212Pb-labeled B7-H3-targeting antibody for pancreatic cancer therapy in mouse models

Kasten, Benjamin B.; Gangrade, Abhishek; Kim, Harrison; Fan, Jinda; Ferrone, Soldano; Zinn, Kurt R.; Buchsbaum, Donald J.

doi:10.1016/j.nucmedbio.2017.12.004

Cited by 52 publications

(29 citation statements)

References 54 publications

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“…Antibodies or antibody fragments can also be conjugated with radioisotopes to deliver localized radiotherapy, known as radioimmunotherapy, and is emerging as an important selection for PDAC patients [83]. Recently, CD147 [84] and B7-H3 [85] were explored as targets of radioimmunotherapy for cancer cells and CSCs, respectively, with a 90 Y-labelled antibody (059-053) and a 212 Pblabelled antibody (376.96) and investigated in preclinical experiments; both achieved promising results and demonstrated potential therapeutic efficacy for PDAC ( Table 1).…”

Section: Protumour Regulatory Cells and Immunosuppressionmentioning

confidence: 99%

Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma

et al. 2020

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Pancreatic ductal adenocarcinoma (PDAC) is an incurable cancer resistant to traditional treatments, although a limited number of early-stage patients can undergo radical resection. Immunotherapies for the treatment of haematological malignancies as well as solid tumours have been substantially improved over the past decades, and impressive results have been obtained in recent preclinical and clinical trials. However, PDAC is likely the exception because of its unique tumour microenvironment (TME). In this review, we summarize the characteristics of the PDAC TME and focus on the network of various tumour-infiltrating immune cells, outlining the current advances in PDAC immunotherapy and addressing the effect of the PDAC TME on immunotherapy. This review further explores the combinations of different therapies used to enhance antitumour efficacy or reverse immunodeficiencies and describes optimizable immunotherapeutic strategies for PDAC. The concordant combination of various treatments, such as targeting cancer cells and the stroma, reversing suppressive immune reactions and enhancing antitumour reactivity, may be the most promising approach for the treatment of PDAC. Traditional treatments, especially chemotherapy, may also be optimized for individual patients to remodel the immunosuppressive microenvironment for enhanced therapy.

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Section: Protumour Regulatory Cells and Immunosuppressionmentioning

confidence: 99%

Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma

et al. 2020

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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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“…). The first pre‐clinical work on using an alpha‐emitter 212 Bi for treatment of experimental pancreatic cancer was described by Kurtzman et al 30 years ago, and recently there has been a resurgent interest towards using alpha‐emitters for targeted radionuclide therapy of PDAC …”

Section: Discussionmentioning

confidence: 99%

“…The first pre-clinical work on using an alphaemitter 212 Bi for treatment of experimental pancreatic cancer was described by Kurtzman et al 30 30 years ago, and recently there has been a resurgent interest towards using alpha-emitters for targeted radionuclide therapy of PDAC. 26,31,32 In our study, we performed side by side comparison of the short-lived alpha-emitter 213 Bi (half-life 46 minutes), and the long-lived beta-emitter 177 Lu (half-life 6.7 days). Our results indicate that 213 Bi is a much more effective radionuclide for CETN1 targeted alpha therapy of PDAC.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of novel highly specific antibodies to cancer testis antigen Centrin‐1 for radioimmunoimaging and radioimmunotherapy of pancreatic cancer

et al. 2019

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Background Pancreatic ductal adenocarcinoma (PDAC) accounts for >90% of pancreatic malignancies, and has median survival of <6 months. There is an urgent need for diagnostic and therapeutic options for PDAC. Centrin1 (CETN1) is a novel member of Cancer/Testis Antigens, with a 25‐fold increase of CETN1 gene expression in PDX from PDAC patients. The absence of selective anti‐CETN1 antibodies is hampering CETN1 use for diagnosis and therapy. Here we report the generation of highly specific for CETN1 antibodies and their evaluation for radioimmunoimaging and radioimmunotherapy (RIT) of experimental PDAC. Methods The antibodies to CETN1 were generated via mice immunization with immunogenic peptide distinguishing CETN1 from CETN2. Patient tumor microarrays were used to evaluate the binding of the immune serum to PDAC versus normal pancreas. The antibodies were tested for their preferential binding to CETN1 over CETN2 by ELISA. Mice bearing PDAC MiaPaCa2 xenografts were imaged with microSPECT/CT and treated with 213 Bi‐ and 177 Lu‐labeled antibodies to CETN1. Results Immune serum bind to 50% PDAC cases on patient tumor microarrays with no specific binding to normal pancreas. Antibodies demonstrated preferential binding to CETN1 versus CETN2. Antibody 69‐11 localized to PDAC xenografts in mice in vivo and ex vivo. RIT of PDAC xenografts with 213 Bi‐labeled antibodies was effective, safe, and CETN1‐specific. Conclusions The results demonstrate the ability of these novel antibodies to detect CETN1 both in vitro and in vivo; as well, the RIT treatment of experimental PDAC when radiolabeled with 213 Bi is highly efficient and safe. Further evaluation of these novel reagents for diagnosis and treatment of PDAC is warranted.

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212Pb-labeled B7-H3-targeting antibody for pancreatic cancer therapy in mouse models

Abstract: Our results provide evidence for the efficacy of B7-H3 targeted RIT against preclinical models of pancreatic ductal adenocarcinoma (PDAC) and support future studies with Pb-376.96 in combination with chemotherapy to potentiate efficacy against PDAC.

Cited by 52 publications

References 54 publications

Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma

Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma

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

Evaluation of novel highly specific antibodies to cancer testis antigen Centrin‐1 for radioimmunoimaging and radioimmunotherapy of pancreatic cancer

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