Comparing High LET &lt;sup&gt;227&lt;/sup&gt;Th- and Low LET &lt;sup&gt;177&lt;/sup&gt;Lu-trastuzumab in Mice with HER-2 Positive SKBR-3 Xenografts

Abbas, Nasir; Heyerdahl, Helèn; Bruland, Øyvind S.; Brevik, Ellen Mengshoel; Dahle, Jostein

doi:10.2174/18744710113069990017

Cited by 15 publications

(8 citation statements)

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“…Intrinsic and acquired resistance to HER2-targeting antibodies or antibody drug conjugates (ADC) necessitates development of novel therapies ( 31 , 32 ). A HER2-TTC, utilizing the HER2 antibody trastuzumab ( 227 Th-trastuzumab), showed significant dose-dependent anti-tumor effects in HER2-expressing breast cancer xenografts ( 33 , 34 ). Moreover, when 227 Th-trastuzumab was compared with lutetium-177 ( 177 Lu; a β-particle emitter) complexed with trastuzumab, in a similar xenograft study, each radionuclide conjugate had significant anti-tumor effects and increased survival, although efficacy was higher with 227 Th-trastuzumab than with 177 Lu-trastuzumab.…”

Section: Ttcs In Cancermentioning

confidence: 99%

Targeted thorium-227 conjugates as treatment options in oncology

et al. 2023

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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.

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Section: Ttcs In Cancermentioning

confidence: 99%

Targeted thorium-227 conjugates as treatment options in oncology

et al. 2023

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“…Association with trastuzumab (Herceptin ® ) for the targeting of human epidermal growth factor receptor-2 (HER2/neu), a tyrosine kinase receptor that is overexpressed in more malignant forms of metastatic breast or ovarian cancers, represents another consequent part of 227 Th investigations. Other reports include 227 Th- p -benzyl-DOTA-trastuzumab (or 227 Th-trastuzumab) on HER2-expressing cell lines from breast and ovarian cancer models [ 296 , 297 , 298 ].…”

Section: Thorium-227mentioning

confidence: 99%

Overview of the Most Promising Radionuclides for Targeted Alpha Therapy: The “Hopeful Eight”

et al. 2021

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Among all existing radionuclides, only a few are of interest for therapeutic applications and more specifically for targeted alpha therapy (TAT). From this selection, actinium-225, astatine-211, bismuth-212, bismuth-213, lead-212, radium-223, terbium-149 and thorium-227 are considered as the most suitable. Despite common general features, they all have their own physical characteristics that make them singular and so promising for TAT. These radionuclides were largely studied over the last two decades, leading to a better knowledge of their production process and chemical behavior, allowing for an increasing number of biological evaluations. The aim of this review is to summarize the main properties of these eight chosen radionuclides. An overview from their availability to the resulting clinical studies, by way of chemical design and preclinical studies is discussed.

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“…In an SKBR-3 breast cancer xenograft model, growth delay resulting from 227 Th versus 177 Lu-conjugated antibody was evaluated (Abbas et al, 2013). Using the percent Source.…”

Section: Rbe Of Alpha-particle Emittersmentioning

confidence: 99%

“…In an SKBR-3 breast cancer xenograft model, growth delay resulting from 227 Th versus 177 Lu-conjugated antibody was evaluated (Abbas et al , 2013). Using the percent increase in the number of days to reach a defined tumor volume as the biological endpoint, the RBE was 2.8 or 2.2 for a 100% and a 50% increase in the number of days for the tumor to reach 500 mm 3 .…”

Section: Radiobiology and Bioeffect Modelingmentioning

confidence: 99%

ICRU REPORT 96, Dosimetry-Guided Radiopharmaceutical Therapy

et al. 2021

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The Commission wishes to express its appreciation to the individuals involved in the preparation of this Report for the time and efforts that they devoted to this task and to express its appreciation to the organizations with which they are affiliated.All rights reserved. No part of this book may be reproduced, stored in retrieval systems or transmitted in any form by any means, electronic, electrostatic, magnetic, mechanical photocopying, recording or otherwise, without the permission in writing from the publishers.

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Comparing High LET <sup>227</sup>Th- and Low LET <sup>177</sup>Lu-trastuzumab in Mice with HER-2 Positive SKBR-3 Xenografts

Abstract: In this xenograft model the RBE was higher for 227Th-trastuzumab than for 177Lu-trastuzumab, while the therapeutic index of 177Lu-trastuzumab was superior to that of 227Th-trastuzumab.

Cited by 15 publications

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Targeted thorium-227 conjugates as treatment options in oncology

Targeted thorium-227 conjugates as treatment options in oncology

Overview of the Most Promising Radionuclides for Targeted Alpha Therapy: The “Hopeful Eight”

ICRU REPORT 96, Dosimetry-Guided Radiopharmaceutical Therapy

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