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  • American Society of Hematology  (21)
  • 1
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2864-2864
    Kurzfassung: Major coronary events are commonly precipitated by thrombotic occlusion of atheromatous vessels. We determined whether d-dimer, C-reactive protein (CRP), or serum amyloid A (SAA), increase in the months prior to an acute coronary events in patients with severe lower extremity peripheral artery disease (PAD). The Biomarker Risk Assessment in Vulnerable Outpatients (BRAVO) Study enrolled patients with PAD and followed them prospectively every two months. At each visit, participants were queried about new hospitalizations, blood was obtained, electrocardiograms performed, and mortality data collected. Two controls for each patient with events were randomly selected from participants without events, matched for age, sex, race, duration in the study, and number of blood draws. D-dimer was measured using an immunoturbidometric assay (Asserachrom D-Di kit, Diagnostica Stago, Parsippany, NJ). CRP and SAA were determined using an immunotechnique on the Behring BN II analyzer (Dade Behring, Wilmington, DE). Changes in levels of these biomarkers during the months leading up to the primary outcome (acute MI, new MI detected by ECG, hospitalization for unstable angina, cardiac death) were the independent variables of interest. A total of 595 participants with PAD were followed for a mean of 1.56 years; 50 (8.4%) experienced 75 acute coronary events. Sixteen of these cases had five complete visits immediately prior to the event, allowing a comparison of D-dimer levels over time within the same cohort of study participants. Their median/interquartile D-dimer (mg/L, log-transformed) just prior to the event was 1.05 (0.62-1.62); the level was significantly lower at each of the other 4 visits (0.69, 0.71, 0.83, 0.86; all P 〈 0.032 based on paired t-tests). We also compared cases with controls; in 19 cases (36 pairs with controls), D-dimer measurements at the 4 visits leading up to an acute event were significantly higher in the cases than in the controls (Table 1). CRP (mg/L) was increased just prior to events only in comparison with visits at 4 and 8 months (n=16; 3.34 vs 2.29, P=0.03; 3.34 vs 1.94, P=0.02), and was not significantly higher in cases than controls. SAA (mg/L) just prior to an event exceeded only one other value (at 8 months; 0.55 vs 0.37, P=0.02), and was higher in cases than controls at only 1 visit. We conclude that levels of D-dimer are significantly higher within 2 months of an acute coronary event compared to values in the same participants in the months before the event. In addition, D-dimer levels are higher in patients than controls during the 8 month period before an acute coronary event. Levels of CRP and SAA are infrequently increased in patients prior to events and in comparison to those without events. Table 1. Median D-dimer (mg/L) during the 8 months leading up to an ischemic heart disease event. Cases vs Controls No. of pairs/cases Median/Interquartile for case Median/Interquartile for control P-value from GEE* Within 2 months 36/19 1.1 (0.62 to 1.67) 0.53 (0.3 to 0.84) 0.01 4 months 36/19 0.95 (0.52 to 1.55) 0.45 (0.28 to 0.9) 0.03 6 months 36/19 0.83 (0.52 to 1.76) 0.5 (0.27 to 0.91) 0.02 8 months 36/19 0.86 (0.48 to 1.45) 0.48 (0.3 to 0.9) 0.01 *P-value based on the General Estimating Equation (GEE) model using LOG transformed values and assuming correlated error structure Disclosures Huffman: AstraZeneca: Research Funding; Boehringer Ingelheim: Research Funding.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2014
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2417-2417
    Kurzfassung: Haploidentical bone marrow transplantation (haplo-BMT) is both clinically effective and widely available because related-donors can be identified for nearly all recipients. Despite the curative promise of this approach, many patients with hematologic malignancies will relapse after haplo-BMT and more effective preparative regimens are necessary. We have shown that anti-CD45 radioimmunotherapy (RIT) delivers high-doses of radiation to hematolymphoid organs while minimizing the radiation exposure to non-targeted tissues. The efficacy of beta-emitting radionuclides may be limited by their relatively low decay energies (0.66 – 2.3 MeV). We have thus investigated the higher energy alpha-emitter astatine-211 (211At) (average decay energy of 6.8 MeV), for targeted anti-CD45 radioimmunotherapy (RIT) in lieu of total body irradiation (TBI) prior to haploidentical BMT in a murine leukemia model to decrease relapse rates. Groups of five B6SJLF1/J mice (allotype H2-Db) received escalated activities (20, 30 or 40 μCi) of 211At-anti-CD45 antibody [100 μg (0.67 nmol) of B10-30F11] given by tail vein injections on day -2 in place of TBI prior to BMT. Animals received cyclophosphamide (CY; 200 mg/kg/day) on days –3, –2, or –1, and +2 for graft-versus-host disease prophylaxis, either alone, or with fludarabine (FLU; 100 mg/kg/day) for 4 days starting day -6. Transplanted mice received 1.5 × 107 haploidentical bone marrow cells from CB6F1/J mice (allotype H2-Dd) on day 0. Peripheral blood from recipient mice was then assayed monthly by flow cytometry to measure chimerism as the percentage of donor (H2-Dd) circulating CD8+ cells. The highest activity delivered of 40 µCi 211At-anti-CD45 RIT was uniformly lethal without BMT rescue, whereas 60% of transplanted mice at this dose survived to assessment at 1 month. Mice treated with 30 µCi of 211At-anti-CD45 RIT with pre- and post-transplant CY and without TBI or FLU, had high levels of engraftment with an average of 83.7 ± 5.8% donor CD8+ cells 1 month after haploidentical BMT (Table 1). The addition of FLU to 211At-anti-CD45 RIT with CY did not significantly improve chimerism levels, with mean donor CD8+ cells in mice treated with 40 µCi 211At-anti-CD45 RIT of 64.5 ± 41.6% compared to 60.0 ± 13.9% in the absence of FLU (p=0.8668). In addition, mice that received 30 µCi 211At-anti-CD45 RIT and pre-transplant CY on either day –3, –2, or –1 showed mean donor CD8+ cells of 83.7 ± 5.8%, 49.9 ± 29.6% and 55.0 ± 46.2% 1 month after haploidentical-BMT, respectively. Importantly, chimerism levels remained stable 2 months after haploidentical BMT with mean donor CD8+ cells of 80.4 ± 16.6%, 47.0 ± 37.7% and 63.2 ± 10.7% in mice treated with 30 µCi 211At-anti-CD45 RIT and pre-transplant CY on day –3, –2, and –1, respectively. Engraftment using 40 or 30 µCi 211At-anti-CD45 RIT was comparable to using 850 or 1000 cGy TBI (mean donor CD8+ cells of 70.2 ± 18.8% and 60.0 ± 4.6%, respectively) prior to haploidentical BMT. RIT alone without any chemotherapy was insufficient to facilitate clinically relevant rates of donor engraftment, as mice treated with 30 µCi 211At-anti-CD45 RIT and no FLU, CY or TBI had 15.9 ± 7.1% mean donor CD8+ cells 1 month after haploidentical BMT. These results suggest that 211At-anti-CD45 RIT prior to haploidentical BMT with pre– and post–transplant CY can result in high levels of donor hematopoietic cell engraftment in the absence of TBI and FLU. This conditioning regimen may be less toxic and more effective at preventing relapse than TBI-based approaches due to the high linear energy transfer of the alpha emissions, or the high decay energy of targeted 211At deposited over its short effective path-length. On-going studies are assessing the efficacy and toxicity associated with 211At-anti-CD45 RIT compared to a TBI-based haploidentical BMT using a syngeneic murine leukemia model. Abstract 2417. Table 1 Preparative Therapy and CD8+ Donor Chimerism at 1 month Group FLU (100mg/kg/d) pre-BMT CY (200mg/kg) TBI 211 At-anti-CD45 RIT post-BMT CY (200mg/kg) Donor CD8+ % 1 – day –3 – 30 µCi day +2 83.7 ± 5.8 2 – day –2 – 30 µCi day +2 49.9 ± 29.6 3 – day –1 – 30 µCi day +2 55.0 ± 46.2 4 – day –3 – 40 µCi day +2 64.5 ± 41.6 5 d –6 to –3 day –3 – 40 µCi day +2 60.0 ± 13.9 6 – – – 30 µCi day +2 15.9 ± 7.1 7 – day –3 – – day +2 4.4 ± 0.6 8 – – 1000 cGy – day +2 60.0 ± 4.6 Disclosures No relevant conflicts of interest to declare.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2014
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
    In: Blood, American Society of Hematology, Vol. 125, No. 13 ( 2015-03-26), p. 2111-2119
    Kurzfassung: α-Emitting radionuclides have the potential to overcome treatment-resistant lymphoma cell clones that evade other forms of therapy. 211At-labeled anti-CD20 monoclonal antibody eradicates lymphoma in a mouse minimal residual disease model.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2015
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
    In: Blood Advances, American Society of Hematology, Vol. 3, No. 23 ( 2019-12-10), p. 4002-4020
    Kurzfassung: To address the global burden of sickle cell disease and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to patient-reported outcome, pain (non–patient-reported outcomes), the brain, end-organ considerations, biomarkers, measurement of cure, and low-resource settings. This article presents the findings and recommendations of the end-organ considerations, measurement of cure, and low-resource settings panels as well as relevant findings and recommendations from the biomarkers panel.
    Materialart: Online-Ressource
    ISSN: 2473-9529 , 2473-9537
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2019
    ZDB Id: 2876449-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1035-1035
    Kurzfassung: Abstract 1035 Poster Board I-57 Little change has been seen over the past two decades in the progression-free survival of patients with Acute Myeloid Leukemia (AML) undergoing allogeneic hematopoietic cell transplantation (HCT). Efforts to decrease the risk of relapse after HCT have included increasing the intensity of the preparative regimen. Our group has focused on targeted radioimmunotherapy using an anti-CD45 antibody (Ab) as part of the preparative regimen prior to HCT. Despite the promise of this approach, recurrent malignancy remains a problem, particularly for patients with high-risk disease. More recently we have explored a pretargeted RIT (PRIT) strategy to augment the anti-tumor efficacy of the transplant preparative regimen while diminishing overall toxicity. These studies have employed an anti-CD45 Ab conjugated to streptavidin (SA) followed by a biotinylated, N-acetylgalactosamine-containing clearing agent (CA) to remove circulating Ab-SA conjugate from the blood and then with radiobiotin using beta-emitting radionuclides that have relatively low energy transfer characteristics and long path lengths that may result in suboptimal killing of leukemia cells and normal organ toxicity due to cross-fire from malignant cells. Alpha-emitting radionuclides exhibit very high cytotoxicity coupled with a short path length, potentially increasing the therapeutic index and making them an attractive alternative to beta-emitting radionuclides. Therefore, we have now employed PRIT using an anti-CD45 Ab-SA conjugate, CA, and biotin labeled with an alpha-emitting radionuclide (213Bi) in mice with human erythroid leukemia (HEL) xenografts. Results of biodistributions of radioactivity demonstrated excellent localization of 213Bi-biotin to tumors with minimal uptake into normal organs due to elimination of non-specific radiation exposure from blood-borne radiolabeled Ab. After 10 minutes, 4.5 ± 1.1% of the injected dose of 213Bi was delivered per gram of tumor (% ID/g). Imaging using a novel alpha camera demonstrated uniform radionuclide distribution within tumor tissue at 10 minutes after 213Bi-biotin injection. Estimated radiation-absorbed doses delivered to HEL xenografts delivered 3.4-and 2.1-fold more radiation to tumor than to liver and lungs, respectively. These target-to-non-target ratios of absorbed radiation obtained using PRIT with 213Bi were similar to those observed using a beta-emitting (90Y) radionuclide in the same animal model. Based on these encouraging results, we conducted therapy experiments in a minimal disease xenograft model using a single dose of 213Bi-biotin given 24 hours after anti-CD45 Ab-SA conjugate. In an initial attempt to compare 90Y and 213Bi, we gave equal μCi doses of each radionuclide. Eighty percent of mice treated with anti-CD45 Ab-SA conjugate followed by 800 μCi of 213Bi-biotin survived leukemia-free for 〉 100 days with minimal toxicity. By comparison, only 20% of mice treated with PRIT anti-CD45 Ab-SA conjugate followed by 800 μCi 90Y-biotin exhibited long term leukemia-free survival. While we acknowledge that equal μCi doses may not necessarily result in equivalent doses delivered to normal tissue, these data suggest that anti-CD45 PRIT using an alpha-emitting radionuclide may be highly effective and minimally toxic for the treatment of myeloid leukemias. Disclosures: No relevant conflicts of interest to declare.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2009
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 6
    In: Blood, American Society of Hematology, Vol. 127, No. 3 ( 2016-01-21), p. 352-359
    Kurzfassung: Anti-CD45 RIT may replace TBI and simplify BMT-preparative regimens. Anti-CD45 RIT and haploidentical BMT, without TBI, prolongs survival in a murine leukemia model.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2016
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 7
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2705-2705
    Kurzfassung: Abstract 2705 Poster Board II-681 Conventional radioimmunotherapy (RIT) with directly radiolabeled anti-B cell antibodies (Ab) induces remissions in 50 to 80% of patients with relapsed or refractory indolent non-Hodgkin lymphomas (NHL). Although administering RIT as consolidation after chemotherapy improves response rates and produces long-term durable remissions in treatment-naïve patients, the β-emitting radionuclides used in current RIT schemes may not be ideal for irradiating the microscopic tumors and the isolated tumor cells present in the setting of minimal residual disease (MRD). RIT with α-emitting radionuclides may be advantageous in the treatment of MRD because the short path length and high energies of α-particles produce optimal cytotoxicity at small target sites while minimizing damage to the surrounding normal tissues. Our group has successfully demonstrated that pretargeted RIT (PRIT) using streptavidin (SA)-Ab and radiolabeled biotin allows rapid specific localization of radioactivity at tumor sites. PRIT using α-emitting radionuclides may be particularly attractive since the most promising α-emitting radionuclides in clinical settings, such as 213Bi (t½ = 46 min), have short half-lives and pretargeting allows the delivery of radioactivity to tumor sites before the activity decays. We therefore performed in vivo studies to evaluate the biodistribution of 213Bi with PRIT. Athymic mice with B-cell NHL (Ramos) xenografts received a tetravalent anti-CD20 (1F5) single-chain (scFv)4SA fusion protein (FP) or a CC49 (scFv)4SA FP (non-binding negative control) followed by an N-acetyl galactosamine clearing agent (CA) and subsequent 213Bi-DOTA-biotin infusion. Tumors, blood, and major organs were collected to determine the percent injected dose per gram (%ID/g) at various time points within ∼3 half-lives of 213Bi. Maximal tumor uptake for 1F5 (scFv)4SA FP was 16.5 ± 7.0 %ID/g at 90 minutes vs. 2.3 ± 0.9 %ID/g for the control FP (p = 0.0001). Biodistributions of 213Bi using a conventional RIT scheme with directly labeled Ab were also evaluated. Athymic mice with Ramos xenografts received 213Bi labeled 1F5 Ab or 213Bi labeled HB8181 Ab (a murine isotype matched nonbinding control). Maximum tumor uptake for 1F5 Ab was 3.0 ± 0.9 %ID/g at 180 minutes vs. 2.3 ± 0.7 %ID/g for the control Ab (p = 0.171). There were no significant differences in tumor uptake and normal organ distribution between the two Ab within 180 minutes of radiolabeled Ab injection presumably due to the protracted circulating half-life of radiolabeled Abs. These results were concordant with our previous experiments using other radionuclides, showing that maximal targeting of radiolabeled Ab occurs between 20 to 24 hours; well beyond the effective half-life of 213Bi. When the results of PRIT and RIT studies were directly compared, tumor-to-blood ratios were 58 to 426-fold higher with PRIT than with conventional RIT. Tumor-to-normal organ ratios of nearly 100:1 were observed with PRIT compared to 3:1 or less with conventional RIT. Using the most favorable PRIT schemes defined in the biodistribution experiments, the therapeutic efficacy of 213Bi was evaluated. Mice treated with PRIT using 1F5 (scFv)4SA FP followed by a CA and 600 μCi 213Bi-DOTA-biotin experienced significant delays in tumor growth. The 1F5 (scFv)4SA FP treated animals had a mean tumor volume of 0.01 ± 0.02 vs. 203.38 ± 83.03 mm3 for the CC49 control group at 19 days (p = 0.0006). The median survival for 1F5 group was not reached after 90 days; whereas, the median survival was 23 days for the CC49 group (p = 0.0019) and 16 days for untreated mice (p = 0.0023). The treatment was well tolerated, with no treatment-related mortalities in any group. These data demonstrate that PRIT using 213Bi has a favorable biodistribution profile and excellent therapeutic efficacy. This model may be particularly effective in MRD settings and further studies are ongoing. Disclosures: No relevant conflicts of interest to declare.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2009
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 8
    In: Blood, American Society of Hematology, Vol. 118, No. 3 ( 2011-07-21), p. 703-711
    Kurzfassung: Pretargeted radioimmunotherapy (PRIT) using an anti-CD45 antibody (Ab)–streptavidin (SA) conjugate and DOTA-biotin labeled with β-emitting radionuclides has been explored as a strategy to decrease relapse and toxicity. α-emitting radionuclides exhibit high cytotoxicity coupled with a short path length, potentially increasing the therapeutic index and making them an attractive alternative to β-emitting radionuclides for patients with acute myeloid leukemia. Accordingly, we have used 213Bi in mice with human leukemia xenografts. Results demonstrated excellent localization of 213Bi-DOTA-biotin to tumors with minimal uptake into normal organs. After 10 minutes, 4.5% ± 1.1% of the injected dose of 213Bi was delivered per gram of tumor. α-imaging demonstrated uniform radionuclide distribution within tumor tissue 45 minutes after 213Bi-DOTA-biotin injection. Radiation absorbed doses were similar to those observed using a β-emitting radionuclide (90Y) in the same model. We conducted therapy experiments in a xenograft model using a single-dose of 213Bi-DOTA-biotin given 24 hours after anti-CD45 Ab-SA conjugate. Among mice treated with anti-CD45 Ab-SA conjugate followed by 800 μCi of 213Bi- or 90Y-DOTA-biotin, 80% and 20%, respectively, survived leukemia-free for more than 100 days with minimal toxicity. These data suggest that anti-CD45 PRIT using an α-emitting radionuclide may be highly effective and minimally toxic for treatment of acute myeloid leukemia.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2011
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 9
    In: Blood, American Society of Hematology, Vol. 121, No. 18 ( 2013-05-02), p. 3759-3767
    Kurzfassung: Astatination of anti-CD45 antibody via a closo-decaborate compound yields a stable conjugate that targets radiation to hematologic organs. 211At-anti-CD45 radioimmunotherapy combined with bone marrow transplantation prolongs survival in a disseminated murine leukemia model.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2013
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 10
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 4415-4415
    Kurzfassung: Stem cell rescue after myeloablative doses of beta particle emitting radiolabeled monoclonal antibodies targeting CD20 antigen can lead to remissions in up to 95% of lymphoma patients who previously failed conventional combination chemotherapy. While encouraging, toxicities with beta particle radioimmunotherapy (RIT) are significant and ∼50% of patients ultimately relapse. Higher doses of absorbed radiation to tumors have correlated with a reduced risk of disease recurrence but dose limiting toxicities prevent escalation. A potential advantage of alpha particle emitting radionuclides is the release of large amounts of energy linearly over a few cell diameters (∼50-80 mm) resulting in irreparable double-strand DNA breaks that overwhelm cellular repair mechanisms. As a result, alpha particles confer a unique capacity to kill individual targeted cells while causing minimal radiation damage to surrounding tissues. To explore alpha-emitter conjugated anti-CD20 RIT, a closo-decaborate(2-) [B10] labeling reagent was developed as a radiolabeling platform capable of providing critical stability to alpha particle-labeled biomolecules. 211At was chosen as a therapeutic radionuclide based on its high linear energy transfer, biologically relevant t1/2 (∼7.2 hr) and absence of toxic daughter radionuclide decay byproducts. Cell binding assays using CD20-expressing Ramos tumor cells demonstrated that B10 conjugated to the anti-CD20 monoclonal antibody (mAb) 1F5 (B10-1F5) was specific and that astatination did not impair antibody binding (211At-B10-1F5 binding was equivalent to 125I-B10-1F5). Blood clearance was similar for 125I-1F5, 211At-B10-1F5 and 125I-B10-1F5 in athymic nude- Foxn1nu mice (23.87 ±5.13 % injected dose/gram [ID/g] , 19.41 ±3.27 %ID/g and 19.80 ±1.44% ID/g respectively) at 17 hr post infusion. In tissue biodistribution studies using nude mice bearing Ramos flank tumor xenografts (10 x106 cells injected) radioactivity was measured in blood, tumor and nonspecific organs harvested 24 hours after injection (n=5/group). Animals received either 125I-1F5, 211At-B10-1F5 and 125I-B10-1F5 (co-injected) or isotype matched control mAb 211At- B10-HB8181 and125I-B10-HB8181(co-injected). Measured activity in tumors was three-fold higher for 125I-1F5, 125I-B10-1F5 and 211At-B10-1F5 (7.62 ± 2.09%ID/g, 7.53 ± 1.59%ID/g and 9.28 ± 1.85%ID/g respectively) than for 125I-B10-HB8181 and 211At-B10-HB8181 controls (2.87 ± 0.35%ID/g and 3.45 ± 0.58%ID/g respectively). In non-target organs no appreciable difference in measured activity was seen with either 211At- or 125I-labeled B10-1F5 and their respective controls. Subsequent therapy studies performed in nude mice bearing Ramos flank tumor xenografts demonstrated only a moderate survival advantage after 211At-B10-1F5 [data not shown]. This finding was consistent with the hypothesis that the alpha particle's short path length may not be ideally suited to models of “bulky” disease. In contrast, therapy studies using disseminated Ramos and Granta tumor cells introduced into NOD-SCID mice suggest a role for alpha particle based RIT in “non-bulky” disease models. In these studies NOD-SCID animals received 1x106 tumor cells iv 48 hours prior to 211At-B10-1F5 (10 μCi or 15 μCi) or control 211At-B10-HB8181 (n=10/group). Stem cell rescue was performed 48 hours after the RIT. Eighty days after treatment 80% of animals receiving 15 μCi of 211At-B10-1F5 and 70% of animals in the 10 μCi treatment group were alive and tumor free while no animals in the non-binding 211At-B10-HB8181 (10 μCi or 15 μCi) control groups survived beyond day 47 (Figure). Blood counts, serum creatinine and transaminase levels measured in 211At-B10-1F5 treated animals ∼180 days after RIT demonstrated no significant long-term bone marrow, renal or liver toxicity. 211At-B10-1F5 can eliminate CD20 expressing tumor cells in this mouse model and further study appears to be warranted. Disclosures: No relevant conflicts of interest to declare.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2013
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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