Olav B. Ryan

Radiolabeled Fucoidan as a P-Selectin Targeting Agent for In Vivo Imaging of Platelet-Rich Thrombus and Endothelial Activation

P-selectin expression is involved in the pathophysiology of biologically active arterial thrombus and endothelial activation after a transient ischemic event. Fucoidan is a polysaccharidic ligand of P-selectin, with a nanomolar affinity. In the present study, we propose a new approach of P-selectin molecular imaging based on radiolabeled fucoidan. Methods: Two kinds of experimental models were selected to evaluate the ability of radiolabeled fucoidan to detect P-selectin expression: platelet-rich arterial thrombi (vegetations of infective endocarditis and arterial mural thrombus) and myocardial ischemia–reperfusion. These 2 settings were chosen because they were clinically relevant, and both were associated with an important overexpression of platelet and endothelial P-selectin, respectively. Results: 99mTc-fucoidan SPECT was able to detect the presence of platelet-rich arterial thrombi in all animals, with a median target-to-background ratio of 5.2 in vegetations of endocarditis and 3.6 in mural aneurysmal thrombus, and to detect a persistent endothelial activation at 2 h after reperfusion. In this latter model, the magnitude of the signal was correlated with the extent of myocardium that underwent transient ischemia. The sensitivity of selectivity of the uptake and retention of 99mTc-fucoidan in both settings was excellent. Conclusion: This study supports 99mTc-fucoidan as a relevant imaging agent for in vivo detection of biologic activities associated with P-selectin overexpression, such as arterial thrombus and ischemic memory. Given the reported wide availability at a low cost, and its low toxicity, fucoidan seems to overcome some of the limitations of previous P-selectin–targeted imaging agents.

In vitro and in vivo efficacy of a novel CD33 targeted thorium-227 conjugate for the treatment of acute myeloid leukemia

The clinical efficacy of the first approved alpha pharmaceutical, Xofigo (radium-223 dichloride, 223RaCl2), has stimulated significant interest in the development of new alpha-particle emitting drugs in oncology. Unlike radium-223 (223Ra), the parent radionuclide thorium-227 (227Th) is able to form highly stable chelator complexes and is therefore amenable to targeted radioimmunotherapy. We describe the preparation and use of a CD33-targeted thorium-227 conjugate (CD33-TTC), which binds to the sialic acid receptor CD33 for the treatment of acute myeloid leukemia (AML). A chelator was conjugated to the CD33-targeting antibody lintuzumab via amide bonds, enabling radiolabeling with the alpha-emitter 227Th. The CD33-TTC induced in vitro cytotoxicity on CD33-positive cells, independent of multiple drug resistance (MDR) phenotype. After exposure to CD33-TTC, cells accumulated DNA double-strand breaks and were arrested in the G2 phase of the cell cycle. In vivo, the CD33-TTC demonstrated antitumor activity in a subcutaneous xenograft mouse model using HL-60 cells at a single dose regimen. Dose-dependent significant survival benefit was further demonstrated in a disseminated mouse tumor model after single dose injection or administered as a fractionated dose. The data presented support the further development of the CD33-TTC as a novel alpha pharmaceutical for the treatment of AML. Mol Cancer Ther; 15(10); 2422–31. ©2016 AACR.

An efficient chelator for complexation of thorium-227.

We present the synthesis and characterization of a highly efficient thorium chelator, derived from the octadentate hydroxypyridinone class of compounds. The chelator forms extremely stable complexes with fast formation rates in the presence of Th-227 (ambient temperature, 20min). In addition, mouse biodistribution data are provided which indicate rapid hepatobiliary excretion route of the chelator which, together with low bone uptake, supports the stability of the complex in vivo. The carboxylic acid group may be readily activated for conjugation through the ɛ-amino groups of lysine residues in biomolecules such as antibodies. This chelator is a critical component of a new class of Targeted Thorium Conjugates (TTCs) currently under development in the field of oncology.

Development of separation technology for the removal of radium-223 from targeted thorium conjugate formulations. Part I: purification of decayed thorium-227 on cation exchange columns

Abstract Targeted thorium conjugates (TTCs) are being explored as a potential future platform for specific tumor targeting pharmaceuticals. In TTCs, the alpha emitting radionuclide thorium-227 (227Th) with a half-life of 18.697 d is labeled to targeting moieties, such as monoclonal antibodies (mAbs). The amount of daughter nuclide radium-223 (223Ra, t1/2 = 11.435 d) will increase during manufacture and distribution, and so a technology for purification is required to assure an acceptable level of 223Ra is administrated to the patient. Since 223Ra is the only progeny of 227Th with a long half-life (days), the progenies of 223Ra will have a very limited stay in the formulation once 223Ra is removed. The focus in this study has, therefore, been on the removal of 223Ra. In this study, the sorption and separation of 223Ra (radium(II)) and 227Th (thorium(IV)) on cation exchange columns has been evaluated as a purification method of decayed 227Th (i.e. prior to radiolabelling of a mAb and formation of TTC). The goal is to minimize the sorption of 227Th and maximize the sorption of 223Ra. Statistical experimental design with formulation and process parameters, including buffered formulations comprising citrate and acetate, at various concentrations and pH, presence of free radical scavenger and chelator, and resin amount have been evaluated for impact on the purification process. The studies have been interpreted by the aid of multivariate data analysis. The correlations between design of experimental variables and sorption are summarized by regression models. The predictive accuracy of radionuclide sorption was given by standard deviation and 95% confidence intervals originating from statistical cross validation. Experimental results and statistical models for citrate-buffered formulations verified reproducible and acceptable sorption levels of 223Ra and 227Th under selected conditions. For acetate-buffered formulations, prediction of 227Th sorption was influenced by complex variable relationships and hence a risk of obtaining irreproducibility. Fine-tuned variable levels showed, however, variable combinations predicting high sorption of 223Ra (>90%) and low sorption of 227Th (<3%) also for the acetate-buffered formulations. The optimal separation conditions should be decided based on tuning the variables levels for 223Ra in the citrate-buffered formulations, while for acetate, the optimal separation should be based on tuning variable levels for 227Th sorption. The ionic strength of the formulation also seemed to affect the radionuclide sorption. Labeling of an antibody-chelator conjugate with purified 227Th (i.e. preparation of TTC) was successful in the selected citrate-buffered formulations tested.

Abstract 5200: Preclinical pharmacology of the PSMA-targeted thorium-227 conjugate PSMA-TTC: a novel targeted alpha therapeutic for the treatment of prostate cancer

Prostate-specific membrane antigen (PSMA, FOLH1) is a type II transmembrane glycoprotein of the M28 peptidase family that acts as a glutamate carboxypeptidase on various substrates. PSMA is well established as a target antigen in prostate cancer due to its high and specific overexpression on the surface of prostate cancer cells at all tumor stages, including metastatic and hormone-refractory disease. Several PSMA targeting antibodies and ligands are currently in clinical development or compassionate use therapeutically or as imaging agents. Targeted alpha therapy (TAT) has an established clinical profile with the successful transition of Ra223, an alpha-particle emitter, from bench to bedside in prostate cancer. Thorium-227 is the immediate precursor for Ra223 via alpha-particle emission. We herein describe the generation of a novel TAT, a high energy, alpha-particle emitting PSMA-targeted thorium-227 conjugate (PSMA-TTC). PSMA-TTC consists of a fully human PSMA targeting IgG1 antibody covalently linked via an amide bond to a chelator moiety (3,2 HOPO), enabling radiolabeling with thorium-227 (227Th). PSMA-TTC was prepared in high radiochemical yield and purity and tested for binding affinity to PSMA target (ELISA) as well as PSMA expressing cell lines (FACS). In vitro cytotoxicity experiments were carried out on prostate CA cell lines with different PSMA levels (from 3.000 to 150.000 mAbs bound/ cell). In vivo biodistribution and anti-tumor efficacy were analyzed after i.v. injection of 100-500 kBq/kg at protein doses of 0.14 mg/kg to mice bearing s.c. prostate cancer xenograft models. Additionally, anti-tumor efficacy was evaluated in a PSMA expressing orthotopic bone xenograft model (LNCaP-Luc) monitored by bioluminescence imaging, micro CT and x-ray. PSMA-TTC retains binding affinities to PSMA target and PSMA positive cancer cells similar to the PSMA antibody. Strong in vitro potency and selectivity of PSMA-TTC was shown on different PSMA positive cells. Biodistribution studies in C4-2 xenografts demonstrated specific tumor uptake of PSMA-TTC with a maximum of 50 % of ID/g at t = 72h post dose administration. Selective significant antitumor efficacy was shown for PSMA-TTC in s.c. prostate CA xenograft models with high (C4-2) and medium/low (22Rv1) PSMA protein levels at doses of 250 and 500 kBq/kg. Furthermore, statistically significant prevention of tumor growth was observed after treatment with PSMA-TTC at a dose of 100 kBq/kg in an orthotopic bone xenograft model (LNCaP-Luc). The promising preclinical antitumor activity of PSMA-TTC supports its development for the treatment of patients with metastatic prostate cancer. Citation Format: Stefanie Hammer, Aasmund Larssen, Christine Ellingsen, Solene Geraudie, Derek Grant, Baard Indrevoll, Oliver von Ahsen, Alexander Kristian, Urs B Hagemann, Jenny Karlsson, Roger M Bjerke, Olav B Ryan, Dominik Mumberg, Bertolt Kreft, Alan Cuthbertson. Preclinical pharmacology of the PSMA-targeted thorium-227 conjugate PSMA-TTC: a novel targeted alpha therapeutic for the treatment of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5200. doi:10.1158/1538-7445.AM2017-5200

Development of separation technology for the removal of radium-223 from decayed thorium-227 in drug formulations. Material screening and method development

Abstract Targeted thorium conjugates are currently being investigated as a new class of alpha-radiopharmaceuticals. The natural decay of thorium-227 (227Th) results in the ingrowth of radium-223 (223Ra). Consideration must, therefore, be given to define acceptable limits of 223Ra in the drug product at the time of dose administration. By effective sequestration of 223Ra, we aim to improve the radiochemical purity and extend the effective user window of drug products containing 227Th. 223Ra is the first progeny of 227Th and the only one with a long half-life (days). We have, therefore, focused on the removal of this specific species since the progenies of 223Ra will have a very limited lifetime in the formulation once 223Ra is removed. In this study, we investigated a multitude of materials for their ability to reduce the 223Ra level by: (1) passive diffusion or (2) by cartridge filtration on gravity columns. In addition, we probe the compatibility of these materials in the presence of antibody trastuzumab to assess the level of protein binding and estimate the quenching of radiolysis by binding of radionuclides. A screening matrix of organic and inorganic materials was established, i.e. strontium and calcium alginate gel beads, distearoyl phosphatidylglycerol (DSPG) liposomes, ceramic hydroxyapatite, Zeolite UOP type 4A and cation exchange resins AG50W-X8 and SOURCE 30S. First, passive diffusional uptake of 223Ra by suspended materials present in the formulation was measured as a decrease in sample radioactivity after separation. Second, selected materials were packed on gravity columns in order to evaluate the efficiency of column separation versus diffusional adsorption. The retention of 223Ra and 227Th were characterized by measuring the radioactivity in the eluate and on the columns. Finally, the compatibility between trastuzumab, as a selected model antibody, and suspensions of the binding materials was analyzed during storage of the drug product in the presence of adsorbent. The formation of H2O2 was evaluated to measure the influence of radionuclide binding material on radiolysis in the formulation. All the materials bound 223Ra by passive diffusional uptake ranging from 31% to 95% with DSPG liposomes demonstrating superiority at 95% efficiency. All materials suitable for assessment by gravity column filtration bound 223Ra almost quantitatively (∼100%) and with minimal variation (relative standard deviation  <1%). The uptake was significantly higher compared to passive diffusional uptake. Alginate gel beads, ceramic hydroxyapatite and SOURCE 30S reduced the antibody concentration in solution to 40–50% while the Zeolite UOP type 4A, AG50W-X8 resin and DSPG liposomes showed ≤10% reduction of antibody concentration. Ceramic hydroxyapatite significantly reduced H2O2 formed by radionuclide initiated radiolysis.

Abstract 855: Increased in vitro potency and in vivo efficacy of FGFR2-targeted thorium-227 conjugate (FGFR2-TTC) in combination with the ATR inhibitor BAY 1895344

Targeted Thorium-227 Conjugates (TTCs) consist of the alpha emitter Thorium-227 (227Th) coupled, by a 3, 2-HOPO chelator, to a tumor specific antibody. The alpha particles release high energy over a short range (2- 10 cell diameters), resulting in a potent local irradiation of the tumor with limited damage to surrounding tissue. Here, we describe the in vitro and in vivo evaluation of an FGFR2 targeted thorium-227 conjugate (FGFR2-TTC) in combination with the ATR inhibitor BAY 1895344. FGFR2 (fibroblast growth factor receptor 2) is a receptor tyrosine kinase and overexpression of FGFR2 has been described in different cancers, while its expression in healthy human tissues is moderate to low. This renders FGFR2 an attractive antigen to explore the concept of targeted alpha therapy (TAT). The mode-of-action of TTCs is based on the induction of clustered DNA double strand breaks and G2 cell cycle arrest. We hypothesized that combination of FGFR2-TTC with inhibitors of DNA damage response (DDRi9s) may enhance potency and efficacy. The ataxia telangiectasia and Rad3-related protein (ATR) kinase is a central mediator of DDR. ATR kinase responds to a broad spectrum of DNA damage, including double-strand breaks (DSB) and lesions derived from interference with DNA replication as well as increased replication stress. Inhibition of ATR kinase activity induces cell death especially in tumors with increased DNA damage, deficiency in DNA damage repair or replication stress. Therefore, we investigated whether the combination of the FGFR2-TTC with the ATRi BAY 1895344 results in enhanced tumor sensitivity in vitro and in vivo. In in vitro cytotoxicity assays, the combination of FGFR2-TTC and BAY 1895344 resulted in increased potency of the FGFR2-TTC on three different cancer cell lines (KATO III (gastric), MFM-223 (triple negative breast cancer), SUM52-PE (triple negative breast cancer)). Mechanistic analysis demonstrated that the combination treatment resulted in reduced levels of G2 arrest and increased levels of DNA damage in comparison to single agent treatments. The combination was further evaluated in vivo using the MFM-223 breast cancer xenograft model. An increased anti-tumor efficacy of a low dose of FGFR2-TTC (100 kBq/kg) was observed in combination with BAY 1895344 compared to animals treated with vehicle. The presented data support the mechanism-based rationale for combining DNA damage induction by FGFR2-TTC with DNA damage repair inhibition using ATRi BAY 1895344. Our findings warrant further exploration of TTCs in combination with BAY 1895344 for cancer therapy. Citation Format: Katrine Wickstroem, Urs B. Hagemann, Antje M. Wengner, Anette Sommer, Alexander Kristian, Christine Ellingsen, Roger M. Bjerke, Jenny Karlsson, Olav B. Ryan, Lars Linden, Bertolt Kreft, Dominik Mumberg, Hanno Wild, Karl Ziegelbauer, Alan Cuthbertson. Increased in vitro potency and in vivo efficacy of FGFR2-targeted thorium-227 conjugate (FGFR2-TTC) in combination with the ATR inhibitor BAY 1895344 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 855.

Abstract 5859: HER2-targeted thorium-227 conjugate (HER2-TTC): Efficacy in preclinical models of trastuzumab and T-DM1 resistance

The human epidermal growth factor receptor 2 (HER2) is encoded by the proto-oncogene c-erbB-2 and initiates downstream signaling pathways leading to cell proliferation and tumorigenesis. HER2 is overexpressed in several cancer (Ca) types and is one of the most strongly validated targets for the treatment of breast and gastric cancer serving as both a prognostic and predictive biomarker. Several HER2-targeting antibodies as well as antibody-drug conjugates are either approved or are in clinical development. Prolonged treatment with monoclonal antibodies and antibody drug conjugates have resulted in development of resistance and so there is still an unmet medical need for drugs of new mechanism of action targeting this important receptor system. We describe herein the generation of a high energy, alpha-particle emitting HER2 targeted thorium-227 antibody-chelator conjugate. HER2-TTC consists of the humanized HER2 targeting IgG1 antibody (trastuzumab) covalently linked via an amide bond to a 3,2-hydroxypyridino-based chelator moiety, enabling efficient radiolabeling with the alpha particle emitting radionuclide thorium-227 (Th-227). HER2-TTC was prepared at high radiochemical yield and purity. When tested for binding to recombinant HER2, HER2-TTC was shown to retain comparable binding affinity to trastuzumab. In vitro cytotoxicity experiments were performed on 8 cell lines with different HER2 expression levels (from 7 000 - 500 000 mAbs bound/ cell as determined by FACS) of breast, ovarian, gastric and lung cancer origin. HER2-TTC demonstrated target mediated in vitro cytotoxicity in the pM-range. In vivo biodistribution and anti-tumor efficacy of HER2-TTC was evaluated in the dose range 100-500 kBq/kg at a protein dose of 0.14 mg/kg and i.v. injection in the s.c. KPL-4 breast and Calu-3 lung model previously described to be resistant to trastuzumab. The biodistribution study demonstrated specific tumor accumulation of HER2-TTC in both models with a maximum of 77 and 50 %ID/g 227Th at t = 168 h post dose (decay corrected to T0), respectively. Significant antitumor efficacy was shown for HER2-TTC in the JIMT-1 s.c. breast Ca xenograft model resistant to trastuzumab and T-DM1. The promising preclinical anti-tumor activity supports the development of the targeted alpha therapeutic HER2-TTC for the treatment of trastuzumab and T-DM1 resistant patients. Citation Format: Jenny Karlsson, Urs B. Hagemann, Christoph Schatz, Derek Grant, Alexander Kristian, Christine Ellingsen, Dessislava Mihaylova, Solene Geraudie, Bard Indrevoll, Uta Wirnitzer, Roger M. Bjerke, Olav B. Ryan, Carl F. Nising, Dominik Mumberg, Alan Cuthbertson. HER2-targeted thorium-227 conjugate (HER2-TTC): Efficacy in preclinical models of trastuzumab and T-DM1 resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5859. doi:10.1158/1538-7445.AM2017-5859

Abstract 5857: HER2-targeted thorium-227 conjugate (HER2-TTC): Efficacy in a HER2 positive orthotopic bone model

In 2015, the estimated incidence of new breast cancer (Ca) cases in the US was 234.190 and number of deaths 40.730. Human epidermal growth factor receptor 2 (HER2) is encoded by the proto-oncogene c-erbB-2 and initiates downstream signaling pathways leading to cell proliferation and tumorigenesis. HER2 is overexpressed in several cancer types and has emerged as one of the most strongly validated targets for the treatment of breast and gastric cancer serving as both a prognostic and predictive biomarker. Given that 20% of breast Ca patients are HER2 positive and 70% of patients with metastatic disease will develop bone metastases and associated morbidities, there is still an unmet medical need for improved therapies targeting HER2. Radium-223 (Ra-223) is a novel targeted alpha therapeutic for treatment of patients with castration-resistant prostate cancer and bone metastases. Localized high energy alpha particle emission induces double-stranded DNA breaks and cellular apoptosis. Thorium-227 (Th-227) is the immediate precursor for Ra-223 which, in contrast to Ra-223, can be complexed by chelating agents at high affinity, allowing targeted delivery to tumor cells via antibodies. We describe herein the generation of a novel HER2-targeted Th-227 conjugate (HER2-TTC). HER2-TTC consists of the humanized HER2 targeting IgG1 antibody trastuzumab covalently linked via an amide bond to a 3,2-hydroxypyridino-based chelator moiety, enabling efficient radiolabeling with the alpha particle emitting radionuclide Th-227. Anonymized samples of consenting breast cancer patients were analyzed by Immunohistochemistry (IHC). The IHC data demonstrated HER2 positive expression in breast tumor and matched bone metastases, supporting the preclinical evaluation of the anti-tumor efficacy of HER2-TTC in the BT-474 orthotopic bone mouse model. HER2-TTC was prepared at high radiochemical yield and purity. When tested for binding to recombinant HER2, HER2-TTC was shown to retain comparable binding affinity to trastuzumab. In vitro cytotoxicity experiment of HER2-TTC demonstrated target mediated in vitro cytotoxicity in the pM-range on breast cancer cell line BT-474 (430 000 mAbs bound/ cell as determined by FACS). Anti-tumor efficacy of HER2-TTC was evaluated at 250 and 500 kBq/kg at a protein dose of 0.14 mg/kg. X-ray imaging, serum bone formation marker PINP, micro CT 3D reconstruction imaging and histological analysis demonstrated significantly reduced bone lesions and tumor induced bone remodeling. The promising preclinical anti-tumor activity supports the development of the HER2-TTC as a novel targeted alpha therapeutic for the treatment of patients with HER2 positive bone metastatic disease. Citation Format: Jenny Karlsson, Urs B. Hagemann, Christoph Schatz, Derek Grant, Christine Ellingsen, Alexander Kristian, Dessislava Mihaylova, Steinar R. Uran, Mari Suominen, Roger M. Bjerke, Olav B. Ryan, Carl F. Nising, Dominik Mumberg, Alan Cuthbertson. HER2-targeted thorium-227 conjugate (HER2-TTC): Efficacy in a HER2 positive orthotopic bone model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5857. doi:10.1158/1538-7445.AM2017-5857

Abstract 2462:In Vivoefficacy of a novel anti-CD33 targeted thorium conjugate (TTC) in mouse models of acute myeloid leukemia (AML)

Introduction: The sialoadhesin receptor CD33 is a well-established target in the treatment of acute myeloid leukemia (AML). CD33 is expressed on leukemic blasts in AML and possibly also on leukemic stem cells in some patients (1). Thorium-227, an alpha-particle emitting radionuclide with a half-life of 18.7 days, is being studied for use as a possible cytotoxic agent. We have developed a novel Targeted Thorium Conjugate (TTC), comprising an anti-CD33 monoclonal antibody conjugated to a chelator for the efficient delivery of high-energy alpha-particles. We present data from in vitro cell cytotoxicity assays as well as biodistribution and efficacy data from preclinical animal models of AML. Experimental procedures: Antibody conjugates were prepared and labeled with 227Th at room temperature giving high radiochemical yields and purity. In vitro cell cytotoxicity experiments were carried out on HL-60 cells and the multi-drug resistant cell line KG-1 by measuring cell viability and monitoring apoptosis. In vivo efficacy and biodistribution were performed in a sub-cutaneous model of AML in athymic nude (nu/nu) mice using HL-60 cells. The 227Th-anti-CD33 conjugate was further tested in a disseminated model of AML using HL-60 cells, injected intravenously 5 days prior to treatment in CB.17 SCID mice with hind-leg paralysis as endpoint. Results: The 227Th-anti-CD33 conjugate was a potent and specific inducer of in vitro cell cytotoxicity independent of MDR-status. Mechanistic studies demonstrated cell arrest in G2 phase with cytotoxicity associated with apoptotic pathways. In vivo biodistribution in a sub-cutaneous model demonstrated a high tumor to blood ratio (TBR ∼ 6) at day 7 post injection based on measured 227Th-activity. Significant efficacy was achieved in two models of AML using human HL-60 cells. In athymic nude mice, a single injection of 227Th-anti-CD33 conjugate at 700 kBq/kg resulted in complete regression of established sub-cutaneous tumors. Importantly, no significant loss in body weight was observed during the course of the study, demonstrating that the dose was well tolerated. In parallel, statistically significant dose dependency of 227Th-anti-CD33 conjugate was demonstrated in a disseminated model of AML with median survival times (MST) of 90 days and 116 days for animals receiving 50 and 150 kBq/kg. Around 80% of animals dosed with either 2 × 150 or 1 × 300 kBq/kg where still alive at the end of the study with no gross pathological findings observed. Conclusions: The data presented are supportive of the further investigation of the 227Th-anti-CD33 conjugate for the treatment of AML. References: (1) Walter RB et al, Blood 2012, Vol 119, Number 26 (“Acute myeloid leukemia stem cells and CD33-targeted immunotherapy”) Citation Format: Urs B. Hagemann, Joergen Borrebaek, Adam O9Shea, Ellen Wang, Katrine Wickstroem, Roger M. Bjerke, Jenny Karlsson, Olav B. Ryan, Alan Cuthbertson. In Vivo efficacy of a novel anti-CD33 targeted thorium conjugate (TTC) in mouse models of acute myeloid leukemia (AML). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2462. doi:10.1158/1538-7445.AM2015-2462