Paradoxical effects of Auger electron-emitting 111 In-DTPA-NLS-CSL360 radioimmunoconjugates on hCD45 + cells in the bone marrow and spleen of leukemia-engrafted NOD/SCID or NRG mice

Bergstrom, Dane; Leyton, Jeffrey V.; Zereshkian, Arman; Chan, Conrad; Cai, Zhongli; Reilly, Raymond M.

doi:10.1016/j.nucmedbio.2016.07.006

Cited by 8 publications

(7 citation statements)

References 21 publications

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“…Bergstrom et al used a different approach by targeting interleukin-3 receptor α-subchain (CD123), which is overexpressed relative to the β-subchain (CD131) on leukemia stem cells with an Auger-emitter 111 In-labeled DTPA-NLS-CSL360 radioimmunoconjugate. 35 In contrast to the beta-emitter, the use of an Auger-emitter resulted in paradoxical radiation priming effect of radioimmunotherapy on increasing the hCD45(+) cell population in the bone marrow and spleen of NOD/SCID or NRG mice.…”

Section: Discussionmentioning

confidence: 99%

“…Very recently, the same group investigated targeting CD45 antigen on leukemic cells with the novel bispecific fusion proteins targeting CD45 and 90 Y‐DOTA 34 and observed tumor reduction, confirming the potential of beta emitters in radioimmunotherapy of AML. Bergstrom et al used a different approach by targeting interleukin‐3 receptor α‐subchain (CD123), which is overexpressed relative to the β‐subchain (CD131) on leukemia stem cells with an Auger‐emitter 111 In‐labeled DTPA‐NLS‐CSL360 radioimmunoconjugate 35 . In contrast to the beta‐emitter, the use of an Auger‐emitter resulted in paradoxical radiation priming effect of radioimmunotherapy on increasing the hCD45(+) cell population in the bone marrow and spleen of NOD/SCID or NRG mice.…”

Section: Discussionmentioning

confidence: 99%

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225Ac‐labeled CD33‐targeting antibody reverses resistance to Bcl‐2 inhibitor venetoclax in acute myeloid leukemia models

et al. 2020

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

225Ac‐labeled CD33‐targeting antibody reverses resistance to Bcl‐2 inhibitor venetoclax in acute myeloid leukemia models

et al. 2020

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“…Moreover, NOD/SCID mice require pre-treatment with 200 cGy of X-radiation to enable AML engraftment. We found that paradoxically, RIT with 111 In-NLS-CSL360 encouraged AML engraftment rather than decreased engraftment, due to a boost in radiation to the BM caused by the γ-photons from 111 In which further primed the BM niche for leukemic cell engraftment (Bergstrom et al 2016). NRG (NOD- Rag1 null IL2rg null , NOD rag gamma) mice that do not harbour this DNA repair defect may be used to study RIT, but these mice are more immunocompromised than NOD/SCID mice and AML engraftment efficiency is often very high, resulting in a high tumour burden that is difficult to eradicate.…”

Section: Preclinical Studiesmentioning

confidence: 99%

Auger electrons for cancer therapy – a review

Facca

Cai

et al. 2019

EJNMMI radiopharm. chem.

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Background: Auger electrons (AEs) are very low energy electrons that are emitted by radionuclides that decay by electron capture (e.g. 111 In, 67 Ga, 99m Tc, 195m Pt, 125 I and 123 I). This energy is deposited over nanometre-micrometre distances, resulting in high linear energy transfer (LET) that is potent for causing lethal damage in cancer cells. Thus, AE-emitting radiotherapeutic agents have great potential for treatment of cancer. In this review, we describe the radiobiological properties of AEs, their radiation dosimetry, radiolabelling methods, and preclinical and clinical studies that have been performed to investigate AEs for cancer treatment. Results: AEs are most lethal to cancer cells when emitted near the cell nucleus and especially when incorporated into DNA (e.g. 125 I-IUdR). AEs cause DNA damage both directly and indirectly via water radiolysis. AEs can also kill targeted cancer cells by damaging the cell membrane, and kill non-targeted cells through a cross-dose or bystander effect. The radiation dosimetry of AEs considers both organ doses and cellular doses. The Medical Internal Radiation Dose (MIRD) schema may be applied. Radiolabelling methods for complexing AE-emitters to biomolecules (antibodies and peptides) and nanoparticles include radioiodination (125 I and 123 I) or radiometal chelation (111 In, 67 Ga, 99m Tc). Cancer cells exposed in vitro to AE-emitting radiotherapeutic agents exhibit decreased clonogenic survival correlated at least in part with unrepaired DNA double-strand breaks (DSBs) detected by immunofluorescence for γH2AX, and chromosomal aberrations. Preclinical studies of AE-emitting radiotherapeutic agents have shown strong tumour growth inhibition in vivo in tumour xenograft mouse models. Minimal normal tissue toxicity was found due to the restricted toxicity of AEs mostly on tumour cells targeted by the radiotherapeutic agents. Clinical studies of AEs for cancer treatment have been limited but some encouraging results were obtained in early studies using 111 In-DTPAoctreotide and 125 I-IUdR, in which tumour remissions were achieved in several patients at administered amounts that caused low normal tissue toxicity, as well as promising improvements in the survival of glioblastoma patients with 125 I-mAb 425, with minimal normal tissue toxicity. Conclusions: Proof-of-principle for AE radiotherapy of cancer has been shown preclinically, and clinically in a limited number of studies. The recent introduction of many biologically-targeted therapies for cancer creates new opportunities to design novel AE-emitting agents for cancer treatment. Pierre Auger did not conceive of the application of AEs for targeted cancer treatment, but this is a tremendously exciting future that we and many other scientists in this field envision.

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“…For RIT studies, we confirmed that an administered amount of panitumumab-MCP- 177 Lu (6.0 MBq; 10 μg) previously found to cause no major normal tissue toxicity for RIT using other 177 Lu-labeled mAbs in NRG mice would be safe to administer to NRG mice for RIT of PANC-1 tumors. NRG mice were selected for RIT because PANC-1 tumors efficiently engraft into these mice, but unlike NOD/SCID mice, these mice do not harbor a germ-line defect in DNA repair that renders NOD/SCID mice unusually radiation sensitive, including to RIT. , No decreases in CBC or increases in serum ALT or Cr compared to mice receiving normal saline were noted (Figure ), indicating no hematopoietic, liver, or kidney toxicity at these amounts. There was also no decrease in body weight in mice treated with panitumumab or with nonspecific IgG RICs (Figure a), indicating no generalized normal tissue toxicity.…”

Section: Discussionmentioning

confidence: 99%

Radioimmunotherapy of PANC-1 Human Pancreatic Cancer Xenografts in NRG Mice with Panitumumab Modified with Metal-Chelating Polymers Complexed to ¹⁷⁷Lu

Aghevlian

Cai

et al. 2018

Mol. Pharmaceutics

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Our aim was to evaluate the effectiveness and normal tissue toxicity of radioimmunotherapy (RIT) of s.c. PANC-1 human pancreatic cancer (PnCa) xenografts in NRG mice using anti-EGFR panitumumab linked to metal-chelating polymers (MCPs) that present 13 DOTA chelators to complex the β-emitter, 177 Lu. The clonogenic survival (CS) of PANC-1 cells treated in vitro with panitumumab-MCP-177 Lu (0.3−1.2 MBq) and DNA double-strand breaks (DSBs) in the nucleus of these cells were measured by confocal immunofluorescence microscopy for γ-H2AX. Subcellular distribution of radioactivity for panitumumab-MCP-177 Lu was measured, and absorbed doses to the cell nucleus were calculated. Normal tissue toxicity was assessed in non tumor-bearing NRG mice by monitoring body weight, complete blood cell counts (CBC), serum alanine aminotransferase (ALT), and creatinine (Cr) after i.v. injection of 6 MBq (10 μg) of panitumumab-MCP-177 Lu. RIT was performed in NRG mice with s.c. PANC-1 tumors injected i.v. with 6 MBq (10 μg) of panitumumab-MCP-177 Lu. Control mice received nonspecific human IgG-MCP-177 Lu (6 MBq; 10 μg), unlabeled panitumumab (10 μg), or normal saline. The tumor growth index (TGI) was compared. Tumor and normal organ doses were estimated based on biodistribution studies. Panitumumab-MCP-177 Lu reduced the CS of PANC-1 cells in vitro by 7.7-fold at the highest amount tested (1.2 MBq). Unlabeled panitumumab had no effect on the CS of PANC-1 cells. γ-H2AX foci were increased by 3.8-fold by panitumumab-MCP-177 Lu. Panitumumab-MCP-177 Lu deposited 3.84 Gy in the nucleus of PANC-1 cells. Administration of panitumumab-MCP-177 Lu (6 MBq; 10 μg) to NRG mice caused no change in body weight, CBC, or ALT and only a slight increase in Cr compared to NRG mice treated with normal saline. Panitumumab-MCP-177 Lu strongly inhibited tumor growth in NRG mice (TGI = 2.3 ± 0.2) compared to normal saline-treated mice (TGI = 5.8 ± 0.5; P < 0.01). Unlabeled panitumumab had no effect on tumor growth (TGI = 6.0 ± 1.6; P > 0.05). The absorbed dose of PANC-1 tumors was 12.3 Gy. The highest normal organ doses were absorbed by the pancreas, liver, spleen, and kidneys. We conclude that EGFR-targeted RIT with panitumumab-MCP-177 Lu was able to overcome resistance to panitumumab in KRAS mutant PANC-1 tumors in NRG mice and may be a promising approach to treatment of PnCa in humans.

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Paradoxical effects of Auger electron-emitting 111 In-DTPA-NLS-CSL360 radioimmunoconjugates on hCD45 + cells in the bone marrow and spleen of leukemia-engrafted NOD/SCID or NRG mice

Cited by 8 publications

References 21 publications

225Ac‐labeled CD33‐targeting antibody reverses resistance to Bcl‐2 inhibitor venetoclax in acute myeloid leukemia models

225Ac‐labeled CD33‐targeting antibody reverses resistance to Bcl‐2 inhibitor venetoclax in acute myeloid leukemia models

Auger electrons for cancer therapy – a review

Radioimmunotherapy of PANC-1 Human Pancreatic Cancer Xenografts in NRG Mice with Panitumumab Modified with Metal-Chelating Polymers Complexed to ¹⁷⁷Lu

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Paradoxical effects of Auger electron-emitting 111 In-DTPA-NLS-CSL360 radioimmunoconjugates on hCD45 + cells in the bone marrow and spleen of leukemia-engrafted NOD/SCID or NRG mice

Cited by 8 publications

References 21 publications

225Ac‐labeled CD33‐targeting antibody reverses resistance to Bcl‐2 inhibitor venetoclax in acute myeloid leukemia models

225Ac‐labeled CD33‐targeting antibody reverses resistance to Bcl‐2 inhibitor venetoclax in acute myeloid leukemia models

Auger electrons for cancer therapy – a review

Radioimmunotherapy of PANC-1 Human Pancreatic Cancer Xenografts in NRG Mice with Panitumumab Modified with Metal-Chelating Polymers Complexed to 177Lu

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Product

Resources

About

Radioimmunotherapy of PANC-1 Human Pancreatic Cancer Xenografts in NRG Mice with Panitumumab Modified with Metal-Chelating Polymers Complexed to ¹⁷⁷Lu