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Alpha-Emitters and Targeted Alpha Therapy in Oncology: from Basic Science to Clinical Investigations

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Abstract

Alpha-emitters are radionuclides that decay through the emission of high linear energy transfer α-particles and possess favorable pharmacologic profiles for cancer treatment. When coupled with monoclonal antibodies, peptides, small molecules, or nanoparticles, the excellent cytotoxic capability of α-particle emissions has generated a strong interest in exploring targeted α-therapy in the pre-clinical setting and more recently in clinical trials in oncology. Multiple obstacles have been overcome by researchers and clinicians to accelerate the development of targeted α-therapies, especially with the recent improvement in isotope production and purification, but also with the development of innovative strategies for optimized targeting. Numerous studies have demonstrated the in vitro and in vivo efficacy of the targeted α-therapy. Radium-223 (223Ra) dichloride (Xofigo®) is the first α-emitter to have received FDA approval for the treatment of prostate cancer with metastatic bone lesions. There is a significant increase in the number of clinical trials in oncology using several radionuclides such as Actinium-225 (225Ac), Bismuth-213 (213Bi), Lead-212 (212Pb), Astatine (211At) or Radium-223 (223Ra) assessing their safety and preliminary activity. This review will cover their therapeutic application as well as summarize the investigations that provide the foundation for further clinical development.

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Abbreviations

2B–DOTA-NCS:

2-(p-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaceticacid

AIC:

Alpha Immunoconjugate

BNL:

Brookhaven National Laboratory

BLIP:

Brookhaven Linac Isotope Producer

C-DEPA:

1, 7-[2-(bis-carboxymethyl-amino)-ethyl]-4,10-biscarboxymethyl-1,4,7,10-tetraaza-cyclododec-1-yl-acetic acid

CHX-A-DTPA:

cyclohexyl diethylenetriaminepentaacetic acid

DMP:

2,3-Dimercapto-1-propanesulfonic acid

DMSA:

Dimercaptosuccinic acid

DOTA:

1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaceticacid

DOTA-SCN:

4-isothiocyanate-benzyl 1,4,7,10-tetraazacyclododecane-N′, N″, N″’,N″” tetraacetic acid

DOTATOC:

2-[4-[2-[[(2R)-1-[[(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-4-[[(2R,3R)-1,3-dihydroxybutan-2-yl]carbamoyl]-7-[(1R)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicos-19-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]-7,10-bis(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid

DOTMP:

1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonic

DOTPA:

1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrapropionic acid

DTPA:

diethylenetriaminepentaaceticacid

EDTA:

2-({2-[Bis(carboxymethyl)amino]ethyl}(carboxymethyl)amino)acetic acid

FcRn:

Neonatal Fc Receptors

HEHA-NCS:

2-(4-isothiocyanatobenzyl)-1,4,7,10,13, 16-hexaazacyclohexadecane- 1,4,7,10,13,16hexaacetic acid

HPLC:

High Pressure Liquid Chromatography

IAEA:

International Atomic Energy Association

IPF:

Isotope Production Facility

LANL:

Los Alamos National Laboratory

LANSCE:

Los Alamos National Laboratory Neutron Sciences Center

LET:

Linear Energy Transfer

MeO-DOTA-NCS:

a-(5-isothiocyanato-2-methoxyphenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaceticacid

MIA:

Melanoma Inhibitory-Activity

MIRD:

Medical Internal Radiation Dosimetry

NSACI:

Nuclear Science Advisory Committee

ORNL:

Oak Ridge National Laboratories

PEPA:

1,4,7,10,13-pentaazacyclpentadecane-N, N, N, N, N pentaacetic acid

PRRT:

Peptide Receptor Radiation Therapy

RBE:

Relative Biological Effectiveness

RIT:

Radio Immuno Therapy

TAT:

Targeted Alpha Therapy

TCMC:

2-(4-isothiocyanotobenzyl)-1, 4, 7, 10-tetraaza-1, 4, 7, 10-tetra-(2-carbamonyl methyl)-cyclododecane

TETPA:

1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrapropionic acid

TETA:

1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid

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Correspondence to Olivier Rixe or Jeffrey P. Norenberg.

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Olivier Rixe has received honorarium as a member of a scientific committee from Areva Med. All other authors declare no conflict of interest.

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Makvandi, M., Dupis, E., Engle, J.W. et al. Alpha-Emitters and Targeted Alpha Therapy in Oncology: from Basic Science to Clinical Investigations. Targ Oncol 13, 189–203 (2018). https://doi.org/10.1007/s11523-018-0550-9

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