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.

Keywords: DNA damage response; alpha emitter; alpha-particle emitter; anti-androgen therapies; immune checkpoint inhibitors; targeted alpha therapy; targeted thorium conjugates; thorium-227.

FIGURE 1

Timeline of TTC development. ARI, androgen receptor inhibitor; CD, cluster of differentiation; FGFR, fibroblast growth factor receptor; HER2, human epidermal growth factor receptor-2; MSLN, mesothelin; PARP, poly (ADP)-ribose polymerase; PD-L1, programmed death-ligand 1; PDX, patient-derived xenograft; PSMA, prostate-specific membrane antigen; TTC, targeted thorium conjugate; AML, acute myeloid leukemia; ATR, ataxia telangiectasia and rad3-related protein; mCRPC, metastatic castration-resistant prostate cancer; ORR, overall response rate; TNBC, triple-negative breast cancer; TEAE, treatment-emergent adverse event.