Application of ²¹²Pb for Targeted α-particle Therapy (TAT): Pre-clinical and Mechanistic Understanding through to Clinical Translation

Abstract

Targeted α-particle therapy (TAT), in which an α-particle emitting radionuclide is specifically directed to a biological target, is gaining more attention to treat cancers as new targets are validated. Bio-vectors such as monoclonal antibodies are able to selectively transport α-particles to destroy targeted cancer cells. TAT has the potential for an improved therapeutic ratio over β-particle targeted conjugate therapy. The short path length and the intense ionization path generated render α-emitters suitable for treatment and management of minimal disease such as micrometastases or residual tumor after surgical debulking. 212Pb is the longer-lived parent radionuclide of 212Bi and serves as an in vivo generator of 212Bi. 212Pb has demonstrated significant utility in both in vitro and in vivo models. Recent evaluation of 212Pb-TCMC-trastuzumab in a Phase I clinical trial has demonstrated the feasibility of 212Pb in TAT for the treatment of ovarian cancer patients. This review highlights progress in radionuclide production, radiolabeling chemistry, molecular mechanisms, and application of 212Pb to targeted pre-clinical and clinical radiation therapy for the management and treatment of cancer.

Preparation of the alpha‐emitting prostate‐specific membrane antigen targeted radioligand [212Pb]Pb‐NG001 for prostate cancer

“…Lead‐212 is a beta emitter that generates alpha particle radiation via its short‐lived progenies 212 Bi ( t 1/2 ≈60.6 minutes) and 212 Po ( t 1/2 ≈0.3 microseconds). DOTA‐conjugated monoclonal antibodies (mAb) form stable complexes with 212 Pb . However, one third of 212 Bi could be lost from the DOTA complex during 212 Pb decay .…”

“…Furthermore, acid‐catalysed dissociation of 212 Pb from DOTA conjugates after internalization has been reported as a source of bone marrow toxicity, as released 212 Pb is transported to the bone where it subsequently decays to 212 Bi . Replacement of the carboxylic acid donor arms of DOTA with amide arms has yielded the chelator S‐2‐(4‐Isothiocyanatobenzyl)‐1,4,7,10‐tetraaza‐1,4,7,10‐tetra(2‐carbamoylmethyl)cyclododecane (TCMC), which to date is the best available chelator for 212 Pb . The complex of lead cation and TCMC is less labile to metal ion release under lower pH conditions, conferring enhanced resistance to acid‐catalysed dissociation within the cell .…”

“…DOTA-conjugated monoclonal antibodies (mAb) form stable complexes with 212 Pb. [17][18][19] However, one third of 212 Bi could be lost from the DOTA complex during 212 Pb decay. 20,21 Furthermore, acid-catalysed dissociation of 212 Pb from DOTA conjugates after internalization has been reported as a source of bone marrow toxicity, as released 212 Pb is transported to the bone where it subsequently decays to 212 Bi.…”

B7-H3-targeted 212Pb radioimmunotherapy of ovarian cancer in preclinical models

“…Replacement of β-particle emitters with α-particle emitting radionuclides for targeted RIT offers greater potential for effective cell death because of the short path length (50-80 μm), high LET (100 keV/μm), and high relative biological effectiveness of α-particles [14-16]. α-particles are widely accepted to cause cell death regardless of the cell’s oxygen levels or sensitivity to chemotherapy or alternative radiotherapy regimens (external beam or β-particle RIT) [14, 17]. The efficacy of targeted RIT using the monoclonal antibody (mAb) trastuzumab conjugated with 212 Pb (t 1/2 = 10.64 h), which decays to the α-particle emitter 212 Bi (t 1/2 = 60.5 min), has been demonstrated in preclinical models of HER2 + human cancer [17].…”

“…α-particles are widely accepted to cause cell death regardless of the cell’s oxygen levels or sensitivity to chemotherapy or alternative radiotherapy regimens (external beam or β-particle RIT) [14, 17]. The efficacy of targeted RIT using the monoclonal antibody (mAb) trastuzumab conjugated with 212 Pb (t 1/2 = 10.64 h), which decays to the α-particle emitter 212 Bi (t 1/2 = 60.5 min), has been demonstrated in preclinical models of HER2 + human cancer [17]. The success of these studies and lack of toxicity in non-human primates [18] led to a phase I clinical trial with 212 Pb-trastuzumab in patients with HER2 + malignancies (ovarian and colon cancer) mainly confined to the peritoneal cavity [19, 20].…”