Purpose: Lintuzumab (HuM195), a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest single-agent activity against acute myeloid leukemia (AML). To increase the potency of the antibody without the nonspecific cytotoxicity associated with β-emitters, the α-particle-emitting radionuclide bismuth-213 ( 213 Bi) was conjugated to lintuzumab. This phase I/II trial was conducted to determine the maximum tolerated dose (MTD) and antileukemic effects of 213 Bi-lintuzumab, the first targeted α-emitter, after partially cytoreductive chemotherapy. Bi-lintuzumab was 37 MB/kg; myelosuppression lasting >35 days was dose limiting. Extramedullary toxicities were primarily limited to grade ≤2 events, including infusion-related reactions. Transient grade 3/4 liver function abnormalities were seen in five patients (16%). Treatmentrelated deaths occurred in 2 of 21 (10%) patients who received the MTD. Significant reductions in marrow blasts were seen at all dose levels. The median response duration was 6 months (range, 2-12). Biodistribution and pharmacokinetic studies suggested that saturation of available CD33 sites by Although standard induction therapy with cytarabine and an anthracycline produces complete remissions (CR) in 50% to 70% of patients with acute myeloid leukemia (AML), long-term survival is seen in only 20% to 40% of patients (1). Following relapse, additional chemotherapy produces remissions in only 20% to 25% of patients. Although allogeneic hematopoietic stem cell transplantation (HSCT) can produce long-term remissions in ∼30% of patients with relapsed AML, most patients are not appropriate candidates due to age, comorbidities, or lack of a suitable donor (2). The prognosis for older patients is even worse, with a 5-year survival rate of 5% for patients ≥65 years of age (3). Therefore, new therapies are needed to improve overall survival and reduce therapyrelated toxicity.Early studies showed that β-particle-emitting anti-CD33 constructs containing iodine-131 or yttrium-90 could eliminate large leukemic burdens but produced prolonged myelosuppression requiring HSCT (4, 5). The unique physical and radiobiological properties of α-particles, however, may provide more efficient tumor cell killing and reduce the nonspecific cytotoxic effects seen with β-emitters. Compared with β-particles, α-particles have a shorter range (50-80 versus 800-10,000 μm) and a higher linear energy transfer (100 versus 0.2 keV/μm; ref. 6). As few as one or two α-particles can kill a target cell. Therefore, the potential for specific antitumor effects makes α-particle immunotherapy an attractive approach for the treatment of cytoreduced or minimal disease.Lintuzumab (HuM195) is a humanized monoclonal antibody that targets CD33, a 67-kDa cell surface glycoprotein expressed on most myeloid leukemia cells. It is also found on committed myelomonocytic and erythroid progenitors but not on pluripotent stem cells, granulocytes, or nonhematopoietic tissues (7,8). Lintuzumab induces Authors' Affiliations:

This work describes a method for the separation and purification of Ac-225 from a Th-229 source. The procedure is based on the combination of ion exchange and extraction chromatographic methods in nitric acid media and allows the preparation of carrier-free, clinical grade Ac-225 with an overall yield exceeding 95%. Quality control of the product is performed using radiometric (alpha, gamma spectrometry) and mass spectrometric methods. The Ac-225 product can be loaded on a radionuclide generator for the preparation of Bi-213 for preclinical and clinical studies of targeted alpha therapy of cancer and infectious diseases.

This study provides proof of concept that targeted local radiotherapy using (213)Bi-DOTA-substance P is feasible and may represent an innovative and effective treatment for critically located gliomas. Primarily non-operable gliomas may become resectable with this treatment, thereby possibly improving the prognosis.

PurposePSMA-617 is a small molecule targeting the prostate-specific membrane antigen (PSMA). In this work, we estimate the radiation dosimetry for this ligand labeled with the alpha-emitter 213Bi.MethodsThree patients with metastatic prostate cancer underwent PET scans 0.1 h, 1 h, 2 h, 3 h, 4 h and 5 h after injection of 68Ga-PSMA-617. Source organs were kidneys, liver, spleen, salivary glands, bladder, red marrow and representative tumor lesions. The imaging nuclide 68Ga was extrapolated to the half-life of 213Bi. The residence times of 213Bi were forwarded to the instable daughter nuclides. OLINDA was used for dosimetry calculation. Results are discussed in comparison to literature data for 225Ac-PSMA-617.ResultsAssuming a relative biological effectiveness of 5 for alpha radiation, the dosimetry estimate revealed equivalent doses of mean 8.1 Sv RBE5/GBq for salivary glands, 8.1 Sv RBE5/GBq for kidneys and 0.52 Sv RBE5/GBq for red marrow. Liver (1.2 Sv RBE5/GBq), spleen (1.4 Sv RBE5/GBq), bladder (0.28 Sv RBE5/GBq) and other organs (0.26 SvRBE5/GBq) were not dose-limiting. The effective dose is 0.56 Sv RBE5/GBq. Tumor lesions were in the range 3.2–9.0 SvRBE5/GBq (median 7.6 SvRBE5/GBq). Kidneys would limit the cumulative treatment activity to 3.7 GBq; red marrow might limit the maximum single fraction to 2 GBq. Despite promising results, the therapeutic index was inferior compared to 225Ac-PSMA-617.ConclusionsDosimetry of 213Bi-PSMA-617 is in a range traditionally considered reasonable for clinical application. Nevertheless, compared to 225Ac-PSMA-617, it suffers from higher perfusion-dependent off-target radiation and a longer biological half-life of PSMA-617 in dose-limiting organs than the physical half-life of 213Bi, rendering this nuclide as a second choice radiolabel for targeted alpha therapy of prostate cancer.Electronic supplementary materialThe online version of this article (10.1007/s00259-017-3817-y) contains supplementary material, which is available to authorized users.

Branched amphiphilic peptide capsules (BAPCs) are peptide nanospheres comprised of equimolar proportions of two branched peptide sequences bis(FLIVI)-K-KKKK and bis(FLIVIGSII)-K-KKKK that self-assemble to form bi-layer delimited capsules. In two recent publications we described the lipid analogous characteristics of our BAPCs, examined their initial assembly, mode of fusion, solute encapsulation, and resizing and delineated their capability to be maintained at a specific size by storing them at 4 °C. In this report we describe the stability, size limitations of encapsulation, cellular localization, retention and, bio-distribution of the BAPCs in vivo. The ability of our constructs to retain alpha particle emitting radionuclides without any apparent leakage and their persistence in the peri-nuclear region of the cell for extended periods of time, coupled with their ease of preparation and potential tune-ability, makes them attractive as biocompatible carriers for targeted cancer therapy using particle emitting radioisotopes. This article is part of a Special Issue entitled: Interfacially active peptides and proteins.

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KEy woRdSmelanoma, metastasis, targeted alpha therapy, Bi-213, alpha radiation, monoclonal antibody 9.2.27, toxicity, response ACKnowlEdGEMEnTSSee page 851. ABSTRACTPurpose: The aim is to assess toxicity and response of systemic alpha therapy for metastatic melanoma.Experimental design: This is an open-labelled Phase 1 dose escalation study to establish the effective dose of the a-immunoconjugate 213 Bi-cDTPA-9.2.27 mAb (AIC). Tools used to investigate the effects were physical examination; imaging of tumors; pathology; GFR; CT and changes in tumor marker. Responses were assessed using RECIST criteria.Results and discussion: Twenty-two patients with stage IV melanoma/in-transit metastasis were treated with activities of 55-947 MBq. Using RECIST criteria 50% showed stable disease and 14% showed partial response. One patient (6%) showed near complete response and was retreated because of an excellent response to the initial treatment. Another patient showed response in his tumor on mandible and reduction in lung lesions. Overall 30% showed progressive disease.The tumor marker melanoma inhibitory activity protein (MIA) showed reductions over eight weeks in most of the patients. The disparity of dose with responders is discussed. No toxicity was observed over the range of administered activities.Conclusion: Observation of responses without any toxicity indicates that targeted alpha therapy has the potential to be a safe and effective therapeutic approach for metastatic melanoma.

Targeted α-therapy is an experimental approach to the management of cancer. Short range α-particle radiation from a radioisotope attached to a targeting monoclonal antibody kills targeted cancer cells. Survival results are analyzed from a previously reported Phase I study of systemic targeted α-therapy for patients with stage IV metastatic melanoma or in-transit metastases. Following intravenous administration of 46-925 MBq of the α-immunoconjugate, (213)Bi-cDTPA-9.2.27, 38 patients were followed to observe response and toxicity. Responses were measured by physical examination, computed tomography at 8 weeks and blood sampling. Toxicity was monitored by blood pathology, urine analysis, glomerular filtration rate and human antimouse antibody response. The maximum tolerance dose was not achieved as there were no adverse events of any type or level. However, an objective partial response rate of 10% was observed, with 40% stable disease at 8 weeks and a median survival of 8.9 months. These results were unexpected because of the short half-life of the (213)Bi and short range of the α-radiation. Survival analysis demonstrated melanoma-inhibitory activity, disease stage, lactate dehydrogenase and treatment effects to be significant prognostic indicators for survival.