Clinical Pharmacology of Radiotheranostics in Oncology

Abstract

The combined use of diagnostic and therapeutic radioligands with the same molecular target, also known as theranostics, enables accurate patient selection, targeted therapy, and prediction of treatment response. Radioiodine, bone‐seeking radioligands and norepinephrine analogs have been used for many years for diagnostic imaging and radioligand therapy of thyroid carcinoma, bone metastases, pheochromocytoma, paraganglioma, and neuroblastoma, respectively. In recent years, radiolabeled somatostatin analogs and prostate‐specific membrane antigen ligands have shown clinical efficacy in the treatment of neuroendocrine tumors and prostate cancer, respectively. Several candidate compounds are targeting novel theranostic targets such as fibroblast activation protein, C‐X‐C chemokine receptor 4, and gastrin‐releasing peptide receptor. In addition, several strategies to improve efficacy of radioligand therapy are being evaluated, including dosimetry‐based dose optimization, multireceptor targeting, upregulation of target receptors, radiosensitization, pharmacogenomics, and radiation genomics. Design and evaluation of novel radioligands and optimization of dose and dose schedules, within the complex context of individualized multimodal cancer treatment, requires a multidisciplinary approach that includes clinical pharmacology. Significant increases in the use of these radiopharmaceuticals in routine oncological practice can be expected, which will have major impact on patient care as well as (radio)pharmacy utilization.

Radiolysis-Associated Decrease in Radiochemical Purity of 177Lu-Radiopharmaceuticals and Comparison of the Effectiveness of Selected Quenchers against This Process

“…The use of radiopharmaceuticals for targeted radionuclide therapy (RNT), the effectiveness of which has been established during clinical trials, is currently recognized as a safe, economically, and logistically competitive method for the treatment of primary cancer, as well as distant metastases [ 1 , 2 , 3 ]. Currently, the segment of therapeutic radiopharmaceuticals comprises approximately one-third of the total number of radiopharmaceuticals in the global pharmacy market.…”

Site-specific Conjugation of 6 DOTA Chelators to a CA19-9-targeting scFv-Fc Antibody for Imaging and Therapy

“…Antibody-radionuclide conjugates (ARCs), also called radiolabeled antibodies or radioimmunoconjugates, can serve as therapeutic and diagnostic (i.e., theranostic) agents. , ARCs leverage an antibody’s selective targeting of tumor-specific antigens to deliver diagnostic or therapeutic radioactive isotopes/nuclides to selectively image or kill tumor cells . The radionuclides are bound to the antibody via metal chelators such as DTPA (diethylenetriamine pentaacetate) or DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). , The protein-chelator conjugation and subsequent radiolabeling conditions must be mild enough to preserve the antibody’s structural integrity, and the antibody–chelator linkage must be stable in vivo and should maintain the native antibody’s antigen-binding affinity/immunoreactivity .…”

“…Therapeutic ARCs are labeled with α-emitting radionuclides (e.g., 213 Bi and 225 Ac) with a radiation radius of 0.05–0.10 mm comparable to a few multiples of a typical tumor cell size (0.010–0.025 mm) or β – -emitters (e.g., 90 Y, 131 I, and 177 Lu) with a longer tissue penetration range (0.5–12 mm). , They deliver cytotoxic radiation that causes DNA damage to tumor cells while sparing surrounding healthy tissues . Diagnostic ARCs are labeled with γ-emitters (e.g., 99m Tc, 111 In, and 123 I) or positron-emitters (e.g., 18 F, 64 Cu, 68 Ga, 89 Zr, and 124 I) that are seen using gamma cameras, single-photon emission computed tomography (SPECT), or positron emission tomography. , The in vivo visualization of where the diagnostic radionuclides settle probes antigen expression and radioactivity uptake in target and non-target tissues, enabling the detection of primary tumors and metastatic sites as well as estimates of the absorbed radiation dose in various tissues. , This information helps to select those patients who might benefit from treatment and an optimal therapeutic ARC dose, thus tailoring treatment for a patient. Diagnostic ARCs are also helpful in post-treatment follow-up to assess the effects of therapy.…”

Pre-clinical Evaluation of Biomarkers for Early Detection of Nephrotoxicity Following Alpha-particle Radioligand Therapy

“…, [ 177 Lu]Lu-PSMA-617) for metastatic castrate-resistant prostate cancer (mCRPC) targeting somatostatin receptor type 2 (SSTR2) and prostate-specific membrane antigen (PSMA), respectively. RLTs are also effective in other SSTR- expressing tumors, such as paraganglioma and pheochromocytoma, thyroid carcinoma, and meningioma[1]. Use of other ligands for overexpressed receptor targets has been demonstrated in breast, colon, myeloma, and ovarian cancer[1], melanoma[2], and hematological malignancies[3].…”

“…Examples of FDA-approved radiopharmaceuticals that are significantly improving outcomes for cancer patients include beta (β)-particle emitting RLTs LUTATHERA ® (i.e., [ 177 Lu]Lu-DOTATATE) for advanced neuroendocrine tumors (NETs) and PLUVICTO ® (i.e., [ 177 Lu]Lu-PSMA-617) for metastatic castrate-resistant prostate cancer (mCRPC) targeting somatostatin receptor type 2 (SSTR2) and prostate-specific membrane antigen (PSMA), respectively. RLTs are also effective in other SSTRexpressing tumors, such as paraganglioma and pheochromocytoma, thyroid carcinoma, and meningioma [1]. Use of other ligands for overexpressed receptor targets has been demonstrated in breast, colon, myeloma, and ovarian cancer [1], melanoma [2], and hematological malignancies [3].…”