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Breaking Chemoresistance and Radioresistance with [213Bi]Anti-CD45 Antibodies in Leukemia Cells

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Breaking Chemoresistance and Radioresistance with [213Bi]Anti-CD45 Antibodies in Leukemia Cells Research Article Breaking Chemoresistance and Radioresistance with [213Bi]anti-CD45 Antibodies in Leukemia Cells Claudia Friesen,1 Gerhard Glatting,1 Bernd Koop,1 Klaus Schwarz,2 Alfred Morgenstern,4 Christos Apostolidis,4 Klaus-Michael Debatin,3 and Sven N. Reske1 1Nuclear Medicine Clinic, 2Department of Transfusion Medicine, and 3University Children’s Hospital, University of Ulm, Ulm, Germany and 4European Commission, Joint Research Centre, Institute for Transuranium Elements, Karlsruhe, Germany Abstract immunotherapy depends on the radionuclide and particularly on the type of emitted radiation (4). Selective targeting of tumor cells Chemoresistance and radioresistance are considered one of the with radiolabeled antibodies for systemic radioimmunotherapy was primary reasons for therapeutic failure in leukemias and solid developed using h-emitting nuclides, such 131I, 90Y, 188Re, or 177Lu, tumors. Targeted radiotherapy using monoclonal antibodies and antibodies, such as anti-CD45, anti-CD66, and anti-CD33 (4). radiolabeled with A-particles is a promising treatment These seem to provide a well-tolerated, safe, and effective approach for high-risk leukemia. We found that targeted therapeutic option for patients with high-risk leukemia (4). There radiotherapy using monoclonal CD45 antibodies radiolabeled has been an emerging interest in using a-particles, such as 213Bi, with the A-emitter 213Bi ([213Bi]anti-CD45) induces apoptosis, for radioimmunotherapy (7–9). Because of the short path length activates apoptosis pathways, and breaks B-irradiation–, (50-80 Am) and high linear energy transfer (f100 keV/Am) of ;-irradiation–, doxorubicin-, and apoptosis-resistance in a-particles emitting radioisotopes, targeted a-particle therapy leukemia cells. In contrast to B-irradiation–, ;-irradiation–, offers the potential for higher biological effectiveness and more and doxorubicin-mediated apoptosis and DNA damage, [213Bi] specific tumor cell kill with less damage to surrounding normal anti-CD45–induced DNA damage was not repaired, and tissues compared with h-emitters and external radiation (9). These apoptosis was not inhibited by the nonhomologous end- properties make targeted a-particle therapy ideal for elimination joining DNA repair mechanism. Depending on the activation of minimal residual or micrometastatic disease (8, 9). Another of caspase-3, caspase-8, and caspase-9, [213Bi]anti-CD45 potential application is in treating lymphoma and leukemia (9). activated apoptosis pathways in leukemia cells through the However, the mechanism of a-particle–induced cell kill in leukemia mitochondrial pathway but independent of CD95 receptor/ cells is poorly understood at the molecular level. CD95 ligand interaction. Furthermore, [213Bi]anti-CD45 reversed Anticancer drugs, h-irradiation, and g-irradiation have been deficient activation of caspase-3, caspase-8, and caspase-9, shown to activate apoptosis pathways in leukemias and solid deficient cleavage of poly(ADP-ribose) polymerase, and defi- tumors (10–18). Caspases play a critical role in apoptosis induction cient activation of mitochondria in chemoresistant and in (18, 19). The apoptotic caspases are divided in two classes: effector radioresistant and apoptosis-resistant leukemia cells. These caspases, such as caspase-3, caspase-6, and caspase-7, and initiator findings show that [213Bi]anti-CD45 is a promising therapeutic caspases, such as caspase-8 and caspase-9 (18). Effector caspases agent to break chemoresistance and radioresistance by are responsible for the cleavages that disassemble the cell, and overcoming DNA repair mechanisms in leukemia cells and initiator caspases initiate the proteolytic cascade (19). Two distinct provide the foundation for discovery of novel anticancer pathways upstream of the caspase cascade have been identified: compounds. [Cancer Res 2007;67(5):1950–8] the ligand/receptor–driven amplifier pathway, such as the CD95 receptor/CD95 ligand system, and the direct mitochondrial Introduction activation pathway without ligand/receptor interaction resulting One of the primary causes for therapeutic failure in radiotherapy in cleavage and activation of effector caspases (20). Anticancer and chemotherapy of leukemia and solid tumors is the resistance drugs, h-irradiation, and g-irradiation have been shown to activate to radiation and chemotherapeutic drugs (1). Attempts to improve the ligand/receptor pathway and the mitochondrial activation the results of chemotherapy and radiotherapy by increasing the pathway in leukemia and tumor cells (10–14, 18, 20). The total radiation absorbed dose, by increasing the concentration of mitochondrial pathway can be activated through the ligand/ chemotherapeutic drugs, or by changing chemotherapeutic drugs receptor system or directly by apoptotic stimuli (19, 20). Caspase-9, have only partly been successful (1). Various approaches using which is released during apoptosis from mitochondria into the native monoclonal antibodies, immunotoxins and radioimmuno- cytosol, triggers caspase-3 activation through the formation of a conjugates have emerged as promising treatment strategies. cytochrome c/Apaf-1/caspase-9–containing apoptosome complex Selective targeting of tumor cells with radiolabeled antibodies (19, 21). Bcl-2 family members regulate the mitochondrial pathway for systemic radioimmunotherapy was developed, which reduces (19, 22). Antiapoptotic Bcl-2 family members, such as Bcl-2 or c toxicity, the limiting factor in treatment of high-risk leukemia and Bcl-xL, inhibit the cytochrome release by modulating the ability lymphoma (2–6). Development of effective strategies for radio- of proapoptotic family members, such as Bax and Bak, to open the voltage dependent ion channels in the outer mitochondrial membrane (19, 22). The effects of the Bcl-2 family members Requests for reprints: Claudia Friesen, Nuclear Medicine Clinic, University of Ulm, depend on the balance between proapoptotic and antiapoptotic Robert-Koch-Straße 8, D-89081 Ulm, Germany. Phone: 49-731-500-61342; Fax: 49-731- family members (19, 22). 500-61302; E-mail: [email protected]. I2007 American Association for Cancer Research. Radiation and anticancer drugs, such as cyclophosphamide, doi:10.1158/0008-5472.CAN-06-3569 cisplatin, doxorubicin, or etoposide, induce DNA damage (23–25). Cancer Res 2007; 67: (5). March 1, 2007 1950 www.aacrjournals.org Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2007 American Association for Cancer Research. Breaking Chemoresistance and Radioresistance The nonhomologous end-joining pathway (NHEJ) is the predom- was f0.4Gy/min; the inhomogeneity within the field was lower than F1%. inant mechanism to repair DNA double-strand breaks (DSBs) in The applied doses were measured with a transmission chamber (PTW, mammalian cells, with DNA-PK and ligase IV playing critical roles Freiburg, Germany), which was referenced against a Farmer 2570 device (26–28). The first step in DSB repair by NHEJ is the binding of equipped with a 0.6-cc sensor (Nuclear Enterprises, Edinburgh, United Ku70/80 to the damaged DNA followed by the recruitment of the Kingdom). catalytic subunit DNA-PK, thereby forming the active DNA-PK Monoclonal CD45 Antibody (anti-CD45) holoenzyme (23). One of the targets of DNA-PK is XRCC4, which The rat IgG2a monoclonal antibody YAML568 recognizes the CD45 forms a stable complex with DNA ligase IV (ligase IV), joining the antigen present on human leukocytes and was provided by Dr. G. Hale (Sir ends of broken DNA strands (23). In the absence of DNA-PK or William Dunn School of Pathology, Oxford, United Kingdom; refs. 34, 35). ligase IV, NHEJ fails to repair DSBs (26–31). Conjugation of Chelate to Anti-CD45 and Radiolabeling with In the present study, we investigate the molecular mechanisms 213Bi or 90Y by which anti-CD45 antibodies labeled with 213Bi ([213Bi]anti-CD45) 213 Anti–CD45-diethylenetriaminepentaacetic acid (antibody conjugate). induced cell death in leukemia cells and the effect of [ Bi]anti- Anti-CD45 in HEPES-buffer (50 mmol/L, pH 9.5) was conjugated with h 00 CD45 on -irradiation–, g-irradiation–, apoptosis-, and doxorubi- p-SCN-CHX-A -diethylenetriaminepentaacetic acid (DTPA) and p-SCN-MX- 213 cin-resistant leukemia cells. We show that Bi bound to CD45 DTPA (Macrocyclics, Dallas, TX), respectively, using an initial molar ratio of antibodies breaks radioresistance and chemoresistance in leukemia 1:5 for 20 h at 25jC. After the reaction, excessive chelator was removed via cells, and we provide the molecular requirements for overcoming PD10 desalting column chromatography. The average number of chelates this resistance and for a-particle–induced cell killing. Understand- per antibody was determined by the yttrium-arsenazo(III) spectrophoto- ing the molecular mechanisms induced by a-irradiation, such as metric method and found to be 3 to 4(36). 213 213 225 213 213Bi, in sensitive and resistant leukemia cells may provide [ Bi]anti-CD45. Bi was produced from a Ac/ Bi generator important implications for the further development of novel system (Institute for Transuranium Elements, Karlsruhe, Germany; ref. 37) and was incubated with antibody conjugate for 5 min. The radiolabeled treatment options in leukemia therapy. antibody was purified by PD10 desalting column chromatography. 90 90 [ Y]anti-CD45. [ Y]YCl3 in 0.05 mol/L HCl (AEA, Braunschweig, Materials and Methods Germany) was diluted with 0.05 mol/L sodium citrate/sodium acetate buffer (pH 5.5) followed incubation with antibody conjugate for
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