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We reviewed 111 In-DOTA-anti-CD45 antibody (BC8) imaging and bone marrow biopsy measurements to ascertain the biodistribution and biokinetics of the radiolabeled antibody and to investigate differences based on type of hematologic malignancy. Methods: Serial whole-body scintigraphic images (4 time points) were obtained after infusion of the 111 In-DOTA-BC8 (176-406 MBq) into 52 adult patients with hematologic malignancies (lymphoma, multiple myeloma, acute myeloid leukemia, and myelodysplastic syndrome). Counts were obtained for the regions of interest for spleen, liver, kidneys, testicles (in men), and 2 marrow sites (acetabulum and sacrum), and correction for attenuation and background was made. Bone marrow biopsies were obtained 14-24 h after infusion, and the percentage of administered activity was determined. Absorbed radiation doses were calculated. Results: Initial uptake in liver averaged 32% ± 8.4% (SD) of administered activity (52 patients), which cleared monoexponentially with a biologic half-time of 293 ± 157 h (33 patients) or did not clear (19 patients). Initial uptake in spleen averaged 22% ± 12% and cleared with a biologic half-time of 271 ± 185 h (36 patients) or longer (6 patients). Initial uptake in kidney averaged 2.4% ± 2.0% and cleared with a biologic half-time of 243 ± 144 h (27 patients) or longer (9 patients). Initial uptake in red marrow averaged 23% ± 11% and cleared with a biologic half-time of 215 ± 107 h (43 patients) or longer (5 patients). Whole-body retention half-time averaged 198 ± 75 h. Splenic uptake was higher in the AML/MDS group than in the lymphoma group ( P ≤ 0.05) or the multiple myeloma group ( P ≤ 0.10). Liver represented the dose-limiting organ. For liver uptake, no significant differences were observed among the 3 malignancy groups. Average calculated radiation absorbed doses per unit of administered activity for a therapy infusion of 90 Y-DOTA-BC8 were 0.35 ± 0.20 cGy/MBq for red marrow, 0.80 ± 0.24 cGy/MBq for liver, 3.0 ± 1.4 cGy/MBq for spleen, 0.055 ± 0.014 cGy/MBq for total body, 0.21 ± 0.15 cGy/MBq for osteogenic cells, and 0.17 ± 0.15 cGy/MBq for kidneys. Conclusion: 111 In-DOTA-BC8 had a long retention time in liver, spleen, kidneys, and red marrow, and the highest absorbed doses were in spleen and liver. Few differences were observed by malignancy type. The exception was greater splenic uptake in the leukemia/MDS group than in the lymphoma or multiple myeloma group., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: External-beam radiation is the single most effective therapy for localized lymphoma. However, toxicity limits its use for multifocal disease. We evaluated CD45 as a therapeutic target for an antibody-radionuclide conjugate (ARC) for the treatment of lymphoma based on its ubiquitous expression, infrequent antigen loss or blockade, and the ability to target minimal disease based on panhematopoietic expression., Patients and Methods: We performed a phase I trial of escalating doses of single-agent CD45-targeted ARC based on per-patient dosimetry using the BC8 antibody labeled with iodine-131 ( 131 I) followed by autologous stem cell support in adults with relapsed, refractory, or high-risk B-cell non-Hodgkin lymphoma (B-NHL), T-cell NHL (T-NHL), or Hodgkin lymphoma. The primary objective was to estimate the maximum tolerated radiation absorbed dose., Results: Sixteen patients were enrolled: 7 patients had B-NHL, 6 had Hodgkin lymphoma, and 3 had T-NHL. Median number of prior therapies was three (range: 2-12). Absorbed doses up to 32 Gy to liver were delivered. No dose-limiting toxicities occurred. Nonhematologic toxicity was infrequent and manageable. Objective responses were seen across histologies. Fourteen patients had measurable disease at enrollment, 57% of whom achieved complete remission (CR), including all 3 with T-NHL. Three patients with B-NHL treated among the highest dose levels (26-32 Gy) remain in CR without subsequent therapy 35-41 months later., Conclusions: CD45-targeted ARC therapy is well-tolerated at doses up to at least 32 Gy to the liver. Objective responses and long-term remissions were observed in patients with relapsed/refractory lymphoma. These data validate continued evaluation of anti-CD45 ARCs in lymphoma., (©2019 American Association for Cancer Research.)

Nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) can provide prolonged remissions in patients with advanced B cell lymphoma (B-NHL) via the graft-versus-lymphoma effect, although inferior results are seen in patients with chemoresistant, bulky, or aggressive disease. Radioimmunotherapy can safely induce responses in B-NHL with minimal nonhematologic toxicity. Initial results of 90 Y-ibritumomab tiuxetan-based allografting demonstrated early safety and disease control in nonremission patients but with short follow-up. Here we report the long-term outcomes of patients treated on this study with specific emphasis on patients achieving early remissions. Eleven of 40 patients were alive at a median follow-up of 9 years (range, 5.3 to 10.2). Fourteen (35%) deaths were due to disease progression and 14 (35%) deaths to complications from HCT. One patient died of a Merkel cell carcinoma. The 5-year overall and progression-free survival for patients with indolent B-NHL was 40% and 27.5%, respectively. None of the patients with diffuse large B cell lymphoma was a long-term disease-free survivor regardless of early remission status. 90 Y-ibritumomab tiuxetan-based allografting represents a viable option in patients with indolent histologies. Improved strategies are needed for aggressive B-NHL. The original trial was registered at www.clinicaltrials.gov as NCT00119392., (Copyright © 2018. Published by Elsevier Inc.)

The objective of this study was to translate reaction conditions and quality control methods used for production of an astatine-211(211At)-labeled anti-CD45 monoclonal antibody (MAb) conjugate, 211At-BC8-B10, from the laboratory setting to cGMP production. Five separate materials were produced in the preparation of 211At-BC8-B10: (1) p-isothiocyanato-phenethyl-closo-decaborate(2-) (B10-NCS), (2) anti-CD45 MAb, BC8, (3) BC8-B10 MAb conjugate, (4) [211At]NaAt, and (5) 211At-BC8-B10. The 211At-labeling reagent, B10-NCS, was synthesized as previously reported. BC8 was produced, then conjugated with B10-NCS under cGMP conditions to form BC8-B10. [211At]NaAt was produced by α-irradiation of Bi targets, followed by isolation of the 211At using a "wet chemistry" method. The clinical product, 211At-BC8-B10, was prepared by reacting [211At]NaAt with BC8-B10 in NH4OAc buffer (pH 5.5) for 2 min at room temperature, followed by size-exclusion chromatography purification. Quality control tests conducted on the 211At-BC8-B10 included evaluations for purity and identity, as well as pyrogen and sterility tests. Stability of the 211At-BC8-B10 in 25 mg/mL sodium ascorbate solution was evaluated at 1, 2, 4, 6 and 21 h post isolation. For qualification, three consecutive 211At-BC8-B10 clinical preparations were successfully conducted in the cGMP suite, and an additional cGMP clinical preparation was carried out to validate each step required to deliver 211At-BC8-B10 to a patient. These cGMP preparations provided 0.80-1.28 Gbq (21.5-34.5 mCi) of 211At-BC8-B10 with radiochemical purity of >97%. The preparations were found to be sterile and have a pyrogen level <0.50 EU/mL. Cell binding was retained by the 211At-BC8-B10. 211At-BC8-B10 in ascorbic acid solution demonstrated a radiochemical stability of >95% for up to 21 h at room temperature. The experiments conducted have defined conditions for translation of 211At-BC8-B10 production from the laboratory to cGMP suite. This study has allowed the initiation of a phase I/II clinical trial using 211At-BC8-B10 (NCT03128034)., Competing Interests: The authors have declared that no competing interests exist.

Therapy of cancer with radiolabeled monoclonal antibodies has produced impressive results in preclinical experiments and in clinical trials conducted in radiosensitive malignancies, particularly B-cell lymphomas. Two "first-generation," directly radiolabeled anti-CD20 antibodies, 131 iodine-tositumomab and 90 yttrium-ibritumomab tiuxetan, were FDA-approved more than a decade ago but have been little utilized because of a variety of medical, financial, and logistic obstacles. Newer technologies employing multistep "pretargeting" methods, particularly those utilizing bispecific antibodies, have greatly enhanced the therapeutic efficacy of radioimmunotherapy and diminished its toxicities. The dramatically improved therapeutic index of bispecific antibody pretargeting appears to be sufficiently compelling to justify human clinical trials and reinvigorate enthusiasm for radioimmunotherapy in the treatment of malignancies, particularly lymphomas. Cancer Res; 77(9); 2191-6. ©2017 AACR ., (©2017 American Association for Cancer Research.)

α-Emitting radionuclides deposit a large amount of energy within a few cell diameters and may be particularly effective for radioimmunotherapy targeting minimal residual disease (MRD). To evaluate this hypothesis, (211)At-labeled 1F5 monoclonal antibody (mAb) (anti-CD20) was studied in both bulky lymphoma tumor xenograft and MRD animal models. Superior treatment responses to (211)At-labeled 1F5 mAb were evident in the MRD setting. Lymphoma xenograft tumor-bearing animals treated with doses of up to 48 µCi of (211)At-labeled anti-CD20 mAb ([(211)At]1F5-B10) experienced modest responses (0% cures but two- to threefold prolongation of survival compared with negative controls). In contrast, 70% of animals in the MRD lymphoma model demonstrated complete eradication of disease when treated with (211)At-B10-1F5 at a radiation dose that was less than one-third (15 µCi) of the highest dose given to xenograft animals. Tumor progression among untreated control animals in both models was uniformly lethal. After 130 days, no significant renal or hepatic toxicity was observed in the cured animals receiving 15 µCi of [(211)At]1F5-B10. These findings suggest that α-emitters are highly efficacious in MRD settings, where isolated cells and small tumor clusters prevail.

The vast majority of patients with plasma cell neoplasms die of progressive disease despite high response rates to novel agents. Malignant plasma cells are very radiosensitive, but the potential role of radioimmunotherapy (RIT) in the management of plasmacytomas and multiple myeloma has undergone only limited evaluation. Furthermore, CD38 has not been explored as a RIT target despite its uniform high expression on malignant plasma cells. In this report, both conventional RIT (directly radiolabeled antibody) and streptavidin-biotin pretargeted RIT (PRIT) directed against the CD38 antigen were assessed as approaches to deliver radiation doses sufficient for multiple myeloma cell eradication. PRIT demonstrated biodistributions that were markedly superior to conventional RIT. Tumor-to-blood ratios as high as 638:1 were seen 24 hours after PRIT, whereas ratios never exceeded 1:1 with conventional RIT. (90)Yttrium absorbed dose estimates demonstrated excellent target-to-normal organ ratios (6:1 for the kidney, lung, liver; 10:1 for the whole body). Objective remissions were observed within 7 days in 100% of the mice treated with doses ranging from 800 to 1,200 μCi of anti-CD38 pretargeted (90)Y-DOTA-biotin, including 100% complete remissions (no detectable tumor in treated mice compared with tumors that were 2,982% ± 2,834% of initial tumor volume in control animals) by day 23. Furthermore, 100% of animals bearing NCI-H929 multiple myeloma tumor xenografts treated with 800 μCi of anti-CD38 pretargeted (90)Y-DOTA-biotin achieved long-term myeloma-free survival (>70 days) compared with none (0%) of the control animals., (©2013 AACR.)

Despite aggressive chemotherapy combined with hematopoietic stem cell transplantation (HSCT), many patients with acute myeloid leukemia (AML) relapse. Radioimmunotherapy (RIT) using monoclonal antibodies labeled with β-emitting radionuclides has been explored to reduce relapse. β emitters are limited by lower energies and nonspecific cytotoxicity from longer path lengths compared with α emitters such as (211)At, which has a higher energy profile and shorter path length. We evaluated the efficacy and toxicity of anti-CD45 RIT using (211)At in a disseminated murine AML model. Biodistribution studies in leukemic SJL/J mice showed excellent localization of (211)At-anti-murine CD45 mAb (30F11) to marrow and spleen within 24 hours (18% and 79% injected dose per gram of tissue [ID/g], respectively), with lower kidney and lung uptake (8.4% and 14% ID/g, respectively). In syngeneic HSCT studies, (211)At-B10-30F11 RIT improved the median survival of leukemic mice in a dose-dependent fashion (123, 101, 61, and 37 days given 24, 20, 12, and 0 µCi, respectively). This approach had minimal toxicity with nadir white blood cell counts >2.7 K/µL 2 weeks after HSCT and recovery by 4 weeks. These data suggest that (211)At-anti-CD45 RIT in conjunction with HSCT may be a promising therapeutic option for AML.

Pretargeted radioimmunotherapy (PRIT) is designed to enhance the directed delivery of radionuclides to malignant cells. Through a series of studies in 19 nonhuman primates (Macaca fascicularis), the potential therapeutic advantage of anti-CD45 PRIT was evaluated. Anti-CD45 PRIT demonstrated a significant improvement in target-to-normal organ ratios of absorbed radiation compared with directly radiolabeled bivalent antibody (conventional radioimmunotherapy [RIT]). Radio-DOTA-biotin administered 48 hours after anti-CD45 streptavidin fusion protein (FP) [BC8 (scFv)(4)SA] produced markedly lower concentrations of radiation in nontarget tissues compared with conventional RIT. PRIT generated superior target:normal organ ratios in the blood, lung, and liver (10.3:1, 18.9:1, and 9.9:1, respectively) compared with the conventional RIT controls (2.6:1, 6.4:1, and 2.9:1, respectively). The FP demonstrated superior retention in target tissues relative to comparable directly radiolabeled bivalent anti-CD45 RIT. The time point of administration of the second step radiolabeled ligand (radio-DOTA-biotin) significantly impacted the biodistribution of radioactivity in target tissues. Rapid clearance of the FP from the circulation rendered unnecessary the addition of a synthetic clearing agent in this model. These results support proceeding to anti-CD45 PRIT clinical trials for patients with both leukemia and lymphoma.

Purpose: Radiolabeled anti-CD20 antibodies have demonstrated impressive efficacy in the treatment of relapsed non-Hodgkin's lymphoma. However, the amount of radiation that can be delivered to eradicate the malignancy is limited by toxicity to normal organs. We examined an "extracorporeal adsorption therapy" (ECAT) method to remove circulating unbound radioimmunoconjugate and improve the ratios of radiation delivered to B-cells in a macaque model., Experimental Design: ECAT was applied with an avidin-agarose column 24 hours after an injection of (111)In- or (177)Lu-DOTA-biotin-rituximab (anti-CD20 antibody) to normal macaques. Two (2) animals were studied in initial blood clearance studies, and 6 additional animals were evaluated in subsequent detailed biodistribution experiments. After the injection of (111)In- or (177)Lu-antibody, 3 animals underwent ECAT circulating one volume/hour while 3 served as controls. Serial blood, marrow, and lymph node samples, gamma-camera images, and necropsy tissues were obtained to estimate radiation-absorbed doses in organs of interest., Results: Optimal blood clearance (98%) was achieved by performing ECAT at a flow rate of one blood volume/hour. Radiation doses to normal organs were reduced with ECAT in kidney (49% +/- 12%), liver (42% +/- 10%), lungs (60% +/- 6%), total body (51% +/- 16%), marrow (50% +/- 15%), spleen (38% +/- 10%), and lymph nodes (19% +/- 3%). Despite dose reduction in both target and nontarget tissues, therapeutic ratios were significantly higher in animals treated with ECAT (20% higher for spleen:kidney and 60% for lymph node:kidney), compared to controls., Conclusions: ECAT is a safe, feasible, and effective method to remove unbound radioimmunoconjugates from the bloodstream and reduce the nonspecific radiation exposure of normal tissues.