distinguish them from the heavy chain variable domains that are present in conventional 4-chain antibodies (which will be referred to herein as “VH domains”) and from the light chain variable domains that are present in conventional 4-chain antibodies (which will be referred to herein as “VL domains”). As mentioned in the prior art referred to above, VHH domains have a number of unique structural characteristics and functional properties which make isolated VHH domains (as well as Nanobodies based thereon, which share these structural characteristics and functional properties with the naturally occurring VHH domains) and proteins containing the same highly advantageous for use as functional antigen-binding domains or proteins. In particular, and without being limited thereto, VHH domains (which have been “designed” by nature to functionally bind to an antigen without the presence of, and without any interaction with, a light chain variable domain) and Nanobodies can function as a single, relatively small, functional antigen-binding structural unit, domain or protein. This distinguishes the VHH domains from the VH and VL domains of conventional 4-chain antibodies, which by themselves are generally not suited for practical application as single antigen-binding proteins or domains, but need to be combined in some form or another to provide a functional antigen-binding unit (as in for example conventional antibody fragments such as Fab fragments; in ScFv's fragments, which consist of a VH domain covalently linked to a VL domain).

[0219] In accordance with the state of the art a skilled person appreciates how the term “humanised antibody” should be interpreted and understands that these are antibodies derived from non-human species whose protein sequence have been modified so as to increase their similarity to antibodies produced naturally in humans. More particularly, the term “humanised antibody” refers to antibodies which comprise heavy and light chain variable region sequences from a non -human species (e.g. a mouse) but in which at least a portion of the VH and / or VL sequence has been altered to be more “human-like”, i.e. more similar to human germline variable sequences. The humanised antibody is an antibody or a variant, derivative, analogue or fragment thereof which immunospecifically binds to an antigen of interest and which comprises a framework (FR) region having substantially the amino acid sequence of a human antibody and a complementary determining region (CDR) having substantially the amino acid sequence of a non-human antibody. By means of illustration and not limitation, humanised antibodies may be derived from conventional antibodies (i.e. an immunoglobulin molecule comprising 2 heavy (H) chains and 2 light (L) chains interconnected by disulfide bonds) from the family Camelidae, in particular from the llama (e.g. Lama paccos, Lama glama or Lama vicugna), whose variable domains exhibit a high degree of amino acid sequence identity with the variable domains of human antibodies.

[0220] Preferably, the CD66-binding component is an antibody such as a monoclonal anti-CD66 antibody, that selectively binds to any combination of CD66a, CD66b, CD66c and CD66e. In certain embodiments, the anti-CD66 antibody specifically binds to only one CD66 selected from the group consisting of: CD66a, CD66b and CD66c. In certain embodiments, the anti-CD66 antibody specifically binds to only two or only three CD66 selected from the group consisting of: CD66a, CD66b, CD66c and CD66e. In preferred embodiments the monoclonal anti-CD66 antibody selectively binds to CD66b or CD66e.

[0221] In highly preferred embodiments the monoclonal anti-CD66 antibody is the antibody is besilesomab (INN name), alternatively identified by its chemical name “monoclonal antibody BW 250 / 183”, its laboratory code name “MAb BW 250 / 183” or its CAS Registry Number “537694-98-7”. Besilesomab is readily available by obtaining the kit “Scintimun®”. Murine, humanized and recombinant forms of this antibody are described in EP-A-0 388 914, EP- A-0 585 570 and EP-A-0 972 528, which are herein incorporated by reference.

[0222] Also envisaged by the present invention are CD66-binding domains that are fusion polypeptides comprising at least one antibody-binding domain and a further domain, e.g. an effector domain, such as an enzyme or cytokine. Preferably, the90Y radionuclide is linked to the CD66-binding component via a structure of the formula

[0223] [(chelating agent)-(Rl)p-(R2-R3)n]m-(CD66-binding component) wherein n is 0 or 1, m is 1 to 15, p is 0 or 1,

[0224] R1 and R3 are independently selected from the group consisting of -NH-CS-NH-, -NHCONH-, -NHCOCH2S-, -S-S-, -NH-NH-, -NH-, -S-, -CONHNH-, -SCH2CH2COONH-, -SCH2CH2SO2-, -SCH2CH2SO2NH-, -CONH-, -O-CH2CH2O-, -CO-, -COO-, -NH-O-, -CONHO-, -S-(CH2)3C(NH)NH-, -NH-COO-, -O- and preferably -NHCSNH-, and R2 is selected from the group consisting of Cl -Cl 8 alkylen, branched Cl -Cl 8, - CH2-C6H10-, p-alkylphenylene, p-phenylene, m-phenylene, p-alkyloxyphenylene, naphthylene, - [CH2CH2O]x-, -[CH2CH2SOCH2CH2]x-,

[0225] -[CH2CH2SO2CH2CH2]x-, or -[NHCHR4CO]y-, wherein x is 1 to 200, y is 1 to 20, and wherein R4 is selected from the group consisting of H-, Me-, HSCH2-, isopropyl, but-2-yl, CH3SCH2CH2-, benzyl, lH-indol-3-yl- methyl, HOCH2-, HOOCCH2-, CH3CH(OH)-, HOOCCH2CH2-, 4-hydroxybenzyl, H2NCOCH2-, H2NCOCH2CH2-, 4-aminobut-l-yl, 2-guanidinoethyl, lH-imidazol-5-yl-methyl and 2-methylprop-l-yl.

[0226] For example, the chelating agent may be selected from the group consisting of diethylenetriaminepentaacetic acid (DTPA), l,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), 1,4,8,11- tetraazacyclotetradecane-N,N',N'',N'' '-tetraacetic acid (TETA), 1, 4, 7-triazonane-N,N',N' '-triacetic acid (NOTA), 2,2’-(2-(((lS,2S)-2-(bis(carboxymethyl)amino)cyclohexyl)- (carboxymethyl)amino)ethylazanediyl)diacetic acid (cyclohexano-DTPA), 2,2’-(2-(((lR,2R)-2- (bis(carboxymethyl)amino)cyclohexyl)-(carboxymethyl)amino)ethylazanediyl)diacetic acid, 2,2’-(2-(((lS,2R)- 2-(bis(carboxymethyl)amino)cyclohexyl)-(carboxymethyl)amino)ethylazanediyl)diacetic acid, 2,2’-(2- (((lR,2S)-2-(bis(carboxymethyl)amino)cyclohexyl)-(carboxymethyl)amino)ethylazanediyl)diacetic acid, 2,2',2",2"'-(2,2'-(lS,2S)-cyclohexane-l,2-diylbis((carboxymethyl)azanediyl)bis(ethane-2,l- diyl))bis(azanetriyl)tetraacetic acid, 2,2',2",2"'-(2,2'-(lS,2R)-cyclohexane-l,2- diylbis((carboxymethyl)azanediyl)bis(ethane-2, l-diyl))bis(azanetriyl)tetraacetic acid, (IR)-l-benzyl- diethylenetriaminepentaacetic acid, (1S)-1 -benzyl-diethylenetriaminepentaacetic acid, (2R)-2 -benzyl- diethylenetriaminepentaacetic acid, (2S)-2-benzyl-diethylenetriaminepentaacetic acid, (2R)-2-benzyl-(3R)-3- methyl-DTPA, (2R)-2-benzyl-(3S)-3 -methyl-DTPA, (2S)-2-benzyl-(3S)-3-methyl-DTPA, (2S)-2-benzyl-(3R)-3- methyl-DTPA, (2R)-2-benzyl-(4R)-4-methyl-DTPA, (2R)-2-benzyl-(4S)-4-methyl-DTPA, (2S)-2-benzyl-(4S)-4- methyl-DTPA, (2S)-2-benzyl-(4R)-4-methyl-DTPA, (lR)-l-benzyl-(3R)-3-methyl-DTPA, (lR)-l-benzyl-(3S)-

[0227] 3 -methyl-DTPA, (lS)-l-benzyl-(3S)-3-methyl-DTPA, (lS)-l-benzyl-(3R)-3-methyl-DTPA, (lR)-l-benzyl-(4R)-

[0228] 4-methyl-DTPA, (lR)-l-benzyl-(4S)-4-methyl-DTPA, (lS)-l-benzyl-(4S)-4-methyl-DTPA, (lS)-l-benzyl-(4R)- 4-methyl-DTPA, 2,2'-((lR,2R)-2-(((R)-2-(bis(carboxymethyl)amino)-3- phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2'-((lS,2S)-2-(((S)-2- (bis(carboxymethyl)amino)-3 -phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2'- ((lR,2R)-2-(((S)-2-(bis(carboxymethyl)amino)-3- phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2'-((lS,2S)-2-(((R)-2- (bis(carboxymethyl)amino)-3 -phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2'- ((lR,2S)-2-(((R)-2-(bis(carboxymethyl)amino)-3- phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2'-((lS,2R)-2-(((S)-2- (bis(carboxymethyl)amino)-3 -phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2'- ((lS,2R)-2-(((R)-2-(bis(carboxymethyl)amino)-3- phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2'-((lR,2S)-2-(((S)-2- (bis(carboxymethyl)amino)-3-phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, (2S)-2- benzyl-l,4,7,10-tetraazacyclododecane-N,N',N”,N” '-tetraacetic acid, (2R)-2-benzyl-l,4,7,10- tetraazacy clododecane-N,N ' ,N ' ' ,N ' ' ' -tetraacetic acid, 6-benzy 1- 1,4,8,11 -tetraazacyclotetradecane- N,N',N'',N” '-tetraacetic acid, 2-benzyl-l, 4, 7-triazonane-N,N',N' '-triacetic acid, benzy 1-3 -methyl- diethylenetriaminepentaacetic acid (2B3M-DTPA), (R)-2-amino-3 -(phenyl)propyl)trans-(S, S)-cyclohexane- 1 ,2- diamine-pentaacetic acid) (Bn-CHX-A”-DTPA, also designated as CHX-A”-DTPA) and salts and derivatives thereof, particularly (R)-2-amino-3-(phenyl)propyl)trans-(S,S)-cyclohexane-l,2-diamine-pentaacetic acid) (Bn- CHX-A”-DTPA, also designated as CHX-A”-DTPA) and salts thereof.

[0229] Particularly, the 99mTc radionuclide is linked to the CD66-binding component via the structure CD66-binding component-NH-CS-NH-Bn-CHX-A”-DTPA:

[0230]

[0231] In another preferred embodiment, the90Yradionuclide is linked to the CD66-binding component by covalent linkage.

[0232] Particularly, the99mTc radionuclide and the CD66-binding component can be linked by reduction / oxidation chemistry, such as using DTT (dithiothreitol) and PTP (propane tetraphosphonate). A skilled person is aware of methods to link 99mTc to antibodies such as the anti-CD66 antibody besilesomab which have been published in the art (e.g. in patent publication FI92075 (B) “Method for the preparation of a technetium-99m-labelled organspecific substance” incorporated herein by reference). Preferably the "mTc is preferably linked to the CD66- binding component by a method comprising using ZnCF as reduction agent, PTP as stabilization agent, and pertechnetate as "mTc source that is attached to reduced hinge region SH bonds.

[0233] A (partial) reduction of the S-S bonds of the antibody such as an anti-CD66 antibody such as besilesomab can be achieved by short-term exposure to mild reducing agents This produces reactive antibody molecules that have neither lost their immunological reactivity nor been fragmented into smaller fragments. In principle, all reducing agents are suitable for the partial reduction of the antibody or the F(ab')2 antibody fragment, which cleave only a part of the S-S bonds even after a longer exposure time and do not lead to fragmentation of the antibody component. In general, after only 10 to 30 minutes, enough SH groups have been formed to bind sufficient amounts of technetium-99m cations.

[0234] Preferably, the imaging RIC is metastable technetium-99 (99mTc) linked to the CD66-binding component BW250 / 183, in the following also designated as99mTc -Besilesomab (also known as Scintimun®) covalently linked to the CD66-binding component by reduction / oxidation chemistry using DTT (Dithiothreitol), PTP (propane tetraphosphonate) and pertechnatate as described in the manufacturer’s description. In brief, besilesomab is reduced using DTT and with the help of PTP and pertechnatate solution99mTc is incorporated in the hinge region of besilesomab, which is oxidized. Preferably,99mTc is bound to hinge region SH bonds of an anti-CD66 antibody without use of chelating agents. The particulars of the subject are not limiting for the invention. However, preferred subjects within the present context are subjects that have, or are considered to have a bone marrow associated disease. Hence, preferred subjects are subjects that have been diagnosed to have a bone marrow associated disease. The term "diagnosing" as used herein is indicative for a process of recognizing, deciding on or concluding on a bone marrow associated disease in a subject on the basis of symptoms and signs and / or from results of various diagnostic procedures (such as, for example, from knowing the presence, absence and / or quantity of one or more biomarkers of or clinical symptoms characteristic for the diagnosed disease or condition). The prognosis of the subject is not limiting for the invention. The subject may therefore be a subject having a good prognosis or a poor prognosis.

[0235] Without limitation, the bone marrow associated disease can be selected from the group consisting of: haematological malignancies, such as a leukemia, which may be selected from multiple myeloma (MM), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL) and lymphoma, preferably multiple myeloma, autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, scleroderma pigmentosa, systemic lupus erythematodes, colitis ulcerosa, Crohn's disease, and systemic sclerosis, AL-amyloidosis, monogenetic diseases, such as aplastic anemia, pure red cell aplasia, paroxysmal nocturnal hemoglobinuria, fanconi anemia, Thalassemia major, sickle cell anemia, severe combined immunodeficiency, Wiskott-Aldrich syndrome, hemophagocytic lymphohistiocytosis, inborn errors of metabolism, epidermolysis bullosa, severe congenital neutropenia, Schwachman-Diamond syndrome, Diamond-Blackfan anemia, and leucocyte adhesion deficiency, and diseases, which can be treated by ex vivo cellular therapy and genetherapy, such as sickle cell anemia, transthyretin amyloidosis (ATTR), hereditary angio edema, acute myeloid leukemia, transfusion-dependent beta thalassemia (TDT), AMD, Diabetic Retinopathy, bleeding disorders such as Hemophilia A and B, lysosomal storage disease such as Hunter syndrome and Huler syndrome, or peripheral neuropathy (Charcot-Marie-Tooth).

[0236] Preferably, the bone marrow associated disease is selected from AL-amylosidosis, multiple myeloma and acute myeloid leukemia.

[0237] In a preferred embodiment, the therapeutic RIC is for administration to a patient who was treated with induction therapy (e.g. velcade, dexamethasone, thalidomide; or velcade, dexamethasone, cyclophosphamide; or velcade, dexamethasone; or melphalan, prednisone; or pomalidomide, dexamethasone) but had disease progression or had a haemotological response.

[0238] In a further preferred embodiment, the therapeutic RIC is for administration to a patient who was treated with induction therapy (velcade, dexamethasone, thalidomide; or velcade, dexamethasone, cyclophosphamicde; or velcade, dexamethasone; or melphalan, prednisone; or pomalidomide, dexamethasone) and had a haematological response to these respective treatment combinations. In a further preferred embodiment, the therapeutic RIC is for administration to a patient who was treated with high-dose melphalan followed by stem cell transplantation but had disease progression. High-dose melphalan treatment can comprise administration of at least 200 mg melphalan / m2 body surface of the patient.

[0239] In a further preferred embodiment, the therapeutic RIC is for administration to a patient who is ineligible to treatment with high dose (HD) melphalan preceding HSCT.

[0240] In a further preferred embodiment, the therapeutic RIC is for administration to a patient who was treated with a combination of up to 4 dmgs selected from doxorubicin, carmustine, cyclophosphamide, dexamethasone, etoposide, melphalan, (methyl)prednisolone, vincristine and idambicin but had disease progression.

[0241] In a further preferred embodiment, the therapeutic RIC is for administration to a patient who is ineligible to treatment with a combination of up to 4 dmgs selected from doxorubicin, carmustine, cyclophosphamide, dexamethasone, etoposide, melphalan, (methyl)prednisolone, vincristine and idarubicin.

[0242] In a further preferred embodiment, the therapeutic RIC is for administration to an AL-amyloidosis patient who was treated with Daratumumab (anti-CD38 antibody) and cyclophosphamide, Bortezomib and dexamethasone (Dara-CyBorD) and who did not achieve a complete remission (CR) 6 months after said treatment.

[0243] In a further preferred embodiment, the therapeutic RIC is for administration to a multiple myeloma patient, who is treatment refractory towards all dmgs approved and used in standard care of multiple myeloma including daratumumab and various chemotherapies and who has cryopreserved stem cells for allowing HSCT following application of the therapeutic RIC.

[0244] In a further preferred embodiment, the therapeutic RIC is for administration to a patient who is eligible for HSCT.

[0245] In a further preferred embodiment, the therapeutic RIC is for taigeted conditioning of High risk AML and MDS patients who cannot be treated by my eloablative conditioning but can only tolerated reduced intensity conditioning proceeding allogeneic bone marrow transplantation. A skilled person appreciates that “targeted conditioning” as used herein does not equal conditioning with chemotherapeutics.

[0246] While the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art in light of the foregoing description. Accordingly, it is intended to embrace all such alternatives, modifications, and variations as follows in the spirit and broad scope of the appended claims. The herein disclosed aspects and embodiments of the invention are further supported by the following non-limiting examples.

[0247] EXAMPLES

[0248] Example 1. Development of a Single Time Point dosimetry method using planar scintigrams

[0249] Materials and Methods

[0250] CD66-binding component The murine IgGl kappa monoclonal antibody anti-CD66 BW 250 / 183 is monomeric with a molecular weight (MW) of 150 kDa protein and composed of IgG heavy and light chains of the expected MW (approx. 50 and 25 kDa, respectively). The antibody is also known as the below:

[0251] INN Name: Besilesomab

[0252] Chemical name: monoclonal antibody BW 250 / 183

[0253] Laboratory Code Name: MAb BW 250 / 183

[0254] CAS Registry Number: 537694-98-7

[0255] NCS-CHX-A"-DTPA chelator

[0256] The synthetic bifunctional chelate used for the covalent conjugation event on the antibody is synthesized by Macrocyclics (1309 Record Crossing, Dallas, TX 75235, USA). The IUPAC name is 2,2'-(2-(((S)-l- (bis(carboxymethyl)amino)-3-(4-isothiocyanatophenyl)propan-2yl) (carboxy-methyl)amino)propylazanediyl)diacetic acid, also known as isothiocyanato-(R)-2-amino-3- (phenyl)propyl)trans-(S,S)-cyclohexane-l,2-diamine-pentaacetic acid) (abbreviated to ITC-CHX-A”-DTPA or ITC-Bn-CHX-A”-DTPA). The low MW chelate (MW: 704 Da) has the following chemical formula C26H34N4O10S.3HC1 and is presented as a solid off-white powder.

[0257] Preparation of the Immunoconjugate (IC)

[0258] The batch size for the CHX-A”-DTPA-anti-CD66 RIC Batch No. AB012 was 122 ml (355 mg), corresponding to 152 ml working volume (426 mg) of the starting monoclonal antibody preparation anti-CD66 Mab 250 / 183 (Orpegen Pharma GmbH or Glycotope Biotechnology GmbH, Germany or Celonic, Germany). The batch size for the CHX-A”-DTPA-anti-CD66 RIC Batch No. AB013 was 250 ml (775 mg), corresponding to 376 ml working volume (1051 mg) of the starting monoclonal antibody preparation anti-CD66 Mab 250 / 183 (Orpegen Pharma GmbH). a) Thawing out of materials

[0259] The first step in the process is the thawing out of the specific number of vials of anti-CD66 Mab specified in the batch record. The Mab is thawed at room temperature in a laminar flow hood (LFH) before combining the vials into a single sterile Falcon tube. An in-process QC sample is taken for size exclusion analysis to confirm that the Mab is predominantly monomeric and the results are reported.

[0260] The chelator ITC-CHX-A”-DTPA is removed from the freezer and allowed to warm to ambient temperature for a minimum of 1 hour at room temperature. b) Crossflow ultrafiltration of Mab - Diafiltration into 0. IM Sodium Carbonate pH 9.0 solution

[0261] The major processing step for the production of the process is the crossflow ultrafiltration / diafiltration (UF / DF) step. These cartridges are disposable, single use and available in a number of different molecular weight cut-offs for processing (Spectmm Laboratories, USA). The cartridge and UF / DF apparatus are pre-conditioned to remove glycerol as recommended by the manufacturer before sterilizing using a validated autoclaving cycle prior to use. In general, the UF / DF step is performed to filter, diafilter (buffer exchange) and concentrate the product throughout to predetermined specifications. The 50 kDa MW cut-off hollow fiber cartridge is operated within defined operating parameters (such as transmembrane pressures, velocity in a low shear manner) that allow the retention of the Mab, whilst allowing salts and other low molecular weight impurities to pass through. The cartridge and assembly is a closed process, which is operated within a grade A laminar flow hood in a grade B clean room background.

[0262] Before processing, a 1 : 10 vokvol of 0.0 IM DTPA solution is added to the Mab solution in the LFH (i.e 1 ml of DTPAper 10 ml of Mab). The Mab is mixed gently and incubated at room temperature for 30 minutes. The Mab solution is introduced into the hollow fiber crossflow assembly in the LFH before the Mab is diafiltered with a minimum of 5 volumes of 0. IM Sodium Carbonate pH 9.0 until the pH is within the acceptable range. In-process QC samples are taken to confirm that the pH is within the 8.9-9.2 pH range required for conjugation. The Mab is recovered from the hollow fiber cartridge into a sterile Falcon tube. An in-process QC sample is taken to monitor the concentration of the Mab by OD 280 nm. c) Conjugation of Mab with chelate

[0263] The amount of ITC-CHX-A”-DTPA chelator required is calculated as follows - 1 mg for every 5 mg of Mab to be conjugated. The chelator is carefully weighed into a sterile container before dissolving in DMSO (dissolve 1 mg of chelator per 20 pl of DMSO). The ITC-CHX-A”-DTPA chelator is added carefully by steady mixing into the Mab (a small volume of carbonate buffer is used to wash out any remaining ligand from the container for adding to the Mab). The lid is replaced on the Mab container and the solution is mixed very gently by hand rotation. The tube is labelled and left at room temperature for 2 hours before incubation overnight at +2 to 8 °C. d) Crossflow ultrafiltration of Mab - Diafiltration / concentration into Acetate buffer

[0264] In an LFH, the Mab solution is diafiltered into 0.1M Ammonium acetate solution pH 6 until in-process QC radiolabeling efficiency achieves > 97%. Once the radiolabeling efficiency is > 97%, the Mab is recovered from the hollow fiber crossflow apparatus into a sterile Falcon tube by releasing the transmembrane pressure. An in- process QC sample is taken to determine the Mab concentration by OD 280 nm and, if required, the Mab is further diluted with the acetate buffer to within the acceptable range of 2.5 -3.3 mg / ml. The final Mab solution is stored at +2 to 8 °C. e) Sterile filtration & filling of IC into cryovials

[0265] In an LFH, in a grade B background, the product is filter sterilized using a 0.22 pM filter into a sterile Falcon tube. The filter is integrity tested to ensure that it is within the acceptable bubble point range. In an LFH, in a grade B background, the product is aseptically dispensed into the sterile cryovials using an autoclaved fixed volume pipette. In processing, E.M is performed by the operators to include continuous air particle counts. The vials are closed and labelled in accordance to GMP before storage at less than -70 °C.

[0266] The bifunctional chelated CHX-A”-DTPA-anti-CD66 monoclonal antibody remains as a monomeric IgGl of the expected MW size and composition. The preparation is shown to maintain its specificity against the CD66 antigen by immunoreactivity assay.

[0267] CHX-A”-DTPA-anti-CD66 monoclonal antibody is readily soluble in water and appears as a colourless, clear solution with no visible particles when dissolved in ammonium acetate buffer pH 6.0.

[0268] 111Indium labelled CHX-A”-DTPA-Anti-CD66 imaging RIC

[0269] ’“Indium labelled CHX-A”-DTPA-Anti CD66 is manufactured in single dosage units for individual patients. The imaging RIC “’Indium labelled CHX-A”-DTPA-Anti CD66 will be prepared with an excess of ’’’Indium to a maximum of 300 MBq to allow for residual activity losses during the manufacture and delay prior to infusion. A dose of 185 MBq ± 10% will be administered to each patient. The volume to be administered will be calculated based on the concentration of radioactivity in the vial. Residual radiolabeled product will be re-measured and reconciled against the original activity to allow accurate recording of actual activity administered to the patient.

[0270] ’’’Indium labelled CHX-A”-DTPA Anti-CD66 is a monoclonal antibody conjugated to a bifunctional chelator, labelled with the radionuclide ’’’Indium.

[0271] The two components of this radiolabeled antibody conjugate are:

[0272] 1) CHX-A”-DTPA-Anti-CD66 Monoclonal antibody

[0273] 2) Radionuclide ’’’Indium

[0274] The radiolabeling of the monoclonal antibody conjugate is prepared individually for each patient by the radiopharmacy departments at each site, following GMP guidelines, and is supplied as a sterile, pyrogen and particle-free solution for intravenous infusion containing besilesomab (0,25-1 mg) diluted to 8.0 ml with 0.9% sodium chloride solution BP, labelled with Indium- 111 to give a final radioactive concentration of approximately 23 MBq / ml (acceptable range 20-30 MBq / ml) at the end of synthesis. The volume of each batch of RIC will be approximately 8-10 ml at the end of manufacture. The patient dose will be presented in one 10 mL syringe.

[0275] Alternatively, radiolabeling of the monoclonal antibody conjugate with ’’’In can be done centrally at a radiopharmaceutical manufacturing site and the RIC will be shipped at 4-8 °C or frozen (-70 °C on dry ice) to the respective transplantation center that treats the patient. -20°C storage conditions are used for storage over prolonged periods (i.e., >24 h) of time.

[0276] 99mTc labelled Anti-CD66 imaging RIC

[0277] 99mTc labelled Anti-CD66 RIC is manufactured in single dosage units for individual patients. Scintimun® (IBA / CIS bio international, Saclay, France) was supplied as a kit containing two types of vials (vial “solvent” and vial “Scintimun”). Reconstitution and quality control of the final solution were done according to the procedure described in the Summary of Product Characteristics (manufacturer’s protocol). In brief, the vial „solvent“ (comprising PTP + SnC12) is reconstituted with 5 ml sodium chloride solution and then the vial „Scintimun“ (comprising reduced besilesomab) is reconstituted with 2-5 ml of the vial „solvent“ and with sodium pertechnetate (99mTc) solution for injection before administration.

[0278] A dose of 400-800 MBq will be administered to each patient. The volume to be administered will be calculated based on the concentration of radioactivity in the vial. Residual radiolabeled product will be re-measured and reconciled against the original activity to allow accurate recording of actual activity administered to the patient.

[0279] 99mTc labelled Anti-CD66 is a monoclonal antibody to which Tc99m is attached via a reduction oxidation technique to the hinge region disulfide bonds.

[0280] The two components of this radiolabeled antibody are:

[0281] 1) Anti-CD66 Monoclonal antibody including a covalent linker

[0282] 2) Radionuclide "mTc

[0283] The radiolabeling of the monoclonal antibody conjugate is prepared individually for each patient by the radiopharmacy departments at each site, following GMP guidelines, and is supplied as a sterile, pyrogen and particle-free solution for intravenous infusion containing besilesomab (0.25-1 mg) diluted to 8.0 ml with 0.9% sodium chloride solution BP, labelled with 99mTc to give a final radioactive concentration of approximately 75 MBq / ml (acceptable range 50-100 MBq / ml) at the end of synthesis. The volume of each batch of RIC will be approximately 8-10 ml at the end of manufacture. The patient dose will be presented in one 10 mL syringe.

[0284] 90Yttrium labelled CHX-A”-DTPA-Anti CD66 therapeutic RIC

[0285] 90Yttrium labelled CHX-A”-DTPA-Anti CD66 RIC is manufactured in single dosage units for individual patients. The composition of each batch / single dosage unit is presented in Table 1 below.

[0286] Table 1: Composition of used dosage units.

[0287] The RIC90Yttrium CHX-A”-Anti-CD66 is prepared with an excess of approximately 25%90Yttrium to allow for residual activity losses during the manufacture. The actual dose administered to the patient will depend on the patient’s lean body weight and the prescribed activity according to the protocol. The volume to be administered is calculated based on these factors together with the concentration of radioactivity in the vial. Residual radiolabeled product is re-measured and reconciled against the original activity to allow accurate recording of actual activity administered to the patient.

[0288] The radiolabeling of the monoclonal antibody conjugate is prepared individually for each patient by the radiopharmacy departments at each site, following GMP guidelines, and is supplied as a sterile, pyrogen and particle free solution for intravenous infusion containing CHX-A”-DTPA Anti-CD66 (1.0-1.5 mg) diluted to approximately 8.0 ml with 0.9% sodium chloride solution BP, labelled with90Yttrium to give a final radioactive concentration in the range of 200-500 MBq / ml at the end of synthesis.

[0289] Alternatively, radiolabeling of the monoclonal antibody conjugate with Y90 can be done centrally at a radiopharmaceutical manufacturing site and the RIC will be shipped at 4-8 °C or frozen (-70 °C on dry ice) to the respective transplantation center that treats the patient. -20°C storage conditions are used for storage over prolonged periods (i.e >24 h) of time.

[0290] Planar scintigraphy

[0291] Imaging RICinIn-DTPA-besilesomab or99mTc-besilesomab was administered intravenously in a buffered saline aqueous solution.

[0292] Planar scintigraphy was performed by taking a gamma-image of at least part of the thorax of the patient using a dual-headed gamma camera (Genesys ADAC) with windows set for the characteristic peak gamma photon energy level of the radionuclide of the imaging RIC. The camera was calibrated for each patient using a standard with a known activity of radionuclide. The radionuclide of the imaging RIC and the standard was identical.

[0293] The thorax was divided in four quadrants as follows: One axis is defined by the thoracic vertebrae; a second axis, which is positioned perpendicular to the first axis, is defined by the 6th sternal ribs. The upper quadrants are the two quadrants adjacent to the head of the patient. The two lower quadrats are the two quadrants adjacent to the hip of the patient.

[0294] Results

[0295] Figures 1 and 3 show a planar whole body scan 24 hours post injection ofluIn-DTPA-besilesomab. Bone marrow is clearly depicted and the ribs can be clearly seen. Liver is marginally seen, spleen shows moderate accumulation of activity.

[0296] The relative signal intensity in the area of the liver (lower left quadrant in the anterior scintigram (left image) and lower right quadrant in the posterior scintigram (right image), respectively) was lower than the relative signal intensity in the area of the bone marrow in the thorax (lower right and upper quadrants in the anterior scintigram (left image) and lower left and upper quadrants in the posterior scintigram (right image)). Thus, the patient was classified to be susceptible for treatment with the therapeutic RIC of the invention.

[0297] Similar findings were made using planar scintigrams generated using "mTc besilesomab 24 hours after administration to a patient with a haematological malignancy (cf. Figure 2).

[0298] Bone marrow is clearly depicted and the ribs can be clearly seen. The relative signal intensity in the area of the liver (lower right quadrant in the posterior scintigram of Fig. 2) was lower than the relative signal intensity in the area of the bone marrow in the thorax (lower left and upper quadrants in the posterior scintigram of Fig. 2). Thus, the patient was classified to be susceptible for treatment with the therapeutic RIC of the invention.

[0299] Planar scintigrams of patients who were classified to not be susceptible for treatment with the therapeutic RIC of the invention are shown in Fig. 4 and 5. The signal in the area of the liver in the planarU1ln DTPA-besilesomab scintigrams dominated over the signal in the area of the bone marrow in the ribs. The relative signal intensity in the area of the liver (lower right quadrant in the posterior scintigram of Fig. 4; lower left quadrant in the anterior scintigrams of Fig. 4 and 5) was significantly higher than the relative signal intensity in the area of the bone marrow in the thorax (lower left and upper quadrants in the posterior scintigram of Fig. 4; lower right and upper quadrants in the posterior scintigrams of Fig. 4 and 5). Administration of the therapeutic RIC according to the invention would result in liver toxicity and no benefit to the patient is to be expected, since bone marrow conditioning would not be achieved. Thus, the patient was classified to not be susceptible for treatment with the therapeutic RIC of the invention.

[0300] Example 2. Informed decision making process for determining whether a subject is to be treated with 45 MBq / kg lean body weight (lbw) of a radioimmunoconjugate (RIC) comprising yttrium-90 (90Y) as radionuclide

[0301] A rational approach for inclusion of patients for treatment (i.e. inclusion in a treatment plan) with a90Y- radionuclide-comprising radioimmunoconjugate such as90Y-DTPA-Besilesomab has been lacking. By extensive analysis of patient data the inventors have developed a rational decision tree, which can be performed as part of a computer-implemented invention. This decision tree is depicted in Figure 6.

[0302] Since90Y-besilesomab only emits P energy (no y energy) which cannot easily be measured using SPECT / CT (only via "Bremsstrahlung" determination), it cannot be directly determined how many Gy the respective organs are exposed to. Therefore, the biodistribution of99mTc-besilesomab (which has a very comparable biodistribution as theU1ln or90Y-DTPAbesilesomab) is determined in the respective patient. Calculations then allow to conclude to which doses this biodistribution would correspond if 45 MBq / kg lbw of90Y-DTPA besilesomab would be used. The doses depicted in Figure 6 as part of the decision tree hence indicate90Y absorption doses, not "mTc absorption doses.

[0303] Example 3. A comparative biodistribution study oflnIn-DTPA-besilesomab and99mTc-besilesomab.

[0304] To further validate the use of99mTc -labeled anti-CD66 (99mTc-besilesomab) as alternative imaging agent toU1ln- labeled anti-CD66 (U1ln-besilesomab), the inventors conducted a comparative biodistribution study at multiple time points post-injection to evaluate the blood clearance kinetics and organ uptake profiles ofU1ln- and ""relabeled anti-CD66 antibodies. These data substantiate the use of99mTc-besilesomab as an alternative toU1ln- DTPA-besilesomab for patient-specific dosimetry and imaging.

[0305] This is the first study to assess the suitability of99mTc -Besilesomab for treatment selection for patient stratification to targeted conditioning using90Y-DTPA-Besilesomab as an alternative toluIn-DTPA Besilesomab. The aim of this study was to compare the blood clearance kinetics and organ distribution ofluIn-DTPA-besilesomab with99mTc-besilesomab results, focusing on uptake in target tissues, especially the bone marrow, as well as in organs at risk, (i.e. healthy organs likely to be exposed to radiation and potential damage thereto) including the liver, spleen, and kidneys up to 24 hours post-injection.

[0306] Method

[0307] The99mTc-Besilesomab study was based on data from 24 patients with suspected osteomyelitis, as documented in the Curium report. This Phase 1 study "Phase I Study with Granulocyte Scintimun BI 71015 in patients with inflammatory diseases”, allowed to study the biodistribution of this compound in 24 patients after intravenous administration. The data provided by this study allow to identify the following binding sites:

[0308] • Liver;

[0309] • Lungs;

[0310] • Spleen;

[0311] • Kidney; • Bone marrow;

[0312] • Remainder of the body.

[0313] For each of these organs, or group of organs (Remainder of the body), the previous study provides data that are directly used to calculate the absorbed dose using the methodology developed by the MIRD (Medical Internal Radiation Dose) that is currently the reference method in internal dosimetry (MIRD PRIMER for Absorbed Dose Calculations, R. Loevinger, T.F. Budinger, A.E. Watson, The Society of Nuclear Medicine, 1991). This method is particularly well adapted to radiation protection, since the concept of "Reference Man" as defined in ICRP Publication No. 23 (CIPR 23, Reference man: anatomical, physiological and metabolic characteristics, 1975) is used.

[0314] Using the absorbed dose determined for each individual organ, it is then possible to calculate the effective dose. To achieve this, it is necessary to use the recommendations of the ICRP, which states, in addition to the general method of calculation, the weighting factors (radiation and tissue) to use. These factors, originally defined by the publication No. 60 of ICRP (CIPR 60, Recommendations of the International Commission on Radiological Protection. ICRP, Publication 60. Ann. ICRP 21 (1-3) 1990) have recently been reassessed and are available in Publication No. 103 (CIPR 103, The 2007 Recommendations of the International Commission on radiological Protection, 2007). This document also recommends a different weighting for the organs that belong to the group "Remainder" as well as a unique expression for the effective dose irrespective of sex.

[0315] As for individual organs, the exposure of the foetus is estimated from the models compatible with the ICRP.

[0316] To calculate the absorbed dose by a given organ, one must identify all potential sources of irradiation first, and then the biological behaviour of the radio-pharmaceutical. The MIRD method is based on this concept which defines the “source organ” and “taiget organ” (MIRD PRIMER for Absorbed Dose Calculations, R. Loevinger, T.F. Budinger, A.E. Watson, The Society of Nuclear Medicine, 1991). From practical point of view, two factors must be considered: the S-factor which depends on the geometry and the radio-nuclide, and the residence time T, which reflects the behaviour of the radio-pharmaceutical. The average absorbed dose per unit administered activity (MBq) for a target organ k, irradiated by a source h, is then simply expressed by:

[0317] D = ThxS(k <— h) for example, in mSv / MBq.

[0318] In our calculations, we will use the OLINDA software (M G Stabin, R B Sparks, E Crowe. OLINDA / EXM: The Second-Generation Personal Computer Software for Internal Dose Assessment in Nuclear Medicine. Journal of Nuclear Medicine Vol. 46 No. 6 1023-1027). This computing environment includes the recommendations of the MIRD Committee and proposes anthropomorphic phantoms that model several situations, including various anatomical stages of pregnancy. Table 2 summarises the phantoms proposed by OLINDA that will be used in this study. Finally, to carry out the calculations, we also have to provide additional information's such as:

[0319] • The radio-nuclide;

[0320] • Organs identified as a potential source of radiation;

[0321] • Residence time associated with these sources.

[0322] Table 2: Phantoms modelled in the Olinda software that will be used to carry out the calculations.

[0323] As emphasised in the introduction, biokinetic data has been extracted from the Phase 1 study previously mentioned. The methodology used is robust. It relies on serial acquisitions overtime to estimate the uptake kinetic of each source organ. Quantification of the images is achieved by normalising the content of each regions of interest by the content of the ROI determined on the initial acquisition, performed 10 min after injection and before excretion. This work has been performed in humans, that greatly minimises the errors of transposition encountered when animal models are implemented. Based on these results, the authors extracted the data summarised in Table 3.

[0324] Table 3: Residence times used for the calculation of individual doses in target organs.

[0325] The “remainder” includes all the organs of “the rest of body” that are not clearly identified as individual sources and in which the radioactivity is considered as distributed homogeneously. The 1990 recommendation of the ICRP (ICRP 60), introduced the concept of effective dose, associated with weighting factors WT. This issue specified the calculation method of the effective dose for organs in the ''remainder" category that were expected to receive a larger dose than any other organ with a dedicated WT.

[0326] In this case, the recommendation was to over-weight the weight of an individual organ while staying in the limit of factors defined for each tissue, organ, or group of organ.

[0327] This method of risk evaluation was in agreement with the idea of calculating the dose in the worst possible situation. However, this method was not in good agreement with the statistical methods that are used for risk evaluation (the effective dose is additive), and the basis of weighting factors calculation.

[0328] In the 2007 recommendation (ICRP publication 103), some of these hypotheses has been modified, including:

[0329] • The number of organs taken into account and the associated wrcoefficients were adjusted according to the latest available epidemiological data (Table 4);

[0330] • The coefficient associated with WT group "Other tissues or organs" is now based on the rule of the arithmetic mean;

[0331] • The effective dose reflects the risk to a population composed of men and women without differentiating a specific risk related to sex.

[0332] This new method of dose calculation can summarised in Figure 11 (from ICRP 103).

[0333] Table 4: Weighting factors WT in ICRP 103.

[0334] * Other tissues or organs, Adrenal glands, Extra thoracic region, Gallbladder, Heart, Kidneys, Lymph nodes, Muscle, Oral mucosa, Pancreas, Prostate, Small intestine, Spleen, Thymus, Uterus / Pelvis.

[0335] Not to mention the method of arithmetic mean to weight the organs WT belonging to the group ’Other organ or tissue” (Rmd in the formulas for Remainder), respectively for men (M) and female (F).

[0336] We see here that the concept of "person" reference replaces that of reference man or woman of reference. These last two are used only to calculate absorbed doses in the various organs modelled by anthropomorphic phantoms. Patient population

[0337] TheluIn-DTPA-Besilesomab study retrospectively analysed data from 28 patients who participated in three independent clinical trials. Each patient received an intravenous administration ofluIn-DTPA Besilesomab for pre-therapeutic dosimetry, followed by therapeutic administration of90Y-labeled Besilesomab.

[0338] Detailed patient demographics and clinical characteristics are presented in Table 5.

[0339] Table 5: Detailed patient characteristics.

[0340] *NA: not available

[0341] Monoclonal antibody

[0342] Besilesomab is a murine IgGl monoclonal antibody. The anti-CD66 mAb besilesomab targets CD66b, expressing myeloid-derived suppressor cells in haematological malignancies (Bosslet et al., Immunohistochemical localization and molecular characteristics of three monoclonal antibody-defined epitopes detectable on carcinoembryonic antigen (CEA). International journal of cancer, 1985). Furthermore, it binds to CD66 antigens on leukemic cells. The antibody is covalently conjugated using a bifunctional chelator (SCN-CHX-A”-DTPA) (diethylenetriamine pentaacetic acid), with DTPA. The chelated complex can be radiolabelled withU1ln.99mTc is labelled to besilesomab using a direct reduction method without the need for a chelator (Bremer et al., Method for producing an organ-specific substance marked with Technetium-99m, Patent DE3783745D1, 1987).

[0343] Blood kinetics

[0344] Blood samples were collected at 5 min, 10 min, 20 min, 30 min, 1 h, 2 h, 5 h, 10 h, and 24 h post administration of99mTc-Besilesomab, and at 5 min, 1 h, 2 h, 3 h, and 21 h after the administration ofluIn-DTPA Besilesomab. The111In data was interpolated to align with the "mTc sample collection time for comparison. Whole blood activity was quantified using a calibrated gamma counter and expressed as a percentage of the injected dose (%ID).

[0345] Patient imaging

[0346] InluIn-DTPA Besilesomab study, multi-time-point (MTP) imaging was performed in 28 patients. Each patient received an intravenous injection ofluIn-DTPA-Besilesomab at a mean activity of 175.6 ± 10.88 MBq. Wholebody planar scintigraphy was conducted at approximately 0.5 hours post-injection, while SPECT / CT imaging was acquired at 24, 72, and 96 hours using a GE Infinia Hawkeye 4 hybrid imaging system. In the99mTc-Besilesomab study, MTP whole-body planar scintigraphy was performed in 24 patients at 0.17, 1, 5, and 24 hours.

[0347] Organ biodistribution study

[0348] Organ biodistribution was assessed to characterise the in vivo localisation and uptake kinetics ofluIn-DTPA- Besilesomab and99mTc-Besilesomab following intravenous administration. Image analysis was performed for all patients administeredluIn-DTPA-Besilesomab using the Xeleris workstation software platform (GE Healthcare). Regions of interest (ROIs) were manually delineated on planar whole-body images acquired at approximately 0.5 hours post-injection, targeting major organs including the bone marrow, spleen, liver, kidneys, and the entire body. Quantitative analysis was conducted by extracting total counts within these ROIs. Bone marrow volume was estimated based on the method described by Shen et al., which extrapolates whole-body red marrow volume from activity measurements in the L2-L4 vertebrae (Shen et al., Improved prediction of myelotoxicity using a patientspecific imaging dose estimate for non-marrow-targeting90Y-antibody therapy, Journal of Nuclear Medicine, 2002). The total body counts from the 0.5-hour whole-body images represent the total injected activity, as all patients were scanned in a pre-void condition. The organ-specific percentage of the injected dose (%ID) at 0.5 hours was calculated as the ratio of organ counts to total body counts. At 24 hours, %ID values were estimated from SPECT-derived organ activity using volumes of interest (VOIs), normalised to the total injected activity of111In-DTPA-Besilesomab .

[0349] For comparison, the mean %ID values for99mTc-Besilesomab were obtained directly from the Curium dataset (Table 6).

[0350] Table 6. %ID values for99mTc-Besilesomab.

[0351] Quantification of these images is achieved by normalising the counts of each organ ROI to the total ROI counts determined on the initial WB acquisitions, performed 10 minutes after injection and before excretion.

[0352] To see the actual uptake in the organs, all the measured counts or activities were decay -corrected to time zero. In addition to %ID in whole organ, the %ID per gram of tissue was also calculated based on the organ masses derived from the standard phantom for the reference man (Bolch et al., MIRD pamphlet no. 21 : a generalized schema for radiopharmaceutical dosimetry — standardization of nomenclature, J Nucl Med, 2009).

[0353] Statistical analysis

[0354] All statistical analyses were performed using Excel 2010. Scatter plots with error bars were used to visualise the clearance of blood activity after administration ofluIn-DTPA-Besilesomab and99mTc-Besilesomab. The relationship of blood clearance between the two radiopharmaceuticals was assessed using correlation analysis, and an unpaired t-test was employed to determine significance. Histograms were used to compare the percentage of the injected dose of two radiopharmaceuticals in the organs at different time points.

[0355] Results and Discussion

[0356] Scintillation imaging with "mTc offers several advantages over111In-based imaging, including a shorter physical half-life, convenient availability via technetium-99m generators, lower radiation exposure to the patient, and improved image quality. These features support its potential use as a substitute forluIn-DTPA-Besilesomab in the context of myeloablative radioimmunotherapy. Here, we compared the blood clearance kinetics and organ biodistribution ofinIn-DTPA-Besilesomab with99mTc-Besilesomab up to 24 hours post-injection.

[0357] Blood kinetics

[0358] The details of the mean percentage injected dose (%ID) in blood after administration are presented in Table 7 and Figure 7. In this study, we found a very strong positive correlation in blood concentration values forluIn-DTPA- Besilesomab and99mTc-Besilesomab (Pearson’s r2= 0.99). We didn't find any significant difference between the means of the two independent populations (p-value =0.53). The whole blood clearance curves exhibited a biphasic profile, characterised by an initial distribution phase (0-3 h) followed by a slower elimination phase (5-24 h) for both radiopharmaceuticals. After correction for radionuclide decay, the calculated half-life for the early phase was approximately 0.5 hours, whereas the terminal elimination phase demonstrated a half-life of approximately 16 hours.

[0359] Table 7: Mean percentage injected dose in blood after administration ofluIn-DTPA-Besilesomab and99mTc- Besilesomab

[0360]

[0361] Organ Biodistribution

[0362] 1. Earlier time-point

[0363] A notably higher uptake in the spleen and lower uptake in the kidneys was observed following administration ofinIn-DTPA-Besilesomab compared to99mTc-Besilesomab. Arelatively similar level of uptake in the bone marrow as well as the liver was observed following administration of both99mTc-Besilesomab andluIn-DTPA- Besilesomab. Detailed quantitative organ uptake data are presented in Table 8 and illustrated in Figure 8. Please note that the99mTc-Besilesomab data were acquired at 0.17h post administration and theluIn-DTPA-Besilesomab at 0.5h.

[0364] Table 8: Mean percentage injected dose per gram tissue (%ID / g) in organs after administration of99mTc- Besilesomab andluIn-DTPA-Besilesomab.

[0365] For both radiopharmaceuticals, the highest activity concentration (%ID / g) was noted in bone marrow followed by spleen, liver and kidneys. Consistent with our findings, previous studies have also reported high uptake of radiolabelled anti-CD66 antibodies in the bone marrow, followed by the spleen and liver (Buchmann et al., Myeloablative Radioimmunotherapy with Re-188-anti-CD66-antibody for conditioning of high-risk leukemia patients prior to stem cell transplantation, Cancer Biotherapy Radiopharm, 2002; Matthews et al., Phase I study of131I-anti-CD45 antibody plus cyclophosphamide and total body irradiation for advanced acute leukemia and myelodysplastic syndrome, Blood, 1999; Winter et al., Optimisation of Radiolabeling of a [90Y]Y-Anti-CD66- Antibody for Radioimmunotherapy before Allogeneic Hematopoietic Cell Transplantation, Cancers (Basel), 2023).

[0366] 2. "mTc-Besilesomab at 5 hours compared toluIn-DTPA-Besilesomab at 24 hours In addition to the early time point, we also compared the relative biodistribution of99mTc-Besilesomab at 5 hours post injection toinIn-DTPA-Besilesomab at 24 hours post-injection. This comparison was performed to evaluate the feasibility of replacing the single time point imaging ofinIn-DTPA-Besilesomab at 24 hours with an earlier time point for99mTc-Besilesomab. The target organ, bone marrow, demonstrated slightly higher uptake at 5 hours post-injection of99mTc-Besilesomab compared to 24 hours post-injection ofinIn-DTPA-Besilesomab. In contrast, a greater percentage uptake in non-target organs, except from the kidneys, was observed at 24 hours post-injection ofluIn-DTPA-Besilesomab compared to the 5-hour time point of99mTc-Besilesomab. Buchmann et al. reported high uptake of99mTc-Besilesomab in bone marrow and moderate hepatic uptake in leukaemia patients (Buchmann et al., A comparison of the biodistribution and biokinetics of99mTc-anti-CD66 mAb BW 250 / 183 and99mTc-anti- CD45 mAb YTH 24.5 with regard to suitability for myeloablative radioimmunotherapy, Eur J Nucl Med Mol Imaging, 2003). Detailed quantitative organ uptake values are presented in Table 9 and visually summarised in Figure 9.

[0367] Table 9: Mean percentage injected dose per gram tissue in organs after 5h administration of99mTc-Besilesomab and 24h administration ofinIn-DTPA-Besilesomab

[0368] In the present study, the kidneys show very high renal uptake of99mTc-Besilesomab compared toluIn-DTPA- Besilesomab across all time points. According to the Scintimun product characteristics sheet, measurement of radioactivity levels in urine indicates that up to 14% of the administered activity is excreted via the bladder within 24 hours post-injection. The low renal clearance of radioactivity suggests that the kidneys are not the primary route of Besilesomab elimination (SUMMARY OF PRODUCT CHARACTERISTICS, Scintimun). The high organ dose estimate is most likely due to the superimposition of background structures on the two-dimensional (2D) kidney regions in whole-body planar imaging with99mTc -Besilesomab. It has been demonstrated that planar imaging tends to overestimate measured activity concentrations and absorbed doses compared to SPECT imaging, and this is overestimation can be substantial especially for the right kidney which overlaps anatomically with the liver in planar imaging (Kupitz et al., Software-assisted dosimetry in peptide receptor radionuclide therapy with 177Lutetium-DOTATATE for various imaging scenarios, PloS one, 2017); Lehnert et al., Impact of Modality (2D Planar, 2D / 3D Hybrid, 3D SPECT) on Kidneys Absorbed Dose in 177Lu-based PRRT, Journal of Nuclear Medicine, 2018), while the left kidney is in the vicinity of the spleen. The uptake of99mTc -Besilesomab in the kidneys increases over time, which may be attributed to tracer degradation and subsequent renal excretion of free pertechnetate. To date, no in vivo studies are available on the stability of99mTc -Besilesomab.

[0369] 3.99mTc-Besilesomab compared toluIn-DTPA-Besilesomab at 24 hours

[0370] The mean percentage of the injected dose per gram of tissue in various organs was evaluated 24 hours postadministration for both99mTc-Besilesomab andinIn-DTPA-Besilesomab. Compared to99mTc-Besilesomab, administration ofluIn-DTPA-Besilesomab resulted in markedly higher uptake in the spleen and lower uptake in the kidneys. The target organ, bone marrow, exhibited maximum uptake at 24 hours post-injection for both radiopharmaceuticals. However, higher marrow uptake was observed following99mTc-Besilesomab administration compared toluIn-DTPA-Besilesomab, likely attributable to differences in imaging modalities and quantification techniques. Detailed quantitative data on organ-specific uptake are provided in Table 10 and visualised in Figure 10.

[0371] Table 10: Mean percentage injected dose per gram tissue in organs at 24h after administration of99mTc- Besilesomab andluIn-DTPA-Besilesomab.

[0372] Conclusion

[0373] The blood clearance of99mTc-Besilesomab is comparable to that ofluIn-DTPA-Besilesomab. In terms of biodistribution, both tracers demonstrate similar uptake in the bone marrow, the primary target organ, as well as in most organs at risk. However, a notably higher percentage of the injected activity is observed in the kidneys following administration of99mTc-Besilesomab compared toluIn-DTPA-Besilesomab. The uptake of99mTc- Besilesomab at 5 hours post-injection was generally comparable to that observed at 24 hours in both target and non-target organs, indicating that imaging for the purpose of dosimetry could be feasible as early as 5 hours postadministration.

[0374] Example 4. A Phase lb, Open-Label, Multicenter Study to Compare the Dosimetry and Safety oflnIn- besilesomab and99mTc-Besilesomab Preceding90Y- besilesomab as a Targeted Conditioning Agent Followed by Reduced Intensity Conditioning (RIC) Prior to allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in High Relapse Risk Acute Myeloid Leukaemia (AML) or High-Risk Myelodysplastic Syndrome (MDS).

[0375] To find out if multi time pointluIn-DTPA-besilesomab pretherapeutic dosimetry can be replaced by single time point99mTc-besilesomab pretherapeutic dosimetry, patients to be eventually treated with90Y-DTPA-besilesomab are injected by diagnostic doses of bothluIn-DTPAbesilesomab and99mTc-besilesomab consequently within about 1 hour and the kinetics of the biodistribution are determined quantitatively using SPECT / CT and planar imaging at defined time points.

[0376] Primary objectives:

[0377] To compare single -timepoint (STP) dosimetry estimates from single photon emission computed tomography / computed tomography (SPECT / CT) acquisitions at, 3-, 6- and 24-hours post 99mTc- Besilesomab infusion with STP dosimetry estimates from SPECT / CT acquisitions at either, 3-, 6- or 24-hours postU1ln-besilesomab infusion and the multi-timepoint (MTP) dosimetry estimate from SPECT / CT acquisitions at 0-, 3-, 6-, 24-, and 96-hours postU1ln-besilesomab infusion to derive the STP and / or MTP timepoint(s) optimal for selecting participants suitable to undergo therapeutic90Y- besilesomab bone marrow conditioning

[0378] To determine the safety ofU1ln-besilesomab and 99mTc-Besilesomab as pre-therapeutic, dosimetric agents and90Y-besilesomab as a conditioning agent followed by reduced intensity conditioning (RIC) prior to allogeneic hematopoietic stem cell transplantation (alloHSCT) in participants with high relapse risk acute myeloid leukaemia (AML) or high risk myelodysplastic syndrome (MDS)

[0379] Secondary objective:

[0380] To determine the efficacy of conditioning and hematopoietic stem cell transplantation (HSCT) in high risk AML / MDS

[0381] Exploratory objectives:

[0382] To determine the incidence of treatment related mortality (TRM), graft-versus-host-disease (GvHD), chimerism, engraftment, and graft failure in participants at high risk of AML relapse or high risk MDS

[0383] To determine measurable residual disease (MRD) status in participants with high relapse risk AML or high risk MDS

[0384] To determine the duration of hospitalisation

[0385] To determine the incidence and percentage of treatment response To determine the incidence and percentage of treatment failure To determine the effect of treatment on the quality of life (QoL)

[0386] Methodology:

[0387] This Phase lb, open-label, single-arm, multicentre study evaluates the safety of the two pre-therapeutic, dosimetric agents (U1ln-besilesomab and 99mTc-Besilesomab) and the bone marrow conditioning agent (90Y-Besilesomab) whose administrations are followed by RIC prior to alloHSCT.

[0388] The radioisotopes Indium 111 (inIn) and Technetium 99m (99mTc) emit gamma (y) photons that can be measured using SPECT or a planar gamma scintigraphy. However, the radioisotope90Y emits cytotoxic beta (B) particles photons but no gamma photons; therefore, practical quantitative evaluation of90Y Besilesomab biodistribution cannot be accomplished with standard clinical imaging devices, necessitating the use ofU1ln-Besilesomab or 99mTc -Besilesomab to predict the organ-specific absorption of subsequent90Y-Besilesomab infusion. The quantitative values derived from pretherapeutic dosimetry withU1ln-Besilesomab and 99mTc -Besilesomab are extrapolated to provide an estimate for the90Y-Besilesomab biodistribution.

[0389] This study provides prospective data to compare the utility of STP dosimetry withU1ln-Besilesomab and STP dosimetry with 99mTc-Besilesomab at different timepoints versus MTP dosimetry withU1ln-Besilesomab for selecting participants eligible to undergo therapeutic90Y-Besilesomab bone marrow conditioning.

[0390] Although participants undergo pre-therapeutic, dosimetric evaluation with bothU1ln-Besilesomab and 99mTc- Besilesomab to enable comparative analysis, the dosimetric results of MTPU1ln-Besilesomab dosimetry are used to select participants eligible to receive90Y-Besilesomab, as determined by the Decision Tree (Figure 6). Participants are selected for90Y-Besilesomab conditioning if the dosimetric results ofU1ln-Besilesomab MTP dosimetry predict that a sufficient absorbed dose of the targeted radiopharmaceuticals will be delivered to the bone marrow without over-dosing non-hematopoietic tissues at risk.

[0391] The acquisition of this comparative data for STP and MTP dosimetry with these 2 different dosimetric agents versus the “gold standard” of MTP dosimetry withinIn-Besilesomab to enable the preferred STP method to be selected.

[0392] At Visit 2 (Day -23 ± 1 or 2 days) recipients undeigo the administration of the two pre-therapeutic, dosimetric agents containing different radioisotopes in a single session, one after another, followed by dosimetric planar and SPECT / CT imaging at Time 0 and 3-, 6, 24-, and 96-hours post infusion for dosimetric evaluation. The imaging evaluations at the 3-, 6- and 24-hours post-infusion provide dual-isotope images for both "mTc andU1ln. The 99mTc isotope has a relatively short half-life; therefore, the imaging evaluations performed at 96-hours postinfusion provide valid imaging for the111In isotope only.

[0393] At Visit 5 (14 days prior to HSCT), selected participants receive a single 45 megabecquerel (MBq) / kg lean body weight (lbw) infusion of90Y-Besilesomab unless the dosimetry results indicate that one or more of the absorbed dose limits may be exceeded (i.e., liver dose > 15 gray [Gy], kidney dose > 13 Gy, or bone marrow dose > 35 Gy) in which case the administered activity may be reduced by up to 20% providing all criteria are then satisfied.

[0394] The Decision Tree (Figure 6) also incorporates the process for dose adjustment (i.e., reduction) in participants predicted to have high ranges of90Y-Besilesomab accumulation in non-hematopoietic tissues at risk. The dosimetric decision for participant eligibility is determined by a central imaging laboratory.

[0395] After receiving90Y-Besilesomab, participants undergo a standardized RIC regimen (fludarabine plus melphalan per the guidelines of the National Comprehensive Cancer Network for Hematopoietic Cell Transplantation). The use of antithymocyte globulin (ATG) is optional. Anti-GvHD prophylaxis is performed per institutional standard- of-care (SOC). HSCT occurs at Day 0.

[0396] Participants who are deemed ineligible by pre-therapeutic dosimetric evaluation do not receive90Y-Besilesomab and undergo bone marrow conditioning by institutional SOC and are excluded from all additional study procedures except the End-of-Study (EOS) Safety Follow-Up Visit (performed as late as possible before commencing bone marrow conditioning by institutional SOC).

[0397] This study comprises 4 study periods: the Screening Period, the Dosimetric Period, the Treatment Period, and the Follow-up Period. The Treatment Period contains two stages: (1) the90Y-Besilesomab Conditioning Stage and (2) the RIC, GvHD prophylaxis, and Transplantation Stage.

[0398] EOS will occur at Day 100 ± 14 days.

[0399] Number of patients:

[0400] Study enrolment continues until a total of 3 male and 3 female AML / MDS participants have undergone conditioning with90Y-Besilesomab followed by RIC prior to alloHSCT. The participant population may be expanded given discrepancy between outcomes for MTP versus STP outcomes for theinIn-Besilesomab and 99mTc-Besilesomab estimates. Expansion of the participant may also be necessary if patient selection byU1ln-Besilesomab and 99mTc-Besilesomab outcomes are not 100% concordant or if bridging results between Celonic- and ProBio-manufactured besilesomab need to be confirmed.

[0401] Diagnosis and main criteria for inclusion:

[0402] This study emolls male and female adults > 18 years of age who have been classified as having high-risk AML according the European LeukemiaNet (ELN) classification, who underwent MDS risk assessment based on cytogenetics and molecular diagnostics and are unable to tolerate standard myeloablative conditioning with sufficient levels of fitness enabling them to comply with study procedures and assessments.

[0403] Main inclusion criteria:

[0404] Unable to tolerate standard myeloablative conditioning;

[0405] Kamofsky score > 70%;

[0406] Absence of dyspnoea with documented diffusion lung capacity for carbon monoxide (TLco) >40% (adjusted for haemoglobin, if available) and forced expiratory volume in 1 second / forced vital capacity (FEV1 / FVC) > 50% of predicted, as determined by institutional standard-of-care procedures;

[0407] Participant is fit for transplantation by assessment of an experienced haematologist:

[0408] Availability of human leucocyte antigen (HLA)-identical sibling; or

[0409] HLA-compatible (> 9 / 10 antigens matched for HLA-A, -B, -C, -DRB1, and -DQB1) unrelated donor;

[0410] AML participants in complete remission 1 (CR1) and complete remission 2 (CR2) classified as high relapse risk who are MRD+ or MRD- or high-risk MDS as defined by the LeukemiaNet 2022 consensus criteria and the MDS Molecular International Prognostic Scoring System (IPSS-M) (Dohner H et al., 2022; Arber DAet al., 2022; Bernard E et al., 2022); and

[0411] Participants may have received prior autologous (but not allogeneic) haematopoietic stem cell transplantation in remission.

[0412] Investigational product, dosage, and mode of administration: inIn-Besilesomab, intravenous, single dose of approximately 185 MBq 99mTc -Besilesomab, intravenous, single dose of approximately 800 MBq 90Y-Besilesomab, intravenous, single dose of 45 MBq / kg lean body weight

[0413] Duration of treatment:

[0414] Participants receive a single dose ofU1ln-Besilesomab via slow intravenous infusion over a 10- to 15 minute period.

[0415] Participants receive a single dose of 99mTc-Besilesomab via slow intravenous infusion.

[0416] Participants receive a single dose of90Y-Besilesomab via flow intravenous infusion over a 10- to 15 minute period Reference therapy, dosage and mode of administration:

[0417] Not applicable.

[0418] Criteria for evaluation:

[0419] Dosimetry:

[0420] Projected organ-specific90Y-Besilesomab absorption as predicted by STP dosimetry with 99mTc- Besilesomab, STP dosimetry withluIn-Besilesomab, and MTP dosimetry withU1ln-Besilesomab

[0421] Efficacy:

[0422] The efficacy of conditioning and HSCT in high risk AML / MDS as determined by the incidence of relapse and onset of acute GVHD Grades II thru IV by EOS

[0423] Exploratory Efficacy:

[0424] Incidence of relapse, TRM, chimerism, engraftment, and time to engraftment over the course of the study and / or at EOS

[0425] Incidence and severity of GvHD and primary and secondary graft failure over the course of the study and / or at EOS

[0426] MRD status at EOS

[0427] Duration of hospitalization

[0428] Incidence and percentage of treatment response, as follows: o Morphological complete remission (CR) o Morphological CR with incomplete count recovery (CRi) o Cytogenetic CR o Multiparameter flow cytometry-MRD (MFC-MRD) (and Molecular MRD assessed by qPCR [Mol-MRD] when present) CR (MRD neg CR) o MFC-MRD (and Mol-MRD when present) CR with incomplete count recovery (MRD neg CRi)

[0429] Incidence and percentage of treatment failure, as follows: o Morphological relapse o MRD relapse o Cytogenetic relapse o Aplasia o Resistant disease o MRD persistence

[0430] Effect of treatment on the quality of life (QoL)

[0431] Safety:

[0432] Incidence and severity of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and clinically significant changes attributable to the study drug Statistical methods:

[0433] No formal statistical analyses of safety, dosimetry, or exploratory efficacy data is performed. An independent data monitoring committee (IDMC) will review dosimetric outcomes after 6 participants have undergone dosimetric evaluation and make recommendations about the utility of MTP versus STP dosimetry for the 2 dosimetric agents and whether the participant population should be expanded to obtain additional dosimetric data.

[0434] Example 5. Clinical study report: A Phase 2a / 2b, Open-Label, Multicentre, Safety, and Efficacy Study of90Y DTPA-besilesomab as a Targeted Conditioning Agent and111In-DTPA-besilesomab and99mTc-besilesomab as Pretherapeutic Dosimetric Patient Selection Agents Preceding Reduced Intensity Conditioning followed by Allogeneic Haematopoietic Stem Cell Transplantation in Patients with Intermediate or High Relapse Risk Acute Myeloid Leukaemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

[0435] This study contains 2 parts, as follows:

[0436] • Part A (Dosimetry) is designed to confirm the feasibility of administering 2 pre-therapeutic imaging agents containing radioisotopes in a single session, one after another, followed by dosimetric planar / SPECT / CT evaluations at Time 0 and 4-, 24-, 72, and 96-hours post infusion. Part A will confirm favourable imaging and safety outcomes, and will provide preliminary prospective data to compare the utility of single -timepoint (STP) versus multi-timepoint (MTP) dosimetry withluIn-DTPA-besilesomab or99mTc-besilesomab for selecting participants to undergo therapeutic90Y-DTPA-besilesomab bone marrow conditioning.

[0437] • Part B (Conditioning) is designed to compare targeted myeloablative bone marrow conditioning with90Y DTPA-besilesomab plus reduced intensity conditioning compared with reduced intensity conditioning alone prior to allogeneic hematopoietic stem cell transplantation (alloHSCT). The first 30 participants randomised into the90Y-DTPA-besilesomab plus reduced intensity conditioning treatment arm will undergo the same dosimetric evaluation performed in Part A. The analysis of dosimetric outcomes in the subgroup will provide sufficient power to select the best single performance dosimetric agent and dosing strategy for the remaining 98 participants randomised into the90Y-DTPA-besilesomab plus reduced intensity conditioning treatment arm. Objectives and endpoints are described in Tables 11 (General), 12 (dosimetric), and 13 (Therapeutic).

[0438] Table 11. Objectives and Endpoints (Part A)

[0439] Study Design (Part A)

[0440] Part A will be open-label and enroll a total of 9 AML / MDS participants at up to 5 investigative sites in the United Kingdom (UK), the European Union (EU) and the United States (US). Study enrollment will continue until a total of 9 AML / MDS participants have undergone conditioning with90Y-DTPA-besilesomab followed by reduced intensity conditioning prior to alloHSCT.

[0441] Participants will undergo pre -therapeutic, dosimetric evaluation with bothluIn-DTPA-besilesomab and99mTc- besilesomab to confirm that a sufficient absorbed radiation dose will be delivered to the bone marrow by the targeted radiopharmaceuticals without over-dosing non-hematopoietic tissues at risk.

[0442] Part A will confirm the feasibility of the dual agent dosimetric methodology, i.e., the infusion ofluIn-DTPA- besilesomab and99mTc-besilesomab in one session followed by imaging evaluations at 4-, 24-, 72-, and 96-hours post-infusion provides adequate imaging and safety outcomes.

[0443] The imaging evaluations at the 4- and 24-hours post-infusion provide dual-isotope images for both99mTc andU1ln. Given the relatively short half-life of the 99mTc isotope, the imaging evaluations performed at 72- and 96-hours post-infusion provide valid imaging for theU1ln isotope only.

[0444] The dosimetric results of MTPluIn-DTPA-besilesomab dosimetry will be used to select participants eligible to receive90Y-DTPA-besilesomab, as determined by the Decision Tree (Figure 6).

[0445] Selected participants will receive a single 45 MBq / kg lean body weight (lbw) infusion of90Y-DTPA-besilesomab unless the dosimetry results indicate that one or more of the absorbed dose limits may be exceeded (i.e., liver dose > 15 Gy, kidney dose > 13 Gy, or bone marrow dose > 35 Gy) in which case the administered activity may be reduced by up to 20% providing all criteria are satisfied. The Decision Tree will also be utilized for dose adjustment (i.e., reduction) in participants predicted to have high ranges of90Y-DTPA-besilesomab accumulation in non-hematopoietic tissues at risk.

[0446] After receiving90Y-DTPA-besilesomab, participants will undergo reduced intensity conditioning with a selection of chemotherapeutic agents permitted per protocol. Participants who fail dosimetric evaluation will not receive90Y-DTPA-besilesomab, undergo bone marrow conditioning by institutional SOC, be excluded from all additional study procedures except the End-of-Study (EOS) Safety Follow-Up (to be performed as late as possible before commencing bone marrow conditioning by institutional SOC).

[0447] Part A will comprise 4 study periods: the Screening Period, the Dosimetric Period, the Treatment Period, and the Follow-up Period. The Treatment Period contains two stages: (1)90Y-DTPA-besilesomab Conditioning Stage and (2) the reduced intensity conditioning, GvHD prophylaxis, and Transplantation Stage. Number of Participants (Part A):

[0448] Approximately 9 participants will be enrolled into the study. Study enrollment will continue until a total of 9 AML / MDS participants have undergone conditioning with90Y-DTPA-besilesomab followed by reduced intensity conditioning prior to alloHSCT.

[0449] Note: Enrolled means a participant’s, or their legally acceptable representative’s, agreement to participate in a clinical study following completion of the informed consent process and the participant has been deemed eligible for participation in the study by the Principal Investigator.

[0450] Study Arms and Duration (Part A):

[0451] Part A is an open-label, single-arm study. The total duration of study participation for each participant will be approximately 5 months.

[0452] Data Monitoring / Other Committee (Part A):

[0453] An independent data monitoring committee (IDMC) will be appointed for this study. The data monitoring committee (board) is a group of independent scientists who are appointed to monitor the safety and scientific integrity of a human research intervention and make recommendations to the sponsor regarding the stopping of a study for efficacy, harms, or futility. The committee will include physicians with experience in the management of AML and a nuclear medicine physician.

[0454] Statistical Analysis Plan (Part A):

[0455] No formal statistical analyses of safety, dosimetric, or efficacy data will be performed. Given no safety signals of concern or technical issues in Part A, Part B will open for patient enrollment.

[0456] Table 12. Dosimetric Objectives and Endpoints (Part B)

[0457] Table 13. Therapeutic Objectives and Endpoints (Part B)

[0458] Study Design (Part B)

[0459] Part B will be open-label and enroll approximately 256 AML / MDS participants at up to 15 investigative sites.

[0460] Participants will be randomised at an allocation ratio of 1: 1 to receive either90Y-DTPA-besilesomab as a conditioning agent followed by reduced intensity conditioning prior to alloHSCT (n = 128) or reduced intensity conditioning alone prior to alloHSCT (n = 128). The reduced intensity conditioning regimen will be performed per institutional SOC. The randomization procedure will distribute age, MRD status, AML or MDS disease status, and HCT-CI grade equally across treatment groups. The first 30 participants randomised to receive90Y-DTPA-besilesomab plus reduced intensity conditioning will undergo the identical pre-therapeutic, dosimetric evaluation andluIn-DTPA-besilesomab plus reduced intensity conditioning therapy administered to participants in Part A.

[0461] In the prior investigator-initiated studies, MTPluIn-DTPA-besilesomab dosimetry was used to select participants for90Y DTPA-besilesomab conditioning. Therefore, in this cohort of 30 participants, although participants will undergo pre-therapeutic, dosimetric evaluation with bothinIn-DTPA-besilesomab and99mTc-besilesomab to enable comparative analysis, the dosimetric results of MTPU1ln DTPA-besilesomab dosimetry will be used to select participants eligible to receive90Y DTPA-besilesomab, as determined by the Decision Tree (Figure 6).

[0462] The dosimetric results of MTPluIn-DTPA-besilesomab dosimetry will be used to select participants eligible to receive90Y-DTPA-besilesomab, as determined by the Decision Tree (Figure 6).

[0463] After these 30 participants have completed dosimetry, the dosimetric results of MTPluIn-DTPA-besilesomab dosimetry will be used as the “gold standard” to compare STPinIn-DTPA-besilesomab, MTP99mTc-besilesomab, and STP99mTc-besilesomab dosimetric outcomes with sufficient power. If the results of this comparative analysis support the use of the chosen STP99mTc-besilesomab dosimetric approach, then STP99mTc-besilesomab dosimetry will be used for the remaining patients recruited to the study. If the results do not support the use of the chosen STP dosimetry approach, then participants will continue to undergo MTP dosimetry withluIn-DTPA- besilesomab.

[0464] Selected participants will receive a single 45 MBq / kg lean body weight (lbw) infusion of90Y DTPA-besilesomab unless the dosimetry results indicate that one or more of the absorbed dose limits may be exceeded (i.e., liver dose > 15 Gy, kidney dose > 13 Gy, or bone marrow dose > 35 Gy) in which case the administered activity may be reduced by up to 20% providing all criteria are satisfied. The Decision Tree will also be utilized for dose adjustment (i.e., reduction) in participants predicted to have high ranges of90Y DTPA-besilesomab accumulation in non-hematopoietic tissues at risk.

[0465] After receiving90Y-DTPA-besilesomab, participants will undergo reduced intensity conditioning with a selection of chemotherapeutic agents permitted per protocol. Participants who fail dosimetric evaluation will not receive90Y-DTPA-besilesomab and will undeigo bone marrow conditioning by institutional SOC and will be excluded from all additional study procedures excepting EOS Safety Follow-Up as late as possible before commencing bone marrow conditioning by institutional SOC.

[0466] Part B will comprise 4 study periods: the Screening Period, the Dosimetric Period, the Treatment Period, and the Follow-up Period. The Treatment Period contains two stages: (1)90Y-DTPA-besilesomab Conditioning Stage and (2) the reduced intensity conditioning, GvHD prophylaxis, and Transplantation Stage.

[0467] Number of Participants:

[0468] Approximately 256 participants are expected to be enrolled into Part B to provide the study sufficient analytical power. The first 30 participants randomised to receive90Y-DTPA-besilesomab plus reduced intensity conditioning will participate in the dosimetric substudy to provide the study sufficient analytical power based on the Dosimetric Primary Objective. Note: Enrolled means a participant’s, or their legally acceptable representative’s, agreement to participate in a clinical study following completion of the informed consent process and the participant has been deemed eligible for participation in the study by the Principal Investigator.

[0469] Study Arms and Duration:

[0470] Part B will be an open-label, randomised study with 2 treatment arms allocated in a 1 : 1 ratio to receive either90Y- DTPA-besilesomab as a conditioning agent followed by reduced intensity conditioning prior to alloHSCT (n = 128) or reduced intensity conditioning alone prior to alloHSCT (n = 128). Thirty (n = 30) participants randomised to receive90Y-DTPA-besilesomab plus reduced intensity conditioning will participate in the dosimetric substudy.

[0471] Participants randomised to receive90Y-DTPA-besilesomab plus reduced intensity conditioning who fail dosimetric evaluation will not receive90Y-DTPA-besilesomab and will undergo bone marrow conditioning by institutional SOC and will be excluded from all additional study procedures excepting EOS Safety Follow-Up as late as possible before commencing bone marrow conditioning by institutional SOC.

[0472] The total duration of study participation for each participant will be approximately 14 months.

[0473] Data Monitoring / Other Committee:

[0474] An independent data monitoring committee (IDMC) will be appointed for this study. The data monitoring committee (board) is a group of independent scientists who are appointed to monitor the safety and scientific integrity of a human research intervention, and to make recommendations to the sponsor regarding the stopping of a study for efficacy, for harms, or for futility. The committee will include physicians with experience in the management of AML and a nuclear medicine physician.

[0475] Statistical Analysis Plan (Part B)

[0476] A review of the literature suggests that up to 90% of the relapses occur within 12 months after alloHSCT in populations approximately > 50 years of age with the remaining relapses occurring within the next 12 months to achieve a steady plateau (Rashidi A et al., 2016) . Therefore, the first efficacy signal (RFS) can be determined at 12 months post-transplant, and 1-year overall survival (OS) can be determined at 12 months post-transplant.

[0477] Study Population

[0478] This study will emoll male and female adults who have been classified as having intermediate or high risk AML according the European LeukemiaNet (ELN) classification (Table 6, Dbhner H, et al., 2022) and who are unable to tolerate standard MAC with sufficient levels of fitness enabling them to comply with study procedures and assessments.

[0479] Inclusion Criteria

[0480] Participants are eligible to be included in the study only if all of the following criteria apply:

[0481] 1) Ability to understand and willingness to sign a written informed consent form and comply with all study requirements

[0482] 2) Male or female participants aged > 18 years of age unable to tolerate standard MAC; 3) Kamofsky score > 70%;

[0483] 4) Absence of dyspnoea with documented diffusion lung capacity for carbon monoxide (TLco) >40% (adjusted for haemoglobin, if available) and FEV1 / FVC > 50% of predicted, as determined by institutional standard-of-care procedures;

[0484] 5) Participant is fit for transplantation by assessment of an experienced haematologist:

[0485] 6) HLA-identical sibling; or

[0486] 7) HLA-compatible (> 9 / 10 antigens matched for HLA-A, -B, -C, -DRB 1, and -DQB 1) unrelated donor; and

[0487] 8) AML participants in CR1 and CR2 classified as intermediate and high relapse risk who are MRD+ or MRD- or high risk MDS as defined by the LeukemiaNet 2022 consensus criteria (Dbhner H., et al 2022; Arber DA et al., 2022).

[0488] 9) Participants may have received prior autologous (but not allogeneic) haematopoietic stem cell transplantation in remission.

[0489] Exclusion Criteria

[0490] A participant will be excluded from participation in the trial if one or more of the following criteria are met:

[0491] 1) Acute promyelocytic leukaemia (APL);

[0492] 2) Severe organ dysfunction, defined as: a) Left ventricular ejection fraction <50%; b) Participants who receive supplementary continuous oxygen; c) Serum bilimbin >1.5 * upper limits of normal (ULN) (if not considered Gilbert-Syndrome); d) aspartate aminotransferase (AS AT) >5 x ULN or alanine aminotransferase (AL AT) >5 x ULN; or e) Glomerular Filtration Rate (GFR) (measured via isotope excretion or similar method) < 50 n / min / 1.73m2);

[0493] 3) Treatment with any investigational drug within 30 days before start of study treatment;

[0494] 4) Treatment with any radiopharmaceutical (within a period corresponding to 10 half-lives of the radionuclide used for labelling the respective radiopharmaceutical) prior to the administration ofluIn-DTPA-besilesomab or99mTc-besilesomab;

[0495] 5) Known history of seropositivity to hepatitis B virus (HBV), hepatitis C (HCV), or human immunodeficiency virus (HIV);

[0496] 6) Known history of tuberculosis (TB) diagnosis;

[0497] 7) Known history of chronic pulmonary disease;

[0498] 8) Uncontrolled infection at the time of enrolment;

[0499] 9) History of allogeneic transplantation; 10) Manifestation of AML in the central nervous system;

[0500] 11) Presence of HAMA;

[0501] 12) Pregnant or breastfeeding women;

[0502] 13) Men unable or unwilling to use adequate contraception methods from enrolment to a minimum of 1 year after the last dose of chemotherapy. Before contraception methods can be stopped, a medical doctor should be consulted;

[0503] 14) Women of childbearing potential unable or unwilling to use adequate contraception methods from enrolment to a minimum of 1 year after the last dose of chemotherapy. Adequate contraception methods are defined as continuous and correct application of a contraception method. Women who fulfill the following criteria are eligible for enrolment: a) Post-menopausal (12 months of natural amenorrhea or 6 months of amenorrhea with Serum Follicle Stimulating Hormone (FSH) > 40 U / L); or b) Permanently sterile; or c) Sexual abstinence; or d) Vasectomy of the sexual partner.

[0504] 15) Any other condition that in the opinion of the Principal Investigator could affect their participation in the study, impair the ability of the Investigator to evaluate the participant, or impair the participant’s ability to complete study, or pose a risk to participant’s health and safety.

[0505] Lifestyle Considerations

[0506] Participants must comply with the radiation protection rules that are used by the treating institution in order to protect their contacts and the general public.

[0507] Meals and Dietary Restrictions

[0508] No dietary restrictions are required prior to dosing.

[0509] Instruct participants to drink a sufficient amount of water to ensure adequate hydration before administration of radiolabelled besilesomab and, to reduce radiation exposure to normal organs, urge them to drink and urinate as often as possible during the first hours following administration.

[0510] Screen Failures

[0511] Screen failures will not count towards total study enrollment.

[0512] A screen failure occurs when a participant who consents to participate in the clinical study is not subsequently enrolled in the study. A minimal set of screen failure information is required to ensure transparent reporting of screen failure participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities.

[0513] Minimal information includes demographics, screen failure details, eligibility criteria, and any AE. Individuals who do not meet the criteria for participation in this study (screen failure) can be rescreened once. Rescreened participants must re-consent and be assigned a new participant number.

[0514] Study Intervention(s) and Concomitant Therapy

[0515] By definition, study interventions are all pre-specified, investigational and non-investigational medicinal products, medical devices and other interventions (e.g., surgical and behavioral) intended to be administered to the study participants during the study conduct.

[0516] Study Intervention(s) Administered

[0517] The three investigational medicinal products (IMPs) to be administered in this study are all radiolabelled versions of besilesomab, a murine monoclonal antibody (mAb) with specificity for CD66 glycoproteins expressed on both precursor and mature cells of myeloid lineage. In clinical application, besilesomab binds primarily to CD66 glycoproteins situated in the bone marrow and spleen with relatively minimal uptake by non-haematopoietic organs (Carrasco et al., CD66 expression in acute leukaemia, Ann Hematol, 2000).

[0518] As such, besilesomab serves as a targeting moiety for the 3 radioisotopes currently employed to (1) select participants suitable for targeted conditioning via RIT, and (2) implement radio-immunotherapy-induced myeloablative conditioning prior to HSCT, as follows:

[0519] 90Y-DTPA-besilesomab : Therapeutic Targeted Conditioning AgentluIn-DTPA-besilesomab: Pretherapeutic Dosimetric Participant Selection Agent

[0520] 99mTc-besilesomab : Pretherapeutic Dosimetric Participant Selection Agent

[0521] For the purpose of this study, all 3 radiolabelled versions of besilesomab are IMPs.

[0522] Table 14 summarizes the characteristics of the 3 radiopharmaceuticals administered in this study.

[0523] Table 14. Study Interventions Administered

[0524] Abbreviations: lbw = lean body weight; IV = intravenous; MBq = Megabecquerel; PO = oral; SOC = standard- of-care

[0525] Dosage and Administration

[0526] In Part A, all participants will receive a single infusion ofluIn-DTPA-besilesomab (approximately 185 MBq) immediately followed by a single infusion of99mTc-besilesomab (between 400 MBq and 800 MBq) in a single session.

[0527] In Part B, the first 30 participants randomised into the90Y-DTPA-besilesomab plus reduced intensity conditioning treatment arm will receive a single infusion ofluIn-DTPA-besilesomab (approximately 185 MBq) immediately followed by a single infusion of99mTc-besilesomab (between 400 MBq and 800 MBq) in a single session. It is anticipated that the remaining 98 participants will randomised into the90Y-DTPA-besilesomab plus reduced intensity conditioning treatment arm will receive a single infusion of 99mTc-besilesomab (between 400 MBq and 800 MBq) alone. If the analysis of dosimetric outcomes does not warrant the use of99mTc-besilesomab, then the remaining 98 participants in Part B randomised into the90Y-DTPA-besilesomab plus reduced intensity conditioning treatment arm will receive a single infusion ofluIn-DTPA-besilesomab (approximately 185 MBq) or99mTc-besilesomab and undergo either STP or MTP imaging evaluations for the purpose of patient selection, as determined by the comparative analysis as the most efficacious.inIn-DTPA-Besilesomab

[0528] The radiolabeledluIn-DTPA-besilesomab solution should be administered intravenously as a single dose only, delivered intravenously as a slow infusion over a 10- to 15-minute period. The medicinal product will be delivered by the manufacturer to the investigative site as radiolabelled solution in a glass vial. The radiolabelled solution is drawn into an aseptic syringe and administered via infused IV. The recommended activity ofluIn-DTPA- Besilesomab is approximately 185 MBq. The product must be administered prior to its expiration date.

[0529] "mTc-Besilesomab

[0530] The radiolabeled 99mTc-besilesomab solution should be administered intravenously as a single dose only. The medicinal product should be reconstituted and radiolabeled immediately before administration to the participant.

[0531] For diagnostic scintigraphic imaging in adults, i.e., for determining the location of inflammation or infection in peripheral bone in adults with suspected osteomyelitis, the recommended activity of99mTc-besilesomab is between 400 MBq and 800 MBq, i.e., corresponding to the administration of 0.25 to 1 mg of besilesomab.

[0532] In this diagnostic application, image acquisition should start 3 to 6 hours after administration with additional acquisition 24 hours after initial injection is recommended, such acquisition can be performed using planar imaging (Scintimun, 2010) and SPECT or SPECT / CT (Bouter C et al, 2019).

[0533] Therefore, in this study, pretherapeutic dosimetry requires imaging at 4 and 24 hours after administration to enable the selection of a STP for post-infusion imaging.

[0534] 90Y-DTPA-Besilesomab

[0535] In Part A, patient selection for treatment with90Y-DTPA-besilesomab will be determined usingluIn-DTPA- besilesomab MTP dosimetry in accordance with the Decision Tree (Figure 6). Participants will be selected for90Y-DTPA-besilesomab conditioning if the dosimetric results of1 1 1In-DTPA-bcsilcsomab MTP dosimetry confirm that a sufficient absorbed dose of the targeted radiopharmaceuticals will be delivered to the bone marrow without over-dosing non-hematopoietic tissues at risk.

[0536] In Part B, patient selection for treatment with90Y-DTPA-besilesomab in the first 30 participants will be determined usingluIn-DTPA-besilesomab MTP dosimetry in accordance with the Decision Tree (Figure 6). Participants will be selected for90Y-DTPA-besilesomab conditioning if the dosimetric results ofluIn-DTPA-besilesomab MTP dosimetry confirm that a sufficient absorbed dose of the targeted radiopharmaceuticals will be delivered to the bone marrow without over-dosing non-hematopoietic tissues at risk.

[0537] It is anticipated that the remaining 98 participants will randomised into the90Y-DTPA-besilesomab plus reduced intensity conditioning treatment arm in Part B will undergo patient selection via STP99mTc-besilesomab dosimetry. If the analysis of dosimetric outcomes does not warrant the use of99mTc-besilesomab, then the remaining 98 participants in Part B randomised into the90Y-DTPA-besilesomab plus reduced intensity conditioning treatment arm will receive a single infusion ofluIn-DTPA-besilesomab (approximately 185 MBq) or99mTc-besilesomab and undergo either STP or MTP imaging evaluations for the purpose of patient selection, as determined by the comparative analysis as the most efficacious.

[0538] Selected participants will receive a single 45 MBq / kg lean body weight (lbw) infusion of90Y-DTPA-besilesomab unless the dosimetry results indicate that one or more of the absorbed dose limits may be exceeded, in which case the administered activity may be reduced by up to 20% providing all criteria are satisfied. The Decision Tree will be utilized for dose adjustment (i.e., reduction) in participants predicted to have high ranges of90Y-DTPA- besilesomab accumulation in non-hematopoietic tissues at risk. A protein dose of 1 to 1.5 mg should be administered depending on radiation activity required (the recommended activity of90Y-DTPA-besilesomab.

[0539] The radiolabeled90Y-DTPA-besilesomab solution should be administered intravenously as a single dose only, delivered intravenously as a slow infusion over a 10- to 15-minute period. The product must be administered prior to its expiration date.

[0540] Contraindications

[0541] The following conditions are contraindications for administering the radiolabelled versions of besilesomab: hypersensitivity to the active substance, other murine antibodies, any of the excipients, or any of the components of the labeled radiopharmaceutical;

[0542] HAMA seropositivity; and / or pregnancy.

[0543] Blinding, Masking

[0544] Not applicable. Both the Part A and Part B will be open-label.

[0545] Dose Modification

[0546] Participants selected to undergo90Y-DTPA-besilesomab conditioning after dosimetric evaluation as determined by the Decision Tree (Figure 6) will receive a single 45 MBq / kg lean body weight (lbw) infusion of90Y-DTPA- besilesomab unless the dosimetry results indicate that one or more of the absorbed organ dose limits may be exceeded. The prespecified organ dose limits are > 15 Gy for the liver dose, > 13 Gy for the kidney dose, and > 35 Gy for the bone marrow dose.

[0547] In the event that dosimetric results indicate these organ dose limits will be exceeded, then these dose limits may be recalculated based on up to a 20% reduction of dose. After such calculation, it should be established that the estimated bone marrow dose will be greater than the liver dose. Given such favorable estimates, the participant is eligible to receive the reduced dose.

[0548] The Decision Tree will be utilized for dose adjustment (i.e., reduction) in participants predicted to have high ranges of90Y-DTPA-besilesomab accumulation in non-hematopoietic tissues at risk.

[0549] Dosimetry Procedures and Assessments During the Dosimetry Period (Day -23 to Day -19) of both the Part A and Part B, participants will undergo dosimetric evaluations.

[0550] The SPECT / CT and planar images collected locally at each investigative site will be transmitted to a central laboratory for evaluation and dosimetry analysis. The decision to select a participant for targeted conditioning with90Y-DTPA-besilesomab will be based on the outcome of the centralized evaluation.

[0551] The Image Acquisition Charter describes the procedures for the acquisition of dosimetry data for both Part A and Part B. The Dosimetry Analysis Manual describes the analytical procedures to be performed by the central analytical facility.

[0552] Dosimetry Procedures during Part A

[0553] All subjects will receive premedication 30 to 60 minutes prior to the infusion ofluIn-DTPA-besilesomab and99mTc-besilesomab consisting of chlorpheniramine 4 mg PO and paracetamol 1 g both PO.

[0554] Vital signs should be taken 15 ± 5 minutes prior to the IMP administration, 15 ± 5 minutes after the end of infusion, and 1 hour ± 5 minutes post-infusion.

[0555] In a single session, participants will receive a single infusion ofluIn-DTPA-besilesomab (approximately 185 MBq) immediately followed by a single infusion of 99mTc-besilesomab (between 400 MBq and 800 MBq) and undergo SPECT / CT and planar image acquisition at the following timepoints post-infusion: whole-body planar scan immediately after the end of infusion (i.e., T = zero; dual-isotope imaging for both "mTc and111In);

[0556] SPECT / CT and whole-body planar scan at 4- and 24-hours post-infusion (dual-isotope imaging for both "mTc and111In); and

[0557] SPECT / CT and whole-body planar scan at 72- and 96-hours post-infusion (single isotope imaging for111In only).

[0558] Dosimetry Procedures during Part B

[0559] All participants randomised to the90Y-DTPA-besilesomab plus reduced intensity conditioning treatment arm, all participants will receive premedication 30 to 60 minutes prior to the infusion of111In-DTPA-besilesomab and / or99mTc-besilesomab consisting of chlorpheniramine 4 mg PO and paracetamol 1 g both PO.

[0560] Vital signs should be taken 15 ± 5 minutes prior to the IMP administration, 15 ± 5 minutes after the end of infusion, and 1 hour ± 5 minutes post-infusion.

[0561] In a single session, these first 30 participants will receive a single infusion of1 1 1In-DTPA-bcsilcsomab (approximately 185 MBq) immediately followed by a single infusion of 99mTc-besilesomab (between 400 MBq and 800 MBq) and undergo SPECT / CT and planar image acquisition at the following timepoints post-infusion: whole-body planar scan immediately after the end of infusion (i.e., T = zero; dual-isotope imaging for both "mTc and111In);

[0562] SPECT / CT and whole-body planar scan at 4- and 24-hours post-infusion (dual-isotope imaging for both "mTc and111In); and SPECT / CT and whole-body planar scan at 72- and 96-hours post-infusion (single isotope imaging for111In only).

[0563] After the first 30 participants have undergone dosimetry, The single timepoint for STP dosimetry will be determined by the comparative analysis of dosimetric outcomes among the first 30 participants, i.e., an analysis of STP and MTP outcomes for bothinIn-DTPA-besilesomab and99mTc-besilesomab dosimetry.

[0564] Thereafter, it is anticipated that the remaining 98 participants randomised to the90Y-DTPA-besilesomab plus reduced intensity conditioning treatment arm will receive a single infusion of99mTc-besilesomab (between 400 MBq and 800 MBq,) and undergo SPECT / CT and planar image acquisition at the following timepoints postinfusion:

[0565] SPECT / CT and whole-body planar scan immediately after the end of infusion (i.e., T = zero);

[0566] SPECT / CT and whole-body planar scan at a single timepoint

[0567] If the analysis of dosimetric outcomes does not warrant the use of99mTc-besilesomab, then the remaining 98 participants in Part B randomised into the90Y-DTPA-besilesomab plus reduced intensity conditioning treatment arm will receive a single infusion ofluIn-DTPA-besilesomab (approximately 185 MBq) or99mTc-besilesomab and undergo either STP or MTP imaging evaluations for the purpose of patient selection, as determined by the comparative analysis as the most efficacious.

[0568] Example 6. Further confirmation of the feasibility of Single-Time-Point Imaging for Organ Dosimetry in90Y- DTPA-Besilesomab radioimmunotherapy in patients with Haematological Malignancies

[0569] Introduction

[0570] As described above traditionally, radioimmunotherapy dosimetry has relied on multiple -time -point (MTP) imaging, incorporating whole-body and SPECT / CT scans alongside serial blood sampling over several days. Whilst MTP dosimetry provides detailed pharmacokinetic data, it is resource intensive, placing a significant burden on both patients and nuclear medicine departments. Additionally, scanner availability can be a limiting factor, particularly in high-throughput centers. By simplifying the process, single -time -point (STP) dosimetry has the potential to reduce patient burden, streamline workflow in nuclear medicine departments, and lower overall costs. Furthermore, the implementation of STP dosimetry could enhance the feasibility of multi-center clinical trials and facilitate broader clinical adoption in routine practice. Given the challenges associated with MTP dosimetry, this study aims to evaluate the feasibility and accuracy of STP dosimetry for 90Y-DTPA-Besilesomab RIT using imaging acquired post-administration.

[0571] Methods

[0572] Radioimmunoconjugates referenced throughout the example were produced as described in Example 1. SPECT / CT imaging data from 28 patients in three clinical trials were retrospectively analyzed. Detailed patient characteristics are shown in Table 15. Each underwent SPECT / CT at approximately 24, 72, and 96h postadministration of 11 lln-DTPA-Besilesomab (175.6±10.8 MBq), a surrogate for90Y-DTPA-Besilesomab.

[0573] Table 15. Patient characteristics (N=28)

[0574] SPECT calibration factors were derived using a cylindrical phantom containing approximately 130MBq of uniformly distributed Indium-Ill. Imaging and reconstruction were performed using the same acquisition parameters as the patient protocol. Detailed SPECT / CT imaging parameters are provided in Table 16. Organ volumes for the liver and kidneys were delineated from low-resolution CT scans acquired during SPECT / CT imaging on an Infinia Hawkeye system. Red marrow volume was estimated using the method of Shen et al. (Improved prediction of myelotoxicity using a patient-specific imaging dose estimate for non-marrow-targeting (90)Y-antibody therapy. J Nucl Med. 2002), which extrapolates whole-body red marrow volumes from measurements in the L2-L4 vertebrae. Mean voxel counts for liver and kidneys were obtained from regions of interest on the SPECT images. For bone marrow, maximum voxel counts were used as a surrogate for mean counts to mitigate partial volume effects due to small organ size. SPECT-derived counts were converted to Indium-Ill activity using the phantom derived calibration factor. Subsequently, the fraction of administeredluIn-DTPA- Besilesomab activity at each time point was used to estimate corresponding activity of90Y-DTPA-Besilesomab in the target and risk organs based on physical decay using respective half-lives. Table 16. Image acquisition parameters

[0575] For multi-time-point dosimetry, time-activity curves were generated for each organ, and a mono-exponential function was fitted to determine the effective half-life ofinIn-DTPA-Besilesomab, along with the percentage of administered activity for each time point. Patient-specific effective half-lives for Yttrium-90 (Teff) were determined from mono-exponential fitting of time-activity data, and residence times were calculated using the following formula: T=l / (LN(2))xTeffxAo / Ainiii, where r is the residence time in h, Aois the calculated activity in the organ at the administration time (tO) measured from mono-exponential fitted time-activity curves and AMU is the administered Indium- 111 activity in MBq. The time-integrated activity was calculated by multiplying equation 1 with the administered Ytrrium-90 activity as follows: A= TXAYSO. S factors, scaled with patient organ mass were multiplied by the time-integrated activity using the following formula to estimate the total dose to the bone marrow, liver, and kidneys: Dose (Gy)= AxSpatient, where A is the time -integrated activity in the organ of interest in MBq-h.

[0576] For STP dosimetry, the mean population effective half-life of Yttrium-90 for each organ of interest was derived from the MTP data. The STP approach estimated the initial activity (Ao) in each organ by extrapolating from the activity measured at the 24-h time point and Teff Time-integrated activity was then determined using as described above (A= TXAY9O), and absorbed doses were subsequently calculated as described above (Dose (Gy)= Residence time was obtained through curve fitting, performed in Microsoft Excel, and dosimetric calculations were carried out using Olinda vl.O software (Hermes Medical Solutions).

[0577] The STP absorbed doses were also calculated using the same method at the 72-h and 96-h imaging time points and compared to those obtained using the 24-h time point.

[0578] All statistical analyses were performed using Excel (Version 2408). Box plots were used to visualize the distribution of effective half-life in the organs. The relationship between referenced MTP and STP was assessed using regression analysis. To check the errors, the percentage change in the total received absorbed dose (Gy) between STP and MTP for bone marrow, liver, and kidneys was estimated at different STP time points.

[0579] Results

[0580] Effective half-life The mean effective half-life in bone marrow, liver and kidneys was 47.4 ±4.31, 69.8 ±11.8, 92.4 ±57.3h, respectively. The detailed graphical representation of the effective half-life distribution estimated using MTP in the organs is provided in Figure 12.

[0581] Organ absorbed doses

[0582] The mean absorbed dose per unit of administered activity (DpA) (mGy / MBq) from 90Y-DTPA-Besilesomab to bone marrow, liver and kidneys in MTP method were 5.79 ±1.74, 2.91±1.88 and 1.33 ±1.56, respectively. Similarly, average absorbed dose per administered activity to bone marrow, liver and kidneys in STP methods were 5.79 ±1.62, 3.10 ±2.44 and 1.28 ±0.84, respectively, for 24h STP method; 6.10 ±1.88, 3.02 ±2.03 and 1.26 ±0.91, respectively, for 72h STP and 5.96 ±1.91, 3.01 ±1.97 and 1.19 ±0.88, respectively, for 96h STP. A detailed overview of MTP and STP doses is provided in Table 17.

[0583] Table 17. Absorbed dose per unit administered activity (DpA) results (mGy / MBq) in bone marrow (BM), liver and kidneys with MTP and STP (24-96h).

[0584] Comparison of 24h STP dosimetry with MTP dosimetry method

[0585] The relationship between STP dosimetry at 24h and MTP dosimetry is illustrated in Figure 13. A strong positive correlation was noted between 24h STP and MTP DpA results for the bone marrow and liver (R=0.98 and R=0.99 respectively). However, the kidney DpA has a larger variability and a moderate positive correlation between STP and MTP (R=0.70).

[0586] Comparison of STP methods at 24, 72 and 96h

[0587] The smallest percentage differences between STP and MTP dosimetry were observed at the 96-hour time point across all organs of interest, with liver dose errors remaining below 10% (Table 18). At 72 hours, liver dose errors remained within 20% for all patients, with 93% falling within 10%. By contrast, at 24 hours, 61% of patients had liver dose errors within 10%, while 14% exceeded 20%. For bone marrow, all STP dose estimates at 96 hours were within 20% of the MTP values, with 93% of estimates within 10%. The percentage of results within 10% reduced at 72h and again at 24h; however, 86% remained within 10%. Table 18. Percent change of total received absorbed dose (Gy) between STP and MTP in the total number of patients (N=28) for bone marrow (BM), liver and kidneys at different STP time points.

[0588] For kidneys, STP dose estimates were within 20% of MTP values in 89% of patients at 96 hours, with the remaining 11% showing larger deviations. Errors were more pronounced at earlier time points: 50% of kidney dose estimates at 72 hours and 75% at 24 hours exceeded 20%. A comparative overview of absorbed dose per unit activity (DpA) from MTP, STP, and the reference study is presented in Figure 14. A detailed comparison of imaging and dose threshold parameters used in the present study and the reference study by Ringhoffer et al. (188Re or 90Y-labelled anti-CD66 antibody as part of a dose-reduced conditioning regimen for patients with acute leukaemia or myelodysplastic syndrome over the age of 55: results of a phase I— II study, Br J Haematol, 2005), are provided in Table 19.

[0589] Table 19. Imaging and dose threshold parameters used in the present study (STP 24h and MTP) and the reference study (Ringhoffer et al.; cited above) Conclusion

[0590] These results show that single-time point dosimetry is feasible for organs in90Y-DTPA-Besilesomab radioimmunotherapy and that the STP dosimetry framework is suitable for measuring the doses of critical organs and taiget volumes. STP dosimetry can therefore provide adequate and reliable absorbed-dose estimates for90Y- DTPA-Besilesomab dosimetry which are comparable to the results derived from MTP methods. From an economic and patient well-being perspective, the 24-h is the most practical time point for dosimetry calculations, offering good accuracy for bone marrow and liver but not kidneys. However, in terms of optimizing dosimetry accuracy in all oigans, the 96-h imaging time point provides the smallest difference to MTP for both the target organ and organs at risk.

Claims

78CLAIMS1. Use of a first (dosimetric) radioimmunoconjugate (RIC) comprising as radionuclide metastable technetium-99 (99mTc) for subject specific dosimetry of an effective amount of a second (therapeutic) RIC comprising yttrium-90 (90Y) as radionuclide.

2. A metastable technetium-99 (99mTc)-comprising RIC for use in determining subject specific dosimetry of an effective amount of a second (therapeutic) RIC comprising yttrium-90 (90Y) as radionuclide.

3. The metastable technetium-99 (99mTc)-comprising RIC for use according to claim 2, wherein the subject specific dosimetry is determined by comparing the signal intensity of the liver and the signal intensity of one or more ribs of the thorax, preferably wherein a safe dose for the subject results in a higher signal intensity of the one or more ribs of the thorax when compared to the signal intensity of the liver, more preferably wherein a suitable dose results in at least a 1,5: 1 rib to liver signal intensity, most preferably at least a 2: 1 rib to liver signal intensity.

4. Use of a first (dosimetric) RIC comprising as radionuclide metastable technetium-99 (99mTc) for identifying by dosimetry subjects eligible for safe and effective exposure to an effective amount of a second (therapeutic) RIC comprising yttrium-90 (90Y) as radionuclide.

5. A metastable technetium-99 (99mTc)-comprising RIC for use in identifying by dosimetry subjects eligible for safe and effective exposure to an effective amount of a second (therapeutic) RIC comprising yttrium-90 (90Y) as radionuclide.

6. The metastable technetium-99 (99mTc)-comprising RIC for use according to claim 5, wherein the eligibility of the subject for safe and effective exposure to an effective amount of a second radioimmunoconjugate (RIC) is determined by comparing the signal intensity of the liver and the signal intensity of one or more ribs of the thorax, preferably wherein the subject is considered eligible upon a higher signal intensity of the one or more ribs of the thorax when compared to the signal intensity of the liver, more preferably wherein the subject is considered eligible upon at least a 1,5:1 rib to liver signal intensity, most preferably at least a 2:1 rib to liver signal intensity.

7. Use of a first (dosimetric) RIC comprising as radionuclide metastable technetium-99 (99mTc) for determining by dosimetry the inclusion of a subject in a treatment plan, said treatment plan comprising the administration of an effective amount of a second (therapeutic) RIC comprising yttrium-90 (90Y) as radionuclide.

8. A metastable technetium-99 (99mTc)-comprising RIC for use in determining the inclusion of a subject in a treatment plan, said treatment plan comprising the administration of an effective amount of second (therapeutic) RIC comprising yttrium-90 (90Y) as radionuclide.

9. The metastable technetium-99 (99mTc)-comprising RIC for use according to claim 8, wherein the inclusion of the subject in the treatment plan is determined by comparing the signal intensity of the liver and the signal intensity of one or more ribs of the thorax, preferably wherein in a subject suited for inclusion in the treatment plan a higher signal intensity of the one or more ribs of the thorax when compared to the signal intensity79 of the liver is observed, more preferably wherein the subject is included in the treatment plan upon at least a 1 ,5 : 1 rib to liver signal intensity, most preferably at least a 2:1 rib to liver signal intensity.

10. The use or metastable technetium-99 (99mTc)-comprising RIC for use according any one of the preceding claims, wherein the effective amount of the RIC comprising yttrium-90 (90Y) as radionuclide is 45 MBq / kg lean body weight (lbw).

11. The use or metastable technetium-99 (99mTc)-comprising RIC for use according any one of the preceding claims, wherein 45 MBq / kg leanbody weight (lbw) of the second RIC comprising yttrium-90 (90Y) as radionuclide is administered as a single dose.

12. The use or metastable technetium-99 (99mTc)-comprising RIC for use according to claim 11, wherein the single dose administration is intravenous single dose administration.

13. The use or metastable technetium-99 (99mTc)-comprising RIC for use according to any one of the preceding claims, wherein said use or method further comprises a step of determining safety and effectiveness of a treatment plan with a yttrium-90 (90Y)-comprising radioimmunoconjugate (RIC) in said subject calculated from (i.e. based on) a scintigram of said subject after receiving a single dose of between 400-800 MBq / patient metastable technetium-99 (99mTc) radionuclide-comprising RIC, wherein:Upon a calculated90Y liver absorption dose of >15Gy, or a calculated90Y kidney absorption dose of >13 Gy, ora calculated90Y bone marrow absorption dose of >35 Gy arrived at by measuring the99mTc absorption doses and wherein a 20% reduction of RIC does not result in a lowering of said calculated 90Y liver absorption dose to 15Gy or less, said calculated90Y kidney absorption dose to 13Gy or less, and said calculated90Y bone marrow absorption dose to 35Gy or less, the subject is excluded from treatment;Upon a calculated90Y liver absorption dose of >15Gy, or a calculated90Y kidney absorption dose of >13 Gy, ora calculated90Y bone marrow absorption dose of >35 Gy arrived at by measuring the99mTc absorption doses, and wherein a 20% reduction of RIC does result in a lowering of said calculated 90Y liver absorption dose to 15Gy or less, said calculated90Y kidney absorption dose to 13Gy or less, and said calculated90Y bone marrow absorption dose to 35Gy or less, subject specific treatment dose is recalculated based on the reduction of RIC;Upon a calculated90Y liver absorption dose of <15Gy, a calculated90Y kidney absorption dose of <13Gy, and a calculated90Y bone marrow absorption dose of <35Gy arrived at by measuring the 99mTc absorption doses, and wherein the calculated90Y bone marrow absorption dose is higher than the calculated90Y liver absorption dose, the subject is eligible for being treated with 45 MBq / kg lean body weight (lbw) yttrium-90 (90Y)-comprising RIC;Upon a calculated90Y liver absorption dose of <15Gy, a90Y kidney absorption dose of <13Gy, a90Y bone marrow absorption dose of <10Gy arrived at by measuring the99mTc absorption doses, and wherein the bone marrow absorption dose is lower than the liver absorption dose, the subject is excluded from treatment.8014. The use or metastable technetium-99 (99mTc)-comprising RIC for use according to any one of the preceding claims, wherein in the planar scintigram the relative signal intensity in the area of the liver and the relative signal intensity of one or more ribs are quantified, preferably by computerised means.

15. The use or metastable technetium-99 (99mTc)-comprising RIC for use according to any one of the preceding claims, wherein the dosimetry is obtained by using SPECT / CT imaging.

16. The use or metastable technetium-99 (99mTc)-comprising RIC for use according to any one of the preceding claims, wherein the dosimetry is Single Time Point (STP) dosimetry.

17. A method of subject specific Single Time Point (STP) dosimetry for an yttrium-90 (90Y)-comprising (therapeutic) RIC, comprising- administration to said subject of a metastable technetium-99 (99mTc)-comprising (dosimetric) RIC;- recording a planar (whole body or thorax) scintigram of said subject at a single point in time; and- determining the relative signal intensity in the area of the liver and the relative signal intensity in the area of at least part of the bone marrow in the thorax based on said planar scintigram.

18. A metastable technetium-99 (99mTc)-comprising (dosimetric) RIC, for use in a method of subject-specific Single Time Point (STP) dosimetry for an yttrium-90 (90Y)-comprising (therapeutic) RIC, comprising- administration to said subject of a metastable technetium-99 (99mTc)-comprising RIC;- recording a planar whole body scintigram of the subject at a single point in time; and- determining the relative signal intensity in the area of the liver and the relative signal intensity in the area of at least part of the bone marrow in the thorax.

19. The method according to claim 17 or the metastable technetium-99 (99mTc)-comprising RIC for use according to claim 18, wherein the STP dosimetry is obtained by using SPECT / CT imaging.

20. The use, method, or metastable technetium-99 (99mTc)-comprising RIC for use according to any one of claims 16 to 19, wherein the STP dosimetry is determined between about 0 and about 96 hours, preferably between about 4 hours and about 36 hours, preferably between about 6 hours and about 36 hours, preferably between about 8 hours and about 36 hours, between about 12 and about 36 hours after use or administration or between about 0 hours and about 24 hours, preferably between about 3 hours and about 6 hours.

21. The use, method, or metastable technetium-99 (99mTc)-comprising RIC for use according to claim 20, wherein the STP dosimetry is determined between 20 and 27 hours, such as at about 24 hours after injection of the RIC comprising as imaging radionuclide metastable technetium-99 (99mTc).

22. The use, method, or metastable technetium-99 (99mTc)-comprising RIC for use according to any one of the preceding claims, wherein the STP dosimetry is determined at about 24 hours after injection of the RIC comprising as imaging radionuclide metastable technetium-99 (99mTc).8123. The use, method, or metastable technetium-99 (99mTc)-comprising RIC for use according to any one of claims 16 to 22, wherein the accuracy of the STP dosimetry is within 20% of the Multiple Time Point (MTP) dose, preferably within 20% of the MTP for bone marrow and / or liver.

24. Use of a radioimmunoconjugate (RIC) comprising a metastable technetium-99 (99mTc) radionuclide as a dosimetry agent for an yttrium-90 (90Y)-comprising RIC.

25. Use of a metastable technetium-99 (99mTc) radionuclide-comprising radioimmunoconjugate (RIC) as pretherapeutic dosimetric patient selection agent for an yttrium-90 (90Y)-comprising RIC.

26. A computer-implemented method for determining subject specific treatment conditions of a yttrium-90 (90Y)-comprising radioimmunoconjugate (RIC), the method comprising:A step of receiving input from either a user or the imaging device used for obtaining a planar scintigram of the thorax of said subject "mTc absorption doses for liver, kidney, and bone marrow after said subject received a single dose of 400-800 MBq / patient metastable technetium-99 (99mTc) radionuclide-comprising RIC;A step of calculating from (i.e. based on) the "mTc absorption doses the 90Y absorption doses for liver, kidney, and bone marrow;A decision making step, said decision making step adhering to the following logic: o Upon a calculated90Y liver absorption dose of >15Gy, or a calculated90Y kidney absorption dose of >13Gy, or a calculated90Y bone marrow absorption dose of >35Gy arrived at by measuring the "mTc absorption doses and wherein a 20% reduction of RIC does not result in a lowering of said calculated90Y liver absorption dose to 15Gy or less, said calculated 90Y kidney absorption dose to 13Gy or less, and said calculated90Ybone marrow absorption dose to 35Gy or less, the subject is excluded from treatment; o Upon a calculated90Y liver absorption dose of >15Gy, or a calculated90Y kidney absorption dose of >13Gy, or a calculated90Y bone marrow absorption dose of >35Gy arrived at by measuring the99mTc absorption doses, and wherein a 20% reduction of RIC does result in a lowering of said calculated90Y liver absorption dose to 15Gy or less, said calculated90Y kidney absorption dose to 13Gy or less, and said calculated90Y bone marrow absorption dose to 35Gy or less, subject specific treatment dose is recalculated based on the reduction of RIC; o Upon a calculated90Y liver absorption dose of <15Gy, a calculated90Y kidney absorption dose of <13Gy, and a calculated90Y bone marrow absorption dose of <35Gy arrived at by measuring the "mTc absorption doses, and wherein the calculated90Y bone marrow absorption dose is higher than the calculated90Y liver absorption dose, the subject is eligible for being treated with 45 MBq / kg lean body weight (lbw) yttrium-90 (90Y)-comprising RIC; o Upon a calculated90Y liver absorption dose of <15Gy, a90Y kidney absorption dose of <13Gy, and a90Y bone marrow absorption dose of <10Gy arrived at by measuring the99mTc absorption doses, and wherein the bone marrow absorption dose is lower than the liver absorption dose, the subject is excluded from treatment;82A step of providing output wherein the decision is provided to a user or stored on a computer- readable storage medium.

27. The computer-implemented method according to claim 26, comprising a further step wherein a user applies the decision to a subject.

28. A computer system configured to perform the method of claim 26.

29. A computer program product comprising instructions which when the program is executed by a computer, cause the computer to carry out the steps of the method of claim 26.

30. A computer-readable storage medium, comprising a data storage material encoded with computer readable data wherein said data comprises one or more planar scintigrams of the thorax of a subject after receiving a single dose of 400-800 MBq metastable technetium-99 (99mTc) radionuclide-comprising RIC configured to perform the method of claim 26.

31. The computer-readable storage medium according to claim 30, further comprising computer readable data wherein said data comprises quantified signal intensities of the liver, kidney, and bone marrow of the subject.

32. The computer system according to claim 28, the computer program product according to claim 29, or the computer-readable storage medium according to claim 30 or 31, further comprising a database containing scintigrams or information on scintigrams of one or more other subjects.

33. A computer-implemented method of determining a sub -population of subjects that can be safely and effectively treated for a disease or disorder by 45 MBq / kg lean body weight (lbw) of a yttrium-90 (90Y)-comprising radioimmunoconjugate (RIC), said method comprising:A step of receiving input from either a user or the imaging device used for obtaining a planar scintigram of the thorax of said subjects99mTc absorption doses for liver, kidney, and bone marrow after said subject received a single dose of 400-800 MBq / patient metastable technetium-99 (99mTc) radionuclide-comprising RIC;A step of calculating from (i.e. based on) the "mTc absorption doses the 90Y absorption doses for liver, kidney, and bone marrow;A decision making step wherein subjects are considered to be safely and effectively treated are characterised upon a calculated90Y liver absorption dose of <15Gy, a calculated90Y kidney absorption dose of <13Gy, a calculated90Y bone marrow absorption dose of <35Gy is obtained, and wherein the bone marrow absorption dose is higher than the liver absorption dose; andA step of providing output wherein the decision is provided to a user or stored on a computer- readable storage medium.

34. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding claims, wherein the RIC comprises a CD66-binding component or83 the first and second RIC comprise a CD66-binding component, preferably wherein both the first and the second RIC comprise the same CD66-binding component.

35. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding claims, wherein both RIC’s are identical except for the radionuclide and chelating agent.

36. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding claims, wherein the CD66-binding component is a polypeptide comprising at least one antibody-binding domain, more preferably an antibody, a chimeric antibody, a humanized antibody or a recombinant antibody, more preferably a single-chain antibody or fragment thereof or a proteolytic antibody fragment such as Fab-, Fab'- or F(ab) 2 -fragment or recombinant antibody fragment such as single-chain Fv-fragments.

37. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding claims, wherein the CD66-binding component is a monoclonal antibody.

38. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding claims, wherein the CD66-binding component is an anti-granulocyte monoclonal antibody.

39. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding claims, wherein the CD66-binding component, preferably an antibody, selectively binds to CD66a, CD66b, CD66c or CD66e, preferably wherein the CD66-binding component, preferably an antibody, selectively binds to CD66b or CD66e.

40. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding claims, wherein the CD66-binding component is BW 250 / 183 antibody.

41. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding claims, wherein the metastable technetium-99 (99mTc)-comprising RIC radionuclide is linked to the CD66-binding component by a method comprising using a reduction agent such as ZnCF. a stabilization agent such as PTP, and pertechnetate as99mTc source that is attached to reduced hinge region SH bonds.

42. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to claim 41, wherein "mTc is bound to hinge region SH bonds without use of a standard chelating agent.

43. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding claims, wherein the90Y radionuclidecomprising RIC is linked to the CD66-binding component via a structure of the formula[(chelating agent)-(R1)p-(R2-R3)n]m-(CD66-binding component)84 wherein n is 0 or 1, m is 1 to 15, p is 0 or 1,R1and R3are independently selected from the group consisting of -NHCSNH-, -NHCONH-, -NHCOCH2S-, -S- S-, -NH-NH-, -NH-, -S-, -CONHNH-, -SCH2CH2COONH-, -SCH2CH2SO2-, -SCH2CH2SO2NH-, -CONH-, -O- CH2CH2O-, -CO-, -COO-, -NH-O-, -CONHO-, -S-(CH2)3C(NH)NH-, -NH-COO-, -O- and, preferably -NH-CS-NH-, andR2is selected from the group consisting of C1-C18 alkylen, branched C1-C18, -CEC-CeHio-, -alkylphcnylcnc. -phcnylcnc. / / / -phenylene, -alkyloxyphcnylcnc. naphthylene, -[CH2CH2O]x-, -[CH2CH2SOCH2CH2]X-, - [CH2CH2SO2CH2CH2]X-, or -[NHCHR4CO]y-, wherein x is 1 to 200, y is 1 to 20, and wherein R4 is selected from the group consisting of H-, Me-, HSCH2-, isopropyl, but-2-yl, CH3SCH2CH2-, benzyl, l / T-indol-3-yl-methyl, HOCH2-, HOOCCH2-, CH3CH(OH)-, HOOCCH2CH2-, 4-hydroxybenzyl, H2NCOCH2-, H2NCOCH2CH2-, 4-aminobut-l-yl, 2-guanidinoethyl, l / / -iinidazol-5-yl-incthyl and 2-methylprop-l-yl.

44. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to claim 43, wherein the chelating agent is selected from the group consisting of diethylenetriaminepentaacetic acid (DTPA), l,4,7,10-tetraazacyclododecane-N,N',N”,N'”- tetraacetic acid (DOTA), l,4,8,ll-tetraazacyclotetradecane-N,N',N”,N'”-tetraacetic acid (TETA), 1,4,7- triazonane-N,N',N' '-triacetic acid (NOTA), 2,2’-(2-(((lS,2S)-2-(bis(carboxymethyl)amino)cyclohexyl)- (carboxymethyl)amino)ethylazanediyl)diacetic acid (cyclohexano-DTPA), 2,2’-(2-(((lR,2R)-2- (bis(carboxymethyl)amino)cyclohexyl)-(carboxymethyl)amino)ethylazanediyl)diacetic acid, 2,2’-(2-(((lS,2R)-2- (bis(carboxymethyl)amino)cyclohexyl)-(carboxymethyl)amino)ethylazanediyl)diacetic acid, 2,2’-(2-(((lR,2S)-2- (bis(carboxymethyl)amino)cyclohexyl)-(carboxymethyl)amino)ethylazanediyl)diacetic acid, 2,2’,2",2'"-(2,2'- ( 1 S,2S)-cyclohexane- 1 ,2-diylbis((carboxymethyl)azanediyl)bis(ethane-2, 1 -diyl))bis(azanetriyl)tetraacetic acid, 2,2',2",2"'-(2,2'-(lS,2R)-cyclohexane-l,2-diylbis((carboxymethyl)azanediyl)bis(ethane-2,l- diyl))bis(azanetriyl)tetraacetic acid, (1R)-1 -benzyl-diethylenetriaminepentaacetic acid, ( IS - 1 -benzyl- diethylenetriaminepentaacetic acid, (2R)-2-benzyl-diethylenetriaminepentaacetic acid, (2.S')-2-bcnzyl- diethylenetriaminepentaacetic acid, (2R)-2-benzyl-(3R)-3 -methyl -DTPA, (2 / ?)-2-bcnzyl-(3.S')-3 -methyl -DTPA, (2.S')-2-bcnzyl-(3.S')-3-mcthyl-DTPA. (2S -2-benzyl-(3R)-3 -methyl -DTPA, (2R)-2-benzyl-(4R)-4-methyl-DTPA, (2R)-2-benzyl-(4S)-4-methyl-DTPA, (2S)-2-benzyl-(4S)-4-methyl-DTPA, (2S)-2-benzyl-(4R)-4-methyl-DTPA, (lR)-l-benzyl-(3R)-3-methyl-DTPA, (lR)-l-benzyl-(3S)-3-methyl-DTPA, (lS)-l-benzyl-(3S)-3-methyl-DTPA, (lS)-l-benzyl-(3R)-3-methyl-DTPA, (lR)-l-benzyl-(4R)-4-methyl-DTPA, (lR)-l-benzyl-(4S)-4-methyl-DTPA, (lS)-l-benzyl-(4S)-4-methyl-DTPA, (lS)-l-benzyl-(4R)-4-methyl-DTPA, 2,2'-((lR,2R)-2-(((R)-2- (bis(carboxymethyl)amino)-3 -phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2'- ((lS,2S)-2-(((S)-2-(bis(carboxymethyl)amino)-3- phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2'-((lR,2R)-2-(((S)-2-(bis(carboxymethyl)amino)-3 -phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2'- ((lS,2S)-2-(((R)-2-(bis(carboxymethyl)amino)-3- phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2'-((lR,2S)-2-(((R)-2- (bis(carboxymethyl)amino)-3 -phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2'- ((lS,2R)-2-(((S)-2-(bis(carboxymethyl)amino)-3- phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2'-(( 1 S,2R)-2-(((R)-2- (bis(carboxymethyl)amino)-3 -phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, 2,2'- ((lR,2S)-2-(((S)-2-(bis(carboxymethyl)amino)-3- phenylpropyl)(carboxymethyl)amino)cyclohexylazanediyl)diacetic acid, (2S)-2-benzyl-l,4,7,10- tetraazacyclododecane-N,N',N' ',N' ' '-tetraacetic acid, (2R)-2-benzyl-l,4,7, 10-tetraazacyclododecane- N,N',N",N" '-tetraacetic acid, 6-benzyl-l,4,8,l l-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid, 2- benzyl-1, 4, 7-triazonane-N,N',N' '-triacetic acid, benzyl-3-methyl-diethylenetriaminepentaacetic acid (2B3M- DTPA), (R)-2-amino-3-(phenyl)propyl)trans-(S, S)-cyclohexane- 1 ,2-diamine-pentaacetic acid) (Bn-CHX-A” - DTPA) and salts and derivatives thereof, particularly (R)-2-amino-3-(phenyl)propyl)trans-(S,S)-cyclohexane-l,2- diamine-pentaacetic acid) (Bn-CHX-A” -DTPA) and salts thereof.

45. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding claims, wherein the radionuclide is linked to the CD66-binding component via the structure CD66-binding SH-99mTc.

46. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding claims, wherein the99mTc radionuclide is covalently linked to the CD66-binding component, particularly by reduction / oxidation chemistry, such as using DTT (dithiothreitol) and PTP (propane tetraphosphonate).

47. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding claims, wherein the subject is a mammalian subject, preferably a human subject.

48. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding claims, wherein the subject has or is considered to have a bone marrow associated disease.

49. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to claim 48, wherein the bone marrow associated disease is selected from the group consisting of: haematological malignancies, such as a leukemia, which may be selected from multiple myeloma (MM), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL) and lymphoma, preferably multiple myeloma, autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, scleroderma pigmentosa, systemic lupus erythematodes, colitis ulcerosa, Crohn's disease, and systemic sclerosis, AL-amyloidosis,monogenetic diseases, such as aplastic anemia, pure red cell aplasia, paroxysmal nocturnal hemoglobinuria, fanconi anemia, Thalassemia major, sickle cell anemia, severe combined immunodeficiency, Wiskott-Aldrich syndrome, hemophagocytic lymphohistiocytosis, inborn errors of metabolism, epidermolyisis bullosa, severe congenital neutropenia, Schwachman-Diamond syndrome, Diamond-Blackfan anemia, and leucocyte adhesion deficiency, and diseases, which can be treated by ex vivo cellular therapy and gene therapy, such as sickle cell anemia, transthyretin amyloidosis (ATTR), hereditary angio edema, acute myeloid leukemia, transfusion-dependent beta thalassemia (IDT), AMD, Diabetic Retinopathy, bleeding disorders such as Hemophilia A and B, lysosomal storage disease such as Hunter syndrome and Huler syndrome, or peripheral neuropathy (Charcot-Marie-Tooth).

50. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding claims, wherein the subject is a subject who was treated with induction therapy but had disease progression or had a haematological response.

51. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding claims, wherein the subject is a subject who was treated with high-dose melphalan followed by stem cell transplantation but had disease progression.

52. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding claims, wherein the subject is a subject who is ineligible to treatment with high dose (HD) melphalan preceding HSCT.

53. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding claims, wherein the subject is a subject who was treated with a combination of up to 4 drugs selected from doxorubicin, carmustine, cyclophosphamide, dexamethasone, etoposide, melphalan, (methyl)prednisolone, vincristine and idarubicin but had disease progression.

54. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding claims, wherein the subject is a subject who is ineligible to treatment with a combination of up to 4 drugs selected from doxorubicin, carmustine, cyclophosphamide, dexamethasone, etoposide, melphalan, (methyl)prednisolone, vincristine and idarubicin.

55. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding claims, wherein the subject is a subject who is eligible for Haematopoietic Stem Cell Transplantation (HSCT).

56. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding claims, wherein the subject is a subject suffering from AL-amyloidosis, who was treated with Daratumumab and cyclophosphamide, Bortezomib and dexamethasone (Dara-CyBorD) and who did not achieve a complete remission (CR) 6 months after treatment.

57. The use, method, metastable technetium-99 (99mTc)-comprising RIC for use, computer system, or computer-readable storage medium according to any one of the preceding claims, wherein the subject is a subject87 suffering from multiple myeloma, who is treatment refractory towards standard care of multiple myeloma including daratumumab and who has cryopreserved haematopoietic stem cells for allowing HSCT following application of the therapeutic RIC.

58. A method of determining subject specific dosimetry of an effective amount of a second (therapeutic) RIC comprising yttrium-90 (90Y) as radionuclide, comprising:- administration to said subject of a first (dosimetric) RIC, said first RIC comprising as imaging radionuclide metastable technetium-99 (99mTc);- recording a planar (whole body or thorax) scintigram of the subject; and- determining the relative signal intensity of the liver and the relative signal intensity of one or more ribs of the thorax based on said planar scintigram.

59. A method of identifying by dosimetry subjects eligible for safe and effective exposure to an effective amount of a second (therapeutic) RIC comprising yttrium-90 (90Y) as radionuclide, comprising:- administration to said subject of a first RIC, said first (dosimetric) RIC comprising as imaging radionuclide metastable technetium-99 (99mTc);- recording a planar (whole body or thorax) scintigram of the subject; and- determining the relative signal intensity of the liver and the relative signal intensity of one or more ribs of the thorax based on said planar scintigram.

60. A method of determining the inclusion of a subject in a treatment plan, said treatment plan comprising the administration of an effective amount of second (therapeutic) RIC comprising yttrium-90 (90Y) as radionuclide, comprising:- administration to said subject of a first RIC, said first (dosimetric) RIC comprising as imaging radionuclide metastable technetium-99 (99mTc);- recording a planar (whole body or thorax) scintigram of the subject; and- determining the relative signal intensity of the liver and the relative signal intensity of one or more ribs of the thorax based on said planar scintigram.

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