Preclinical evaluation of 227Th-labeled and 177Lu-labeled trastuzumab in mice with HER-2-positive ovarian cancer xenografts

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

doi:10.1097/mnm.0b013e328354df7c

Cited by 27 publications

(23 citation statements)

References 25 publications

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“…Although herein we do not conduct a comparison with conventional anti-HER2 177 Lu-RIT with an IgG radiolabeled with 177 Lu, it was previously reported by Rasaneh et al 29 with 8- to 10-week-old inbred female BALB/c mice that the calculated mean absorbed doses to tumor and blood during treatment with 7.4 MBq were 6.35 ± 1.2 Gy MBq -1 and 1.62 ± 0.13 Gy MBq -1 , leading to a mean TI for blood of 3.9. During a comparative study of 227 Th-labeled and 177 Lu-labeled trastuzumab in mice bearing HER2(+) SKOV-3 ovarian cancer xenografts, absorbed radiation doses from β-particles emitted from 177 Lu in the tumor and blood were 3.82 ± 0.64 Gy and 1.57 ± 0.64 Gy for 72 MBq/kg 177 Lu-trastuzumab injection, giving an approximate mean TI of 2.4 for blood 30 . In addition, although dosimetry was not described, Ray et al reported that i.p.…”

Section: Discussionmentioning

confidence: 99%

Theranostic pretargeted radioimmunotherapy of internalizing solid tumor antigens in human tumor xenografts in mice: Curative treatment of HER2-positive breast carcinoma

Cheal¹,

Xu²,

Guo³

et al. 2018

Theranostics

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In recent reports, we have shown that optimized pretargeted radioimmunotherapy (PRIT) based on molecularly engineered antibody conjugates and 177Lu-DOTA chelate (DOTA-PRIT) can be used to cure mice bearing human solid tumor xenografts using antitumor antibodies to minimally internalizing membrane antigens, GPA33 (colon) and GD2 (neuroblastoma). However, many solid tumor membrane antigens are internalized after antibody binding and it is generally believed that internalizing tumor membrane antigens are not suitable targets for PRIT. In this study, we tested the hypothesis that DOTA-PRIT can be performed successfully to target HER2, an internalizing membrane antigen widely expressed in breast, ovarian, and gastroesophageal junction cancers.Methods: DOTA-PRIT was carried out in athymic nude mice bearing BT-474 xenografts, a HER2-expressing human breast cancer, using a three-step dosing regimen consisting of sequential intravenous administrations of: 1) a bispecific IgG-scFv (210 kD) format (BsAb) carrying the IgG sequence of the anti-HER2 antibody trastuzumab and the scFv “C825” with high-affinity, hapten-binding antibody for Bn-DOTA (metal) (BsAb: anti-HER2-C825), 2) a 500 kD dextran-based clearing agent, followed by 3) 177Lu-DOTA-Bn. At the time of treatment, athymic nude mice bearing established subcutaneous BT-474 tumors (medium- and smaller-sized tumors with tumor volumes of 209 ± 101 mm3 and ranging from palpable to 30 mm3, respectively), were studied along with controls. We studied single- and multi-dose regimens. For groups receiving fractionated treatment, we verified quantitative tumor targeting during each treatment cycle using non-invasive imaging with single-photon emission computed tomography/computed tomography (SPECT/CT).Results: We achieved high therapeutic indices (TI, the ratio of radiation-absorbed dose in tumor to radiation-absorbed dose to critical organs, such as bone marrow) for targeting in blood (TI = 28) and kidney (TI = 7), while delivering average radiation-absorbed doses of 39.9 cGy/MBq to tumor. Based on dosimetry estimates, we implemented a curative fractionated therapeutic regimen for medium-sized tumors that would deliver approximately 70 Gy to tumors, which required treatment with a total of 167 MBq 177Lu-DOTA-Bn/mouse (estimated absorbed tumor dose: 66 Gy). This regimen was well tolerated and achieved 100% complete responses (CRs; defined herein as tumor volume equal to or smaller than 4.2 mm3), including 62.5% histologic cure (5/8) and 37.5% microscopic residual disease (3/8) at 85 days (d). Treatment controls showed tumor progression to 207 ± 201% of pre-treatment volume at 85 d and no CRs. Finally, we show that treatment with this curative 177Lu regimen leads to a very low incidence of histopathologic abnormalities in critical organs such as bone marrow and kidney among survivors compared with non-treated controls.Conclusion: Contrary to popular belief, we demonstrate that DOTA-PRIT can be successfully adapted to an internalizing antigen-antibody system such as HER2, with suffi...

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Section: Discussionmentioning

confidence: 99%

Theranostic pretargeted radioimmunotherapy of internalizing solid tumor antigens in human tumor xenografts in mice: Curative treatment of HER2-positive breast carcinoma

Cheal¹,

Xu²,

Guo³

et al. 2018

Theranostics

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“…These specific activities are at least10-fold greater than what has been previously reported for 227 Th-trastuzumab. 39, 54–56 Meanwhile, the reported labeling yields for 227 Th-trastuzumab range from 6% to 90%. 55, 56 The percent bound to HER2 was 53.7% for 227 Th-trastuzumab and 26.2% for 227 Th-panitumumab to HER1.…”

Section: Resultsmentioning

confidence: 99%

“…24 This data is consistent with a report by Abbas et al, in which 227 Th-trastuzumab was evaluated in a murine model for ovarian cancer. 54 Others have demonstrated tumor targeting with low uptake in normal organs following i.p. injection of 227 Th-trastuzumab in mice bearing i.p.…”

Section: Resultsmentioning

confidence: 99%

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Comparative studies on the therapeutic benefit of targeted α-particle radiation therapy for the treatment of disseminated intraperitoneal disease

et al. 2017

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Identification of the appropriate combination of radionuclide, target and targeting vehicle is critical for successful radioimmunotherapy. For the treatment of disseminated peritoneal diseases such as pancreatic or ovarian cancer, α-emitting radionuclides have been proposed for targeted radiation therapy. This laboratory has taken a systematic approach investigating targeted α-radiation therapy, allowing comparisons to now be made between 211At, 227Th, 213Bi and 212Pb. Herein, trastuzumab radiolabeled with 211At and 227Th was evaluated for therapeutic efficacy in the LS-174T i.p. tumor model. A dose escalation study was conducted with each radioimmunoconjugate (RIC). Therapeutic benefit was realized with 211At-trastuzumab with doses of 20, 30 and 40 μCi. At doses > 40 μCi, toxicity was observed with greater weight loss and 2-fold higher decrease in the platelet counts. Following a second study comparing the effect of 20, 30 and 40 μCi of 211At-trastuzumab, 30 μCi was selected as the dose for future studies. A parallel study was performed evaluating 0.25, 0.5, 1.0, 2.0 and 5.0 μCi of 227Th-trastuzumab. The 0.5 and 1.0 μCi injected dose resulted in a therapeutic response; a lower degree of weight loss was experienced by the mice in the 0.5 μCi cohort. When the data is normalized for comparing 211At, 227Th, 213Bi and 212Pb, the choice of radionuclide for RIT is perhaps not entirely based on simple therapeutic efficacy, other factors may play a role in choosing the “right” radionuclide.

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“…Th-trastuzumab turned out to be significantly better than the b --particle-emitting 177 Lu-trastuzumab. 26 The RBE was also studied in mice with breast cancer xenografts, and it was found that it was higher for 227 Th-trastuzumab than for 177 Lutrastuzumab, infact, to achieve 100% prolonged growth delay the absorbed radiation dose of 227 Th-trastuzumab was three times lower than with 177 Lu-trastuzumab. 26 By contrast, the therapeutic index of 177 Lu-trastuzumab was superior to the 227 Th-trastuzumab as when compared with a 50% decrease in the number of white blood cells, the growth delay was three times longer with 177 Lu-trastuzumab than with 227 Thtrastuzumab.…”

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confidence: 99%

Targeted Alpha Therapy with Thorium-227

Frantellizzi

Cosma

Brunotti

et al. 2020

Cancer Biotherapy and Radiopharmaceuticals

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Targeted alpha therapy (TAT) can deliver high localized burden of radiation selectively to cancer cells as well as the tumor microenvironment, while minimizing toxicity to normal surrounding cell. Radium-223 (223 Ra), the first-in-class a-emitter approved for bone metastatic castration-resistant prostate cancer has shown the ability to prolong patient survival. Targeted Thorium-227 (227 Th) conjugates represent a new class of therapeutic radiopharmaceuticals for TAT. They are comprised of the a-emitter 227 Th complexed to a chelator conjugated to a tumor-targeting monoclonal antibody. In this review, the authors will focus out interest on this therapeutic agent. In recent studies 227 Th-labeled radioimmunoconjugates showed a relevant stability both in serum and vivo conditions with a significant antigen-dependent inhibition of cell growth. Unlike 223 Ra, the parent radionuclide 227 Th can form highly stable chelator complexes and is therefore amenable to targeted radioimmunotherapy. The authors discuss the future potential role of 227 Th TAT in the treatment of several solid as well as hematologic malignancies.

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Preclinical evaluation of 227Th-labeled and 177Lu-labeled trastuzumab in mice with HER-2-positive ovarian cancer xenografts

Cited by 27 publications

References 25 publications

Theranostic pretargeted radioimmunotherapy of internalizing solid tumor antigens in human tumor xenografts in mice: Curative treatment of HER2-positive breast carcinoma

Theranostic pretargeted radioimmunotherapy of internalizing solid tumor antigens in human tumor xenografts in mice: Curative treatment of HER2-positive breast carcinoma

Comparative studies on the therapeutic benefit of targeted α-particle radiation therapy for the treatment of disseminated intraperitoneal disease

Targeted Alpha Therapy with Thorium-227

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