212Pb: Production Approaches and Targeted Therapy Applications

Kokov, Konstantin; Egorova, Bayirta V.; German, M. N.; Klabukov, Ilya; Крашенинников, М. Е.; Larkin-Kondrov, Antonius A.; Makoveeva, K. A.; Овчинников, М. В.; Sidorova, M. V.; Chuvilin, D. Yu.

doi:10.3390/pharmaceutics14010189

Cited by 35 publications

(41 citation statements)

References 116 publications

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“…Thus, 212 Pb radio-ligand therapy may be a promising approach not only for small molecule ligands (8) but also large molecules such as a full-length monoclonal antibody including an IgG molecule. With the recently improved production of 224 Ra-212 Pb and 203 Pb as the imaging theranostic pair, the pace of 212 Pb-based radio-ligand therapy development is expected to accelerate (30)(31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

CD46 targeted²¹²Pb alpha particle radioimmunotherapy for prostate cancer treatment

Huang

Hua

et al. 2022

Preprint

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We recently identified CD46 as a novel prostate cancer cell surface antigen that shows lineage independent expression in both adenocarcinoma and small cell neuroendocrine subtypes of metastatic castration resistant prostate cancer (mCRPC), discovered an internalizing human monoclonal antibody YS5 that binds to a tumor selective CD46 epitope, and developed a microtubule inhibitor-based antibody drug conjugate that is in a multi-center phase I trial for mCRPC (NCT03575819). Here we report the development of a novel CD46-targeted alpha therapy based on YS5. We conjugated 212Pb, an in vivo generator of alpha-emitting 212Bi and 212Po, to YS5 through the chelator TCMC to create the radioimmunoconjugate, 212Pb-TCMC-YS5. We characterized 212Pb-TCMC-YS5 in vitro and established a safe dose in vivo. We next studied therapeutic efficacy of a single dose of 212Pb-TCMC-YS5 using three prostate cancer small animal models: a subcutaneous mCRPC cell line-derived xenograft (CDX) model (subcu-CDX), an orthotopically grafted mCRPC CDX model (ortho-CDX), and a prostate cancer patient-derived xenograft model (PDX). In all three models, a single dose of 20 microcurie 212Pb-TCMC-YS5 was well tolerated and caused potent and sustained inhibition of established tumors, with significant increases of survival in treated animals. A lower dose (10 microcurie 212Pb-TCMC-YS5) was also studied on the PDX model, which also showed a significant effect on tumor growth inhibition and prolongation of animal survival. These results demonstrate that 212Pb-TCMC-YS5 has an excellent therapeutic window in preclinical models including PDXs, opening a direct path for clinical translation of this novel CD46-targeted alpha emitter radioimmunotherapy for mCRPC treatment.

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Section: Discussionmentioning

confidence: 99%

CD46 targeted²¹²Pb alpha particle radioimmunotherapy for prostate cancer treatment

Huang

Hua

et al. 2022

Preprint

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“…Lead-212 is suitable for radiolabeling of mAbs, peptides, or other targeting vectors conjugated with appropriate bifunctional chelators. Conjugates of 212 Pb/ 212 Bi have already been tested in clinical trials for cancer treatment (51)(52)(53). Moreover, these daughter nuclides can be conjugated to chelated targeting agents in the radiopharmaceutical solution of 224 Ra in equilibrium with progeny (Figure 2), such as EDTMP for retention of progeny in bone, or a cancer-specific ligand/mAb with a bifunctional chelator TCMC (S-2-(4-isothiocyanatobenzyl)-1,4,7,10tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane) for cancer cell targeting (41,54,55).…”

Section: Pb In One Solutionmentioning

confidence: 99%

Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach

Juzeniene

Stenberg²,

Bruland³

et al. 2023

Front. Med.

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Metastases are the primary cause of death among cancer patients and efficacious new treatments are sorely needed. Targeted alpha-emitting radiopharmaceuticals that are highly cytotoxic may fulfill this critical need. The focus of this paper is to describe and explore a novel technology that may improve the therapeutic effect of targeted alpha therapy by combining two radionuclides from the same decay chain in the same solution. We hypothesize that the dual targeting solution containing bone-seeking 224Ra and cell-directed complexes of progeny 212Pb is a promising approach to treat metastatic cancers with bone and soft tissue lesions as well as skeletal metastases of mixed lytic/osteoblastic nature. A novel liquid 224Ra/212Pb-generator for rapid preparation of a dual targeting solution is described. Cancer cell targeting monoclonal antibodies, their fragments, synthetic proteins or peptides can all be radiolabeled with 212Pb in the 224Ra-solution in transient equilibrium with daughter nuclides. Thus, 224Ra targets stromal elements in sclerotic bone metastases and 212Pb-chelated-conjugate targets tumor cells of metastatic prostate cancer or osteosarcoma. The dual targeting solution may also be explored to treat metastatic breast cancer or multiple myeloma after manipulation of bone metastases to a more osteoblastic phenotype by the use of bisphosphonates, denosumab, bortezomib or hormone therapy prior to treatment. This may improve targeting of bone-seeking 224Ra and render an augmented radiation dose deposited within metastases. Our preliminary preclinical studies provide conceptual evidence that the dual 224Ra-solution with bone or tumor-targeted delivery of 212Pb has potential to inhibit cancer metastases without significant toxicity. In some settings, the use of a booster dose of purified 212Pb-conjugate alone could be required to elevate the effect of this tumor cell directed component, if needed, e.g., in a fractionated treatment regimen, where the dual targeting solution will act as maintenance treatment.

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“…Over the last 20 years, several α-particle-emitting radionuclides have been investigated as TATs, including: actinium-225 ( 225 Ac, half-life 9.9 days); astatine-211 ( 211 At, half-life 7.2 h); bismuth-213 ( 213 Bi, half-life 45.6 min); radium-223 ( 223 Ra, half-life 11.4 days); and thorium-227 ( 227 Th, half-life 18.7 days) ( 1 ). Lead-212 ( 212 Pb, half-life 10.64 h) is a β-emitter; however, it generates the daughter nuclides bismuth-212 ( 212 Bi) and polonium-212 ( 212 Po), which are short-lived α-particle emitters ( 10 ). 223 Ra dichloride was the first and is still the only approved TAT ( 11 , 12 ), and is approved for use in metastatic castration-resistant prostate cancer (mCRPC) with bone metastases ( 13 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

Targeted thorium-227 conjugates as treatment options in oncology

et al. 2023

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Targeted alpha therapy (TAT) is a promising approach for addressing unmet needs in oncology. Inherent properties make α-emitting radionuclides well suited to cancer therapy, including high linear energy transfer (LET), penetration range of 2–10 cell layers, induction of complex double-stranded DNA breaks, and immune-stimulatory effects. Several alpha radionuclides, including radium-223 (223Ra), actinium-225 (225Ac), and thorium-227 (227Th), have been investigated. Conjugation of tumor targeting modalities, such as antibodies and small molecules, with a chelator moiety and subsequent radiolabeling with α-emitters enables specific delivery of cytotoxic payloads to different tumor types. 223Ra dichloride, approved for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) with bone-metastatic disease and no visceral metastasis, is the only approved and commercialized alpha therapy. However, 223Ra dichloride cannot currently be complexed to targeting moieties. In contrast to 223Ra, 227Th may be readily chelated, which allows radiolabeling of tumor targeting moieties to produce targeted thorium conjugates (TTCs), facilitating delivery to a broad range of tumors. TTCs have shown promise in pre-clinical studies across a range of tumor-cell expressing antigens. A clinical study in hematological malignancy targeting CD22 has demonstrated early signs of activity. Furthermore, pre-clinical studies show additive or synergistic effects when TTCs are combined with established anti-cancer therapies, for example androgen receptor inhibitors (ARI), DNA damage response inhibitors such as poly (ADP)-ribose polymerase inhibitors or ataxia telangiectasia and Rad3-related kinase inhibitors, as well as immune checkpoint inhibitors.

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212Pb: Production Approaches and Targeted Therapy Applications

Cited by 35 publications

References 116 publications

CD46 targeted²¹²Pb alpha particle radioimmunotherapy for prostate cancer treatment

CD46 targeted²¹²Pb alpha particle radioimmunotherapy for prostate cancer treatment

Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach

Targeted thorium-227 conjugates as treatment options in oncology

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212Pb: Production Approaches and Targeted Therapy Applications

Cited by 35 publications

References 116 publications

CD46 targeted212Pb alpha particle radioimmunotherapy for prostate cancer treatment

CD46 targeted212Pb alpha particle radioimmunotherapy for prostate cancer treatment

Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach

Targeted thorium-227 conjugates as treatment options in oncology

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CD46 targeted²¹²Pb alpha particle radioimmunotherapy for prostate cancer treatment

CD46 targeted²¹²Pb alpha particle radioimmunotherapy for prostate cancer treatment