Towards translation of 212Pb as a clinical therapeutic; getting the lead in!

Yong, Kwon Joong; Brechbiel, Martin W.

doi:10.1039/c0dt01387k

Cited by 92 publications

(76 citation statements)

References 71 publications

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“…TCMC was chosen based on its stability at low pH, because DOTA undergoes acidic catalysis within lysosomes after internalization and this can dissociate the radio-metal from the chelator, leading to release of isotopes and toxicity [38], [44], [45]. The mAb final concentration was quantified using the BCA Protein Assay Reagent (Pierce, Netherlands).…”

Section: Methodsmentioning

confidence: 99%

Comparison between Internalizing Anti-HER2 mAbs and Non-Internalizing Anti-CEA mAbs in Alpha-Radioimmunotherapy of Small Volume Peritoneal Carcinomatosis Using 212Pb

et al. 2013

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Background and PurposeWe assessed the contribution of antibody internalization in the efficacy and toxicity of intraperitoneal α-radioimmunotherapy (RIT) of small volume carcinomatosis using 212Pb-labeled monoclonal antibodies (mAbs) that target HER2 (internalizing) or CEA (non-internalizing) receptors.Materials and MethodsAthymic nude mice bearing 2–3 mm intraperitoneal tumor xenografts were intraperitoneally injected with similar activities (370, 740 and 1480 kBq; 37 MBq/mg) of 212Pb-labeled 35A7 (anti-CEA), trastuzumab (anti-HER2) or PX (non-specific) mAbs, or with equivalent amounts of unlabeled mAbs, or with NaCl. Tumor volume was monitored by bioluminescence and survival was reported. Hematologic toxicity and body weight were assessed. Biodistribution of 212Pb-labeled mAbs and absorbed dose-effect relationships using MIRD formalism were established.ResultsTransient hematological toxicity, as revealed by white blood cells and platelets numbering, was reported in mice treated with the highest activities of 212Pb-labeled mAbs. The median survival (MS) was significantly higher in mice injected with 1.48 MBq of 212Pb-35A7 (non-internalizing mAbs) (MS = 94 days) than in animals treated with the same activity of 212Pb-PX mAbs or with NaCl (MS = 18 days). MS was even not reached after 130 days when follow-up was discontinued in mice treated with 1.48 MBq of 212Pb-trastuzumab. The later efficacy was unexpected since final absorbed dose resulting from injection of 1.48 MBq, was higher for 212Pb-35A7 (35.5 Gy) than for 212Pb-trastuzumab (27.6 Gy). These results also highlight the lack of absorbed dose-effect relationship when mean absorbed dose was calculated using MIRD formalism and the requirement to perform small-scale dosimetry.ConclusionsThese data indicate that it might be an advantage of using internalizing anti-HER2 compared with non-internalizing anti-CEA 212Pb-labeled mAbs in the therapy of small volume xenograft tumors. They support clinical investigations of 212Pb-mAbs RIT as an adjuvant treatment after cytoreductive surgery in patients with peritoneal carcinomatosis.

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Section: Methodsmentioning

confidence: 99%

Comparison between Internalizing Anti-HER2 mAbs and Non-Internalizing Anti-CEA mAbs in Alpha-Radioimmunotherapy of Small Volume Peritoneal Carcinomatosis Using 212Pb

et al. 2013

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“…212 Pb is the longer-lived parental radionuclide of 212 Bi and, as such, it serves as an in vivo generator of 212 Bi. The 212 Pb/ 212 Bi system, therefore, is a promising α-particle emitting source that provides an alternative option for the treatment and management of cancer (8, 11). …”

Section: Introductionmentioning

confidence: 99%

212Pb-Radioimmunotherapy Induces G2 Cell-Cycle Arrest and Delays DNA Damage Repair in Tumor Xenografts in a Model for Disseminated Intraperitoneal Disease

Yong

Milenic

Baidoo

et al. 2012

Molecular Cancer Therapeutics

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In pre-clinical studies, targeted radioimmunotherapy using 212Pb-TCMC-trastuzumab as an in vivo generator of the high energy α-particle emitting radionuclide 212Bi is proving an efficacious modality for the treatment of disseminated peritoneal cancers. To elucidate mechanisms associated with this therapy, mice bearing human colon cancer LS-174T i.p. xenografts were treated with 212Pb-TCMC-trastuzumab and compared to the non-specific control 212Pb-TCMC-HuIgG, unlabeled trastuzumab, and HuIgG, as well as untreated controls. 212Pb-TCMC-trastuzumab treatment induced significantly more apoptosis and DNA double stranded breaks (DSBs) at 24 h. Rad51 protein expression was down-regulated, indicating delayed DNA double strand damage repair compared to 212Pb-TCMC-HuIgG, the non-specific control. 212Pb-TCMC-trastuzumab treatment also caused G2/M arrest, depression of the S phase fraction and depressed DNA synthesis that persisted beyond 120 h. In contrast, the effects produced by 212Pb-TCMC-HuIgG appeared to rebound by 120 h. In addition, 212Pb-TCMC-trastuzumab treatment delayed open chromatin structure and expression of p21 until 72 h, suggesting a correlation between induction of p21 protein and modification in chromatin structure of p21 in response to 212Pb-TCMC-trastuzumab treatment. Taken together, increased DNA DSBs, impaired DNA damage repair, persistent G2/M arrest, and chromatin remodeling were associated with 212Pb-TCMC-trastuzumab treatment and may explain its increased cell killing efficacy in the LS-174T i.p. xenograft model for disseminated intraperitoneal disease.

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“…During 212 Pb decay, g-ray emissions compete with internal conversion over 30% of the time. The ejection of conversion electrons brings 212 Bi to highly ionized states (e.g., Bi 51 and Bi 71 ), destabilizing the bismuth complexes and ultimately liberating the radionuclide (32). Although free 212 Pb accumulates in the blood, liver, bone, and kidneys, 212 Bi accumulates mainly in the kidneys and urine.…”

Section: Atmentioning

confidence: 99%

α-Emitters for Radiotherapy: From Basic Radiochemistry to Clinical Studies—Part 1

et al. 2018

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Learning Objectives: On successful completion of this activity, participants should be able to (1) cite α-emitter families available for therapeutic use and understand their current production limit; (2) consider radiation safety concerns when handling α-emitters; and (3) overcome radiolabeling and daughter redistribution hurdles with the approaches described in this educational review. CME Credit: SNMMI is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing education for physicians. SNMMI designates each JNM continuing education article for a maximum of 2.0 AMA PRA Category 1 Credits. Physicians should claim only credit commensurate with the extent of their participation in the activity. For CE credit, SAM, and other credit types, participants can access this activity through the SNMMI website (http://www.snmmilearningcenter.org) through June 2021.With a short particle range and high linear energy transfer, α-emitting radionuclides demonstrate high cell-killing efficiencies. Even with the existence of numerous radionuclides that decay by α-particle emission, only a few of these can reasonably be exploited for therapeutic purposes. Factors including radioisotope availability and physical characteristics (e.g., half-life) can limit their widespread dissemination. The first part of this review will explore the diversity, basic radiochemistry, restrictions, and hurdles of α-emitters. Radi onuclide strategies for curative therapy, disease control, or palliation are positioned to constitute a major portion of nuclear medicine. The range of available therapeutic radioisotopes, including a, b, or Auger electron emission, has considerably expanded over the last century (1). Matching the particle decay pathway, effective range, and relative biological effectiveness to tumor mass, size, radiosensitivity, and heterogeneity is the primary consideration for maximizing therapeutic efficacy. b-emitting radioisotopes have the longest particle pathlength (#12 mm) and lowest linear energy transfer (LET) (;0.2 keV/mm), supporting their effectiveness in medium to large tumors (Fig. 1). Although the long b-particle range is advantageous in evenly distributing radiation dose in heterogeneous tumors, it can also result in the irradiation of healthy tissue surrounding the tumor site. Conversely, Auger electrons have high LET (4-26 keV/mm) but a limited pathlength of 2-500 nm that restricts their efficacy to single cells, thus requiring the radionuclide to cross the cell membrane and reach the nucleus. Finally, a-particles have a moderate pathlength (50-100 mm) and high LET (80 keV/mm) that render them especially suitable for small neoplasms or micrometastases. A recent clinical study highlighted the ability of a-radiotherapy to overcome treatment resistance to b-particle therapy, prompting a paradigm shift in the approach toward radionuclide therapy (2).For optimized therapeutic efficacy, the a-cytotoxic payload is expected to accumulate selectively in diseased tissue and deliver a suf...

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Towards translation of 212Pb as a clinical therapeutic; getting the lead in!

Cited by 92 publications

References 71 publications

Comparison between Internalizing Anti-HER2 mAbs and Non-Internalizing Anti-CEA mAbs in Alpha-Radioimmunotherapy of Small Volume Peritoneal Carcinomatosis Using 212Pb

Comparison between Internalizing Anti-HER2 mAbs and Non-Internalizing Anti-CEA mAbs in Alpha-Radioimmunotherapy of Small Volume Peritoneal Carcinomatosis Using 212Pb

212Pb-Radioimmunotherapy Induces G2 Cell-Cycle Arrest and Delays DNA Damage Repair in Tumor Xenografts in a Model for Disseminated Intraperitoneal Disease

α-Emitters for Radiotherapy: From Basic Radiochemistry to Clinical Studies—Part 1

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