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Novel Radiopharmaceuticals for Therapy

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Nuclear Oncology

Abstract

In the era of personalized medicine, “targeted radionuclide therapy” (TRT) is designed to damage only the cancerous cells while sparing unnecessary damage to the adjacent healthy cells/tissues. Unlike conventional external beam radiation therapy, TRT is intended to cause less or no collateral damage to normal tissues, as it aims at achieving targeted drug delivery either to a clinically diagnosed cancer not amenable to surgery or to metastatic tumor cells and tumor cell clusters, thus providing systemic therapy of cancer. Currently there are hundreds of new pathway-targeted anticancer agents undergoing phase II and phase III clinical trials. TRT is just one type within the domain of “targeted therapies.” In addition to the effective targeted radiopharmaceuticals already well validated for routine clinical use, newer radiolabeled agents are still in the phase of either preclinical or clinical validation.

This chapter describes the main physical and radiochemical characteristics of radionuclides that have potential or have already been employed to label biologically reactive molecules for the development of novel radiopharmaceuticals for therapy. Some of these agents have entered advanced clinical trials in tumor-bearing patients. Results of these clinical trials cover a wide spectrum of potential clinical usefulness.

The chapter is divided into two main parts depending on the type of particle emission (α or β− associated or not with the emission of either γ-rays or β+ particles). Within each domain, there is some exchange of experience and shift of focus in the various phases of development, depending on the modalities of ascertaining efficient tumor targeting according to the principles of theranostics. Theranostics is often performed utilizing the same molecule labeled with two different radionuclides, one radionuclide for imaging and another for therapy, in order to achieve a personalized treatment approach to the patient. Nowadays, the fields of interest include the well-established use of radioactive iodine in differentiated thyroid cancer, radiolabeled metaiodobenzylguanidine (MIBG) in neuroblastoma, and the clinical impact of peptide receptor radionuclide therapy (PRRT) in the management of neuroendocrine tumors. Furthermore, the more cutting-edge and recently introduced theranostic approaches will be reviewed, such as the radioligand therapy with 177Lu-PSMA-ligand and targeted alpha therapy in castration-resistant prostate cancer.

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Abbreviations

ALP:

Alkaline phosphatase

AUNP:

Gold nanoparticle

BBN:

Bombesin

BsMAb:

Bispecific monoclonal antibody

CAIX:

Carbonic anhydrase isoenzyme 9

ccRCC:

Clear-cell renal carcinoma

CEA:

Carcinoembryonic antigen

CI:

Confidence interval

DOTA:

2-(4-isothiocyanatobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (macrocyclic coupling agent to label compounds of biological interest with metal radionuclides)

EBRT:

External beam radiation therapy

ECM:

Extracellular matrix

EDTMP:

Ethylenediamine tetra(methylene phosphonic acid)

EMA:

European Medicines Agency

FDA:

Food and Drug Administration of the United States of America

FN:

Fibronectin

GA:

Arabic glycoprotein

HA:

Hydroxyapatite

HAMA:

Human anti-mouse antibody

HER2:

Human epidermal growth factor receptor 2, also known as receptor tyrosine-protein kinase erbB-2, or HER2/neu

HSG:

Histamine-succinyl-glutamine hapten

L-19 SIP:

Small immunoreactive protein, (scFv) 2, derived from monoclonal antibody L19

L-19:

Monoclonal antibody recognizing the EDB domain of fibronectin

MAA:

Macroaggregated albumin

mAb:

Monoclonal antibody

mCRPC:

Metastatic castrate-resistant prostate cancer

MIBG:

Metaiodobenzylguanidine

MTA-1:

Metastasis-associated protein encoded by the MTA1 gene

MTC:

Medullary thyroid cancer

MTD:

Maximum tolerated dose

MTRD:

Maximum tolerated radiation dose

MX35:

A monoclonal antibody recognizing the sodium-dependent phosphate transport protein 2b

NaPi2b:

Sodium-dependent phosphate transport protein 2b

NCA:

No-carrier-added

NHL:

Non-Hodgkin’s lymphoma

PAI2-uPAR:

Proteases, members of the urokinase-type plasminogen activator family

PCa:

Prostatic carcinoma

PET:

Positron emission tomography

PRRT:

Peptide receptor radionuclide therapy

PSA:

Prostate-specific antigen

PSMA:

Prostate-specific membrane antigen

RE:

Radioembolization

RIT:

Radioimmunotherapy

[211At]SAPC:

N-succinimidyl 5-[211At]astato-3-pyridinecarboxylate

SCID:

Severe combined immunodeficiency

SPECT:

Single-photon emission computed tomography

SRE:

Skeletal-related event

TAT:

Targeted alpha therapy

TCMC:

2-(4-isothiocyanatobenzyl-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamonylmetyl)-cyclododecane (macrocyclic coupling agent to label compounds of biological interest with metal radionuclides)

Theranostic:

An agent with both diagnostic and therapeutic capabilities (e.g., 131I-iodide, in low activity it is a diagnostic agent; in high activity it is a therapeutic agent)

TROP-2:

Cell-surface glycoprotein overexpressed in adenocarcinomas, correlated with tumor aggressiveness

TRT:

Targeted radionuclide therapy

VGEF:

Vascular endothelial growth factor

WHO:

World Health Organization

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Authors and Affiliations

  1. Regional Center of Nuclear Medicine, Department of Translational Research and Advanced Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy

    Federica Guidoccio

  2. Nuclear Medicine Service, Town Hospital of Leghorn, Leghorn, Italy

    Sara Mazzarri

  3. Nuclear Medicine Unit, “Maggiore della Carità” University Hospital, Novara, Italy

    Federica Orsini

  4. Nuclear Medicine Unit, Department of Translational Research and Advanced Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy

    Paola A. Erba & Giuliano Mariani

  5. Department of Translational Research and Advanced Technologies in Medicine, Regional Center of Nuclear Medicine, University of Pisa, Pisa, Italy

    Tommaso Depalo

  6. Nuclear Medicine Unit, Department of Medical Sciences, University Hospital of Siena, Siena, Italy

    Federica Orsini

Authors
  1. Federica Guidoccio
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  2. Sara Mazzarri
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  3. Tommaso Depalo
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  4. Federica Orsini
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  5. Paola A. Erba
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  6. Giuliano Mariani
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Correspondence to Federica Guidoccio .

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Editors and Affiliations

  1. Nuclear Medicine Unit Department of Translational Research and Advanced Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy

    Duccio Volterrani

  2. Nuclear Medicine Unit Department of Translational Research and Advanced Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy

    Paola A. Erba

  3. Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    H. William Strauss

  4. Nuclear Medicine Unit Department of Translational Research and Advanced Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy

    Giuliano Mariani

  5. Molecular Imaging and Targeted Therapy Service Department of Radiology, Sloan Kettering Institute, New York, NY, USA

    Steven M. Larson

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Guidoccio, F., Mazzarri, S., Depalo, T., Orsini, F., Erba, P.A., Mariani, G. (2022). Novel Radiopharmaceuticals for Therapy. In: Volterrani, D., Erba, P.A., Strauss, H.W., Mariani, G., Larson, S.M. (eds) Nuclear Oncology. Springer, Cham. https://doi.org/10.1007/978-3-031-05494-5_36

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