Evaluation of cetuximab as a candidate for targeted α-particle radiation therapy of HER1-positive disseminated intraperitoneal disease

Milenic, Diane E.; Baidoo, Kwamena E.; Kim, Young-Seung; Brechbiel, Martin W.

doi:10.4161/19420862.2014.985160

Cited by 35 publications

(30 citation statements)

References 52 publications

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“…212 Pb-376.96 or 212 Pb-F3-C25 was applied to the cells one day after treatment with carboplatin, since carboplatin treatment followed by RIT with 212 Pb has been shown to be more effective than alternative treatment schedules in other cancer models [35, 36]. Combining 5 μmol/L carboplatin with 2, 7, or 21 kBq/mL 212 Pb-376.96 decreased clonogenic survival of A2780cp20 adherent cells and CICs to a greater extent than either agent alone (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

“…The doses selected for these studies were comparable to doses of alternative 212 Pb-RICs that produced significant therapeutic effects (two- to ten-fold greater than non-treated control groups) in mice with i.p. xenografts of human malignancies [35, 36, 48]. The trend of prolonged mouse survival with higher doses of 212 Pb-376.96, coupled with the finding that all mice eventually succumbed to disease burden, suggests that in vivo saturation of the target epitope had not occurred with the doses used here [47].…”

Section: Discussionmentioning

confidence: 99%

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

Kasten

Arend

Katre

et al. 2017

Nuclear Medicine and Biology

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Introduction Novel therapies that effectively kill both differentiated cancer cells and cancer initiating cells (CICs), which are implicated in causing chemotherapy-resistance and disease recurrence, are needed to reduce the morbidity and mortality of ovarian cancer. These studies used monoclonal antibody (mAb) 376.96, which recognizes a B7-H3 epitope expressed on ovarian cancer cells and CICs, as a carrier molecule for targeted α-particle radioimmunotherapy (RIT) in preclinical models of human ovarian cancer. Methods mAb 376.96 was conjugated to the chelate 2-(4-isothiocyanotobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoylmethyl)-cyclododecane (TCMC) and radiolabeled with 212Pb, a source of α-particles. In vitro Scatchard assays determined the specific binding of 212Pb-376.96 to adherent differentiated or non-adherent CIC-enriched ES-2 and A2780cp20 ovarian cancer cells. Adherent ovarian cancer cells and non-adherent CIC-enriched tumorspheres treated in vitro with 212Pb-376.96 or the irrelevant isotype-matched 212Pb-F3-C25 were assessed for clonogenic survival. Mice bearing i.p. ES-2 or A2780cp20 xenografts were injected i.p. with 0.17-0.70 MBq 212Pb-376.96 or 212Pb-F3-C25 and were used for in vivo imaging, ex vivo biodistribution, and therapeutic survival studies. Results 212Pb-376.96 was obtained in high yield and purity (>98%); Kd values ranged from 10.6-26.6 nM for ovarian cancer cells, with 104-105 binding sites/cell. 212Pb-376.96 inhibited the clonogenic survival of ovarian cancer cells up to 40 times more effectively than isotype-matched control 212Pb-F3-C25; combining 212Pb-376.96 with carboplatin significantly decreased clonogenic survival compared to either agent alone. In vivo imaging and biodistribution analysis 24 h after i.p. injection of 212Pb-376.96 showed high peritoneal retention and tumor tissue accumulation (28.7% ID/g in ES-2 ascites, 73.1% ID/g in A2780cp20 tumors); normal tissues showed lower and comparable uptake for 212Pb-376.96 and 212Pb-F3-C25. Tumor-bearing mice treated with 212Pb-376.96 alone or combined with carboplatin survived 2-3 times longer than mice treated with 212Pb-F3-C25 or non-treated controls. Conclusion These results support additional RIT studies with 212Pb-376.96 for future evaluation in patients with ovarian cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Kasten

Arend

Katre

et al. 2017

Nuclear Medicine and Biology

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“…The anti-tumour efficacy of 212 Pb has been demonstrated in preclinical studies; in several animal models of peritoneal cancer [16][17][18][19][20][21][22], prostate cancer, melanoma, pancreatic cancer and breast cancer [23][24][25][26]. It has also been applied in a pre-targeting setting [27,28].…”

Section: Introductionmentioning

confidence: 99%

Targeted alpha therapy for chronic lymphocytic leukaemia and non-Hodgkin’s lymphoma with the anti-CD37 radioimmunoconjugate 212Pb-NNV003

et al. 2020

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Relapse of chronic lymphocytic leukaemia and non-Hodgkin's lymphoma after standard of care treatment is common and new therapies are needed. The targeted alpha therapy with 212 Pb-NNV003 presented in this study combines cytotoxic α-particles from 212 Pb, with the anti-CD37 antibody NNV003, targeting B-cell malignancies. The goal of this study was to explore 212 Pb-NNV003 for treatment of CD37 positive chronic lymphocytic leukaemia and non-Hodgkin's lymphoma in preclinical mouse models.An anti-proliferative effect of 212 Pb-NNV003 was observed in both chronic lymphocytic leukaemia (MEC-2) and Burkitt's lymphoma (Daudi) cells in vitro. In biodistribution experiments, accumulation of 212 Pb-NNV003 was 23%ID/g and 16%ID/g in Daudi and MEC-2 tumours 24 h post injection. In two intravenous animal models 90% of the mice treated with a single injection of 212 Pb-NNV003 were alive 28 weeks post cell injection. Median survival times of control groups were 5-9 weeks. There was no significant difference between different specific activities of 212 Pb-NNV003 with regards to therapeutic effect or toxicity. For therapeutically effective activities, a transient haematological toxicity was observed. This study shows that 212 Pb-NNV003 is effective and safe in preclinical models of CD37 positive chronic lymphocytic leukaemia and non-Hodgkin's lymphoma, warranting future clinical testing.

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“…disease would be an attractive pursuit. A recent study from Milenic et al demonstrated that 212 Pb-cetuximab, which binds to HER1, had a therapeutic efficacy similar to that of 212 Pb-trastuzumab, providing the possible option for a second component of a multimodality therapy regimen [76]. Recent developments in recombinant DNA technology have also allowed synthesis of antibody formats, small antibody fragments such as F(ab’) 2 to improve tumor penetration and pharmacokinetics.…”

Section: Discussionmentioning

confidence: 99%

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

Yong¹,

Brechbiel

2015

medicalScience

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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.

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Evaluation of cetuximab as a candidate for targeted α-particle radiation therapy of HER1-positive disseminated intraperitoneal disease

Cited by 35 publications

References 52 publications

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

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

Targeted alpha therapy for chronic lymphocytic leukaemia and non-Hodgkin’s lymphoma with the anti-CD37 radioimmunoconjugate 212Pb-NNV003

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

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