Targeted thorium-227 conjugates as treatment options in oncology

Abstract

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.

Alpha-Emitting Radionuclides: Current Status and Future Perspectives

“…Another possibility is also to focus on the development, evaluation, and application of another alpha in vivo nanogenerator, thorium-227 ( 227 Th, τ½ = 18.9 d) [ 12 ]. There is, however, one significant difference between 227 Th and 225 Ac, which is that they have concretely different equilibria.…”

“…The DOTA chelator [ 25 ] has been widely used for the alpha-emitting radionuclides actinium-225, bismuth-213, and terbium-149, frequently for thorium-227, and some trials were made for radium-223 [ 12 , 26 , 27 , 28 ]. Elevated temperatures of up to 90–100 °C and a labeling time of 15–30 min were typically required for labeling, making this chelator unfavorable for sensitive biomacromolecules like proteins or antibodies.…”

Optimizing the Safety and Efficacy of Bio-Radiopharmaceuticals for Cancer Therapy

“…227 Th is another attractive alpha-emitting radionuclide that has been used for TRT. It has been conjugated to mAbs targeting PSMA, HER2, mesothelin, and CD22 by means of a bifunctional chelator such as octadentate 3,2-hydroxypyridinone (3,2-HOPO) and was shown to have therapeutic efficacy in various pre-clinical tumor models [ 101 ]. Pre-clinical successes have led to several clinical trials (NCT03724747, NCT02581878, and NCT04147819).…”

Efficacy of a HER2-Targeted Thorium-227 Conjugate in a HER2-Positive Breast Cancer Bone Metastasis Model

“…In preclinical in vitro and in vivo experiments, radium-223 has been shown to directly inhibit the proliferation of cancer cells in both osteolytic breast cancer and osteoblastic prostate cancer bone metastases and to inhibit the differentiation of osteoblasts and osteoclasts due to both its physical bone-homing properties and its active incorporation by osteoblasts [ 15 ]. The lack of suitable chelating agents for radium-223 has limited its use for TATs, whereas thorium-227 (half-life of 18.7 days), the parent radionuclide of radium-223 ( Figure 1 A), offers promise as a wider-ranging alternative due to the availability of efficient chelators, such as 3,2-hydroxypyridinone (3,2-HOPO) [ 10 , 18 , 19 ]. The 3,2-HOPO chelator can be conjugated to a range of targeting moieties, such as antibodies, delivering the radiation dose specifically to cancer cells, and thereby minimizing exposure of the normal tissue [ 20 , 21 ].…”

“…The 3,2-HOPO chelator can be conjugated to a range of targeting moieties, such as antibodies, delivering the radiation dose specifically to cancer cells, and thereby minimizing exposure of the normal tissue [ 20 , 21 ]. We have previously described the properties of several targeted thorium-227 conjugates (TTCs) binding to a variety of tumor antigens in various cancers [ 2 , 10 , 11 , 19 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ].…”