Preclinical Efficacy and Safety of an Anti-Human VEGFA and Anti-Human NRP1 Dual-Targeting Bispecific Antibody (IDB0076)

Although bevacizumab (Avastin®) has been approved as an antiangiogenic agent against some cancers, the efficacy is transient and unsatisfactory in other cancers most likely owing to the presence of alternative proangiogenic factors. Therefore, simultaneous blocking of several proangiogenic factors may be a promising strategy for antiangiogenic cancer therapeutics. Accordingly, neuropilin-1 (NRP1) is an attractive target because it serves as a multifunctional receptor for the vascular endothelial growth factor (VEGF) family. Here, we aimed to generate and test an anti-VEGFA and anti-NRP1 dual-targeting bispecific antibody (named as IDB0076) by genetic fusion of an NRP1-targeting peptide to the C-terminus of the bevacizumab heavy chain. Similar to the parental antibody (bevacizumab), IDB0076 suppressed VEGFA-induced migration of human endothelial cells. In contrast, IDB0076 inhibited endothelial-cell migration induced by other angiogenesis growth factors and manifested a more potent antitumor activity than that of bevacizumab in a murine tumor xenograft model. When toxicity was preliminarily evaluated in cynomolgus monkeys, IDB0076 showed no substantial adverse effects, e.g., the absence of noticeable nephrotoxicity, which has previously been documented for the combination therapy of bevacizumab and an anti-NRP1 antibody. Thus, VEGFA-and-NRP1 dual-targeting bispecific antibody IDB0076 may be a potent and safe anticancer agent worthy of further preclinical and clinical studies.

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An engineered anti-CA19-9 cys-diabody for PET imaging of pancreas cancer and targeting of polymerized liposomal nanoparticles.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.198 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 198-198

Author(s):

M. D. Girgis ◽

K. McCabe ◽

T. Olafsen ◽

F. Bergara ◽

V. Kenanova ◽

...

Keyword(s):

Pancreatic Cancer ◽

Flow Cytometry ◽

Cancer Cells ◽

Xenograft Model ◽

Tumor Xenograft ◽

Human Pancreatic Cancer ◽

Pancreatic Cancer Cells ◽

Mouse Xenograft Model ◽

Parental Antibody ◽

G Ratio

198 Background: Antibody-based therapeutics is a rapidly growing field. Small engineered antibody fragments, such as the cys-diabody demonstrate similar antigen affinity compared to the parental antibody but have a shorter serum half-life (4hrs) and possess the ability to be conjugated to nanoparticles. Our goal was to engineer an anti-CA19-9 cys-diabody fragment in hopes of imaging and targeting pancreatic cancer. Methods: The anti-CA19-9 cys-diabody was created by cloning the variable region of the parental antibody, engineering a C-terminus cysteine, expressing in NS0 cells followed by protein purification utilizing HPLC. Maleimide chemistry was used to conjugate the cys-diabody to PLNs through the engineered cysteine residues. Immunofluorescence and flow cytometry were used to evaluate targeting of cys-diabody and diabody conjugated PLNs to human pancreatic cancer cell lines. The cys-diabody was evaluated in a mouse xenograft model harboring CA19-9 positive (BxPC3) and negative (MiaPaca) tumors. The cys-diabody was radiolabeled with a positron emitter (I-124) and microPET/CT were performed after tail vein injection. Percent of injected dose per gram (%ID/g) of radioactivity was measured in blood and tumor to provide objective confirmation of the microPET images. Results: Immunofluorescence and flow cytometry showed specific binding of the anti-CA19-9 cys- diabody. Tumor xenograft imaging of the anti-CA19-9 cys-diabody demonstrated an average tumor:blood (%ID/g) ratio of 3.3 and positive:negative tumor ratio of 7.4. Successful conjugation of the cys-diabody to PLNs was indicated by immunofluorescence showing specific targeting of PLN-cys- diabody conjugate to human pancreatic cancer cells in vitro. Conclusions: Our results show that the anti-CA19.9 cys- diabody targets pancreatic cancer providing specific molecular imaging in tumor xenograft models. Furthermore, the PLN-cys-diabody conjugate targets human pancreatic cancer cells with the potential to deliver targeted treatment. Further studies evaluating the in vivo ability of the PLN-cys-diabody conjugate to target pancreatic cancer need to be performed. No significant financial relationships to disclose.

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Faculty Opinions recommendation of Development of a human IgG4 bispecific antibody for dual targeting of interleukin-4 (IL-4) and interleukin-13 (IL-13) cytokines.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718046073.793481009 ◽

2013 ◽

Author(s):

Richard L Stevens

Keyword(s):

Bispecific Antibody ◽

Interleukin 4 ◽

Interleukin 13 ◽

Dual Targeting

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LINC00958 promotes the proliferation of TSCC via miR-211-5p/CENPK axis and activating the JAK/STAT3 signaling pathway

Cancer Cell International ◽

10.1186/s12935-021-01808-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Bo Jia ◽

Junfeng Dao ◽

Jiusong Han ◽

Zhijie Huang ◽

Xiang Sun ◽

...

Keyword(s):

Noncoding Rna ◽

Xenograft Model ◽

Tumor Xenograft ◽

Luciferase Reporter ◽

Cell Cycle Regulators ◽

Normal Tissues ◽

Stat3 Signaling ◽

Long Intergenic Noncoding Rna

Abstract Background Tongue squamous cell carcinoma (TSCC) is one of the most common oral tumors. Recently, long intergenic noncoding RNA 00958 (LINC00958) has been identified as an oncogene in human cancers. Nevertheless, the role of LINC00958 and its downstream mechanisms in TSCC is still unknown. Methods The effect of LINC00958 on TSCC cells proliferation and growth were assessed by CCK-8, colony formation, 5-Ethynyl-2′-deoxyuridline (EdU) assay and flow cytometry assays in vitro and tumor xenograft model in vivo. Bioinformatics analysis was used to predict the target of LINC00958 in TSCC, which was verified by RNA immunoprecipitation and luciferase reporter assays. Results LINC00958 was increased in TSCC tissues, and patients with high LINC00958 expression had a shorter overall survival. LINC00958 knockdown significantly decreased the growth rate of TSCC cells both in vitro and in vivo. In mechanism, LINC00958 acted as a ceRNA by competitively sponging miR-211-5p. In addition, we identified CENPK as a direct target gene of miR-211-5p, which was higher in TSCC tissues than that in adjacent normal tissues. Up-regulated miR-211-5p or down-regulated CENPK could abolish LINC00958-induced proliferation promotion in TSCC cells. Furthermore, The overexpression of CENPK promoted the expression of oncogenic cell cycle regulators and activated the JAK/STAT3 signaling. Conclusions Our findings suggested that LINC00958 is a potential prognostic biomarker in TSCC.

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Gamma-radiated immunosuppressed tumor xenograft mice can be a new ideal model in cancer research

Scientific Reports ◽

10.1038/s41598-020-80428-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hamid Khodayari ◽

Saeed Khodayari ◽

Solmaz Khalighfard ◽

Arash Tahmasebifar ◽

Mahboubeh Tajaldini ◽

...

Keyword(s):

Gamma Radiation ◽

High Capacity ◽

Xenograft Model ◽

Tumor Xenograft ◽

Whole Body ◽

Cell Injection ◽

Tumor Tissues ◽

Post Radiation ◽

Xenograft Models ◽

Xenograft Mice

AbstractTumor xenograft models can create a high capacity to study human tumors and discover efficient therapeutic approaches. Here, we aimed to develop the gamma-radiated immunosuppressed (GIS) mice as a new kind of tumor xenograft model for biomedical studies. First, 144 mice were divided into the control and treated groups exposed by a medical Cobalt-60 apparatus in 3, 4, and 5 Gy based on the system outputs. Then, 144 BALB/c mice were divided into four groups; healthy, xenograft, radiation, and radiation + xenograft groups. The animals in the xenograft and radiation + xenograft groups have subcutaneously received 3 × 106 MCF-7 cells 24 h post-radiation. On 3, 7, 14, and 21 days after cell injection, the animals were sacrificed. Then, the blood samples and the spleen and tumor tissues were removed for the cellular and molecular analyses. The whole-body gamma radiation had a high immunosuppressive effect on the BALB/c mice from 1 to 21 days post-radiation. The macroscopic and histopathological observations have proved that the created clusters' tumor structure resulted in the xenograft breast tumor. There was a significant increase in tumor size after cell injection until the end of the study. Except for Treg, the spleen level of CD4, CD8, CD19, and Ly6G was significantly decreased in Xen + Rad compared to the Xen alone group on 3 and 7 days. Unlike IL-4 and IL-10, the spleen level of TGF-β, INF-γ, IL-12, and IL-17 was considerably decreased in the Xen + Rad than the Xen alone group on 3 and 7 days. The spleen expressions of the VEGF, Ki67, and Bax/Bcl-2 ratio were dramatically increased in the Xen + Rad group compared to the Xen alone on 3, 7, 14, and 21 days. Our results could confirm a new tumor xenograft model via an efficient immune-suppressive potential of the whole-body gamma radiation in mice.

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SPECT and Near-Infrared Fluorescence Imaging of Breast Cancer with a Neuropilin-1-Targeting Peptide

Journal of Controlled Release ◽

10.1016/j.jconrel.2014.07.039 ◽

2014 ◽

Vol 192 ◽

pp. 236-242 ◽

Cited By ~ 14

Author(s):

Guo-Kai Feng ◽

Rong-Bin Liu ◽

Meng-Qing Zhang ◽

Xiao-Xuan Ye ◽

Qian Zhong ◽

...

Keyword(s):

Breast Cancer ◽

Fluorescence Imaging ◽

Near Infrared ◽

Near Infrared Fluorescence ◽

Neuropilin 1 ◽

Targeting Peptide ◽

Near Infrared Fluorescence Imaging

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Theranostic Design of Angiopep-2 Conjugated Hyaluronic Acid Nanoparticles (Thera-ANG-cHANPs) for Dual Targeting and Boosted Imaging of Glioma Cells

Cancers ◽

10.3390/cancers13030503 ◽

2021 ◽

Vol 13 (3) ◽

pp. 503

Author(s):

Angela Costagliola di Polidoro ◽

Giorgia Zambito ◽

Joost Haeck ◽

Laura Mezzanotte ◽

Martine Lamfers ◽

...

Keyword(s):

Hyaluronic Acid ◽

Clinical Care ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Glioma Cells ◽

Drug Molecules ◽

Dual Targeting ◽

Density Lipoprotein Receptor ◽

Targeting Peptide

Glioblastoma multiforme (GBM) has a mean survival of only 15 months. Tumour heterogeneity and blood-brain barrier (BBB) mainly hinder the transport of active agents, leading to late diagnosis, ineffective therapy and inaccurate follow-up. The use of hydrogel nanoparticles, particularly hyaluronic acid as naturally occurring polymer of the extracellular matrix (ECM), has great potential in improving the transport of drug molecules and, furthermore, in facilitatating the early diagnosis by the effect of hydrodenticity enabling the T1 boosting of Gadolinium chelates for MRI. Here, crosslinked hyaluronic acid nanoparticles encapsulating gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) and the chemotherapeutic agent irinotecan (Thera-cHANPs) are proposed as theranostic nanovectors, with improved MRI capacities. Irinotecan was selected since currently repurposed as an alternative compound to the poorly effective temozolomide (TMZ), generally approved as the gold standard in GBM clinical care. Also, active crossing and targeting are achieved by theranostic cHANPs decorated with angiopep-2 (Thera-ANG-cHANPs), a dual-targeting peptide interacting with low density lipoprotein receptor related protein-1(LRP-1) receptors overexpressed by both endothelial cells of the BBB and glioma cells. Results showed preserving the hydrodenticity effect in the advanced formulation and internalization by the active peptide-mediated uptake of Thera-cHANPs in U87 and GS-102 cells. Moreover, Thera-ANG-cHANPs proved to reduce ironotecan time response, showing a significant cytotoxic effect in 24 h instead of 48 h.

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Abstract 1391: Self-assembling and disassembling bispecific antibody platform for pretargeted radioimmunotherapy against GPA33 in a xenograft model of colorectal peritoneal carcinomatosis

10.1158/1538-7445.am2021-1391 ◽

2021 ◽

Author(s):

Sebastian Chung ◽

Mao Wang ◽

Darren Veach ◽

Sarah Cheal ◽

Daniela Burnes Vargas ◽

...

Keyword(s):

Peritoneal Carcinomatosis ◽

Bispecific Antibody ◽

Xenograft Model ◽

Self Assembling ◽

Pretargeted Radioimmunotherapy

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The metastasis suppressor, NDRG1, attenuates oncogenic TGF-β and NF-κB signaling to enhance membrane E-cadherin expression in pancreatic cancer cells

Carcinogenesis ◽

10.1093/carcin/bgy178 ◽

2018 ◽

Vol 40 (6) ◽

pp. 805-818 ◽

Cited By ~ 14

Author(s):

Sharleen V Menezes ◽

Leyla Fouani ◽

Michael L H Huang ◽

Bekesho Geleta ◽

Sanaz Maleki ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Membrane ◽

Cancer Cells ◽

Transforming Growth Factor ◽

Xenograft Model ◽

Tumor Xenograft ◽

Metastasis Suppressor ◽

Mesenchymal Transition ◽

Pancreatic Cancer Cells ◽

E Cadherin

AbstractThe metastasis suppressor, N-myc downstream-regulated gene-1 (NDRG1), plays multifaceted roles in inhibiting oncogenic signaling and can suppress the epithelial mesenchymal transition (EMT), a key step in metastasis. In this investigation, NDRG1 inhibited the oncogenic effects of transforming growth factor-β (TGF-β) in PANC-1 pancreatic cancer cells, promoting expression and co-localization of E-cadherin and β-catenin at the cell membrane. A similar effect of NDRG1 at supporting E-cadherin and β-catenin co-localization at the cell membrane was also demonstrated for HT-29 colon and CFPAC-1 pancreatic cancer cells. The increase in E-cadherin in PANC-1 cells in response to NDRG1 was mediated by the reduction of three transcriptional repressors of E-cadherin, namely SNAIL, SLUG and ZEB1. To dissect the mechanisms how NDRG1 inhibits nuclear SNAIL, SLUG and ZEB1, we assessed involvement of the nuclear factor-κB (NF-κB) pathway, as its aberrant activation contributes to the EMT. Interestingly, NDRG1 comprehensively inhibited oncogenic NF-κB signaling at multiple sites in this pathway, suppressing NEMO, Iĸĸα and IĸBα expression, as well as reducing the activating phosphorylation of Iĸĸα/β and IĸBα. NDRG1 also reduced the levels, nuclear co-localization and DNA-binding activity of NF-κB p65. Further, Iĸĸα, which integrates NF-κB and TGF-β signaling to upregulate ZEB1, SNAIL and SLUG, was identified as an NDRG1 target. Considering this, therapies targeting NDRG1 could be a new strategy to inhibit metastasis, and as such, we examined novel anticancer agents, namely di-2-pyridylketone thiosemicarbazones, which upregulate NDRG1. These agents downregulated SNAIL, SLUG and ZEB1 in vitro and in vivo using a PANC-1 tumor xenograft model, demonstrating their marked potential.

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