scholarly journals An IL-2-grafted antibody immunotherapy with potent efficacy against metastatic cancer

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Dilara Sahin ◽  
Natalia Arenas-Ramirez ◽  
Matthias Rath ◽  
Ufuk Karakus ◽  
Monika Hümbelin ◽  
...  
Keyword(s):  
Single Molecule ◽  
First Generation ◽  
Metastatic Cancer ◽  
Interleukin 2 ◽  
Antigen Binding ◽  
Cancer Models ◽  
Advanced Malignancies ◽  
Antibody Immunotherapy ◽  
Binding Groove

AbstractModified interleukin-2 (IL-2) formulations are being tested in cancer patients. However, IL-2 immunotherapy damages IL-2 receptor (IL-2R)-positive endothelial cells and stimulates IL-2Rα (CD25)-expressing lymphocytes that curtail anti-tumor responses. A first generation of IL-2Rβ (CD122)-biased IL-2s addressed some of these drawbacks. Here, we present a second-generation CD122-biased IL-2, developed by splitting and permanently grafting unmutated human IL-2 (hIL-2) to its antigen-binding groove on the anti-hIL-2 monoclonal antibody NARA1, thereby generating NARA1leukin. In comparison to hIL-2/NARA1 complexes, NARA1leukin shows a longer in vivo half-life, completely avoids association with CD25, and more potently stimulates CD8+ T and natural killer cells. These effects result in strong anti-tumor responses in various pre-clinical cancer models, whereby NARA1leukin consistently surpasses the efficacy of hIL-2/NARA1 complexes in controlling metastatic disease. Collectively, NARA1leukin is a CD122-biased single-molecule construct based on unmutated hIL-2 with potent efficacy against advanced malignancies.

scholarly journals A cytokine receptor-masked IL2 prodrug selectively activates tumor-infiltrating lymphocytes for potent antitumor therapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Eric J. Hsu ◽  
Xuezhi Cao ◽  
Benjamin Moon ◽  
Joonbeom Bae ◽  
Zhichen Sun ◽  
...  
Keyword(s):  
Metastatic Cancer ◽  
Interleukin 2 ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Checkpoint Blockade ◽  
Targeting Therapy ◽  
Protease Substrate ◽  
Reduced Toxicity ◽  
Infiltrating Lymphocytes ◽  
Receptor Beta

AbstractAs a potent lymphocyte activator, interleukin-2 (IL-2) is an FDA-approved treatment for multiple metastatic cancers. However, its clinical use is limited by short half-life, low potency, and severe in vivo toxicity. Current IL-2 engineering strategies exhibit evidence of peripheral cytotoxicity. Here, we address these issues by engineering an IL-2 prodrug (ProIL2). We mask the activity of a CD8 T cell-preferential IL-2 mutein/Fc fusion protein with IL2 receptor beta linked to a tumor-associated protease substrate. ProIL2 restores activity after cleavage by tumor-associated enzymes, and preferentially activates inside tumors, where it expands antigen-specific CD8 T cells. This significantly reduces IL-2 toxicity and mortality without compromising antitumor efficacy. ProIL2 also overcomes resistance of cancers to immune checkpoint blockade. Lastly, neoadjuvant ProIL2 treatment can eliminate metastatic cancer through an abscopal effect. Taken together, our approach presents an effective tumor targeting therapy with reduced toxicity.

Oncotherapeutic application of resveratrol-based inorganic nanoparticles

2021 ◽  
Vol 09 ◽  
Author(s):  
Angela Perris ◽  
Sanchari Bhattacharya ◽  
Junaid Jawed ◽  
Muddasarul Hoda
Keyword(s):  
Metallic Nanoparticles ◽  
Metastatic Cancer ◽  
Inorganic Nanoparticles ◽  
Carcinogenic Agent ◽  
Non Invasive ◽  
Therapeutic Benefits ◽  
Cancer Models ◽  
Nano Science

Background: Potential therapeutic benefits of natural phytoconstituents and the emergence of nano-structured drug delivery systems have expanded the scope of enhanced chemotherapy with minimal adverse effects. Various in vivo and in vitro studies have revealed Resveratrol to be a potent anti-carcinogenic agent. Researchers are ly applying the concept of nano-science for enhancing the delivery of phyto-drugs like resveratrol, in order to carry the drug to the affected tissues and organs of cancer patients with much ease and efficiency. Methods: The review emphasizes the use of inorganic nanoparticles for enhancing the delivery and efficacy of resveratrol into otherwise inaccessible tumorigenic tissues. Conclusion: The present review work summarizes a comprehensive update on the mechanism of actions of the resveratrol-based inorganic nanocomposite particles that are ly being studied against various cancer models. This work may be significant in laying the foundation for the future of metallic nanoparticles-based delivery and efficacy of phytochemicals in general and resveratrol in specific against non-invasive metastatic cancer.

scholarly journals Combination of rAd-p53 in situ gene therapy and anti-PD-1 antibody immunotherapy induced anti-tumor activity in mouse syngeneic urogenital cancer models

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Naoto Kunimura ◽  
Koichi Kitagawa ◽  
Ryota Sako ◽  
Keita Narikiyo ◽  
Shoko Tominaga ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Combination Therapy ◽  
In Vivo Experiments ◽  
Cancer Models ◽  
C3h Mice ◽  
Antibody Immunotherapy ◽  
Adenovirus Receptor ◽  
Urogenital Cancers

Abstract In this study we undertook a novel combination therapy using rAd-p53 in situ gene therapy and immunotherapy with immune checkpoint inhibitor (ICI) anti-PD-1 antibody for urogenital cancers. Three mouse syngeneic tumor cell lines, TRAMP-C2 (prostate cancer derived from C57BL/6 mice), MBT-2 (bladder cancer derived from C3H mice) and Renca (kidney cancer derived from BALB/c mice) were used in this study. The highest coxsackie and adenovirus receptor (CAR) mRNA expression was observed in TRAMP-C2 cells, followed by Renca and then MBT-2 cells. Consistent with the CAR expressions, rAd-p53 at 160 multiplicity of infection (MOI) significantly inhibited the cell proliferation of TRAMP-C2 and Renca cells, but not MBT-2 cells. In in vivo experiments, the combination of intratumoral injections of rAd-p53 (1 × 109 plaque-forming units) every other day and intraperitoneal injections of anti-mouse PD-1 antibody (200 μg) twice a week suppressed tumor growth and prolonged survival compared to rAd-p53 or anti-PD-1 antibody monotherapy in both the TRAMP-C2 and Renca models. Our results encourage the clinical development of combination therapy comprised of in situ gene therapy with rAd-p53 and immunotherapy with an ICI anti-PD-1 antibody for urogenital cancers.

scholarly journals A cytokine receptor-masked IL2 prodrug selectively activates tumor-infiltrating lymphocytes for potent antitumor therapy

2020 ◽  
Author(s):  
Eric Hsu ◽  
Xuezhi Cao ◽  
Benjamin Moon ◽  
joonbeom Bae ◽  
Zhichen Sun ◽  
...  
Keyword(s):  
Metastatic Cancer ◽  
Interleukin 2 ◽  
Body Weight Loss ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Checkpoint Blockade ◽  
Targeting Therapy ◽  
Protease Substrate ◽  
Reduced Toxicity ◽  
Receptor Beta

Abstract Interleukin-2 (IL-2) is an FDA approved treatment for multiple metastatic cancers. However, while IL-2 is a potent activator of CD8 and NK cells, its clinical use is limited by short in vivo half-life, low potency, and severe in vivo toxicity. Current strategies of reducing IL-2 receptor alpha binding and increasing IL-2 receptor beta binding reduce efficacy or increase toxicity. Here, we address these issues by engineering a novel IL-2 prodrug (ProIL2). We mask the activity of a CD8 T cell-preferred IL-2 mutein/Fc fusion protein with IL2 receptor beta linked to a tumor-associated protease substrate. ProIL2 restores activity after cleavage by tumor-associated enzymes, and preferentially activates inside tumors, where it is efficiently cleaved and expands CD8 T cells. This significantly reduces IL-2 associated cytokine storm, body weight loss, and mortality without compromising antitumor efficacy. ProIL2 also overcomes resistance of cancers to immune checkpoint blockade. Lastly, neoadjuvant ProIL2 treatment can effectively eliminate metastatic cancer by inducing an abscopal effect. Taken together, our approach presents an effective tumor targeting therapy with reduced toxicity.

In vivo and in vitro activation of natural killer cells in advanced cancer patients undergoing combined recombinant interleukin-2 and LAK cell therapy.

1987 ◽  
Vol 5 (12) ◽  
pp. 1933-1941 ◽  
Author(s):  
J H Phillips ◽  
B T Gemlo ◽  
W W Myers ◽  
A A Rayner ◽  
L L Lanier
Keyword(s):  
T Cells ◽  
Cytotoxic Activity ◽  
Nk Cells ◽  
Natural Killer ◽  
Cultured Cells ◽  
Metastatic Cancer ◽  
Interleukin 2 ◽  
Lak Cell ◽  
Recombinant Interleukin 2

Patients with advanced metastatic cancer were given combined autologous lymphokine activated killer (LAK) cell and recombinant interleukin-2 (rIL-2) therapy on a National Cancer Institute extramural phase II trial. Systemic administration of rIL-2 resulted in pronounced lymphocytopenia. Within two days after completion of in vivo rIL-2 therapy, there was a dramatic increase in absolute numbers of circulating lymphocytes, and cytotoxic activity against tumor cell targets was mediated by peripheral blood lymphocytes, indicating in vivo generation of LAK activity. Patients were leukapheresed and cells cultured for three to four days in rIL-2. rIL-2 cultured cells from all patients demonstrated cytotoxic activity. In order to characterize the effector cell, T cells and natural killer (NK) cells were isolated to greater than 95% purity by flow cytometry. Cytotoxic activity was mediated by rIL-2--activated NK cells, whereas T cells demonstrated no substantial activity. The circulating in vivo cytotoxic effectors detected after in vivo rIL-2 therapy were also shown to be rIL-2--activated NK cells. Results from these studies demonstrate that all patients were capable of generating a cytotoxic response, and that the cytotoxic effector cells were rIL-2--activated NK cells, identified by the phenotype CD3--, Leu 19+.

The truncated somatostatin receptor sst5TMD4 stimulates the production of pro-angiogenic factors in in vitro and in vivo breast cancer models

2014 ◽  
Author(s):  
Raul M Luque ◽  
Mario Duran-Prado ◽  
David Rincon-Fernandez ◽  
Marta Hergueta-Redondo ◽  
Michael D Culler ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Somatostatin Receptor ◽  
Angiogenic Factors ◽  
Cancer Models

Nitroxyl Modified Tobacco Mosaic Virus as a Metal-Free High-Relaxivity MRI and EPR Active Superoxide Sensor

2018 ◽  
Author(s):  
Madushani Dharmarwardana ◽  
André F. Martins ◽  
Zhuo Chen ◽  
Philip M. Palacios ◽  
Chance M. Nowak ◽  
...  
Keyword(s):  
Tobacco Mosaic Virus ◽  
Mosaic Virus ◽  
Single Molecule ◽  
Biological Fluids ◽  
Cellular Respiration ◽  
Organic Radical ◽  
Paramagnetic Resonance ◽  
Metal Free ◽  
Disease States

Superoxide overproduction is known to occur in multiple disease states requiring critical care yet non-invasive detection of superoxide in deep tissue remains a challenge. Herein, we report a metal-free magnetic resonance imaging (MRI) and electron paramagnetic resonance (EPR) active contrast agent prepared by “click conjugating” paramagnetic organic radical contrast agents (ORCAs) to the surface of tobacco mosaic virus (TMV). While ORCAs are known to be reduced <i>in vivo</i> to an MRI/EPR silent state, their oxidation is facilitated specifically by reactive oxygen species—in particular superoxide—and are largely unaffected by peroxides and molecular oxygen. Unfortunately, single molecule ORCAs typically offer weak MRI contrast. In contrast, our data confirm that the macromolecular ORCA-TMV conjugates show marked enhancement for <i>T<sub>1</sub></i> contrast at low field (<3.0 T), and <i>T<sub>2</sub></i> contrast at high field (9.4 T). Additionally, we demonstrated that the unique topology of TMV allows for “quenchless fluorescent” bimodal probe for concurrent fluorescence and MRI/EPR imaging, which was made possible by exploiting the unique inner and outer surface of the TMV nanoparticle. <a>Finally, we show TMV-ORCAs do not respond to normal cellular respiration, minimizing the likelihood for background, yet still respond to enzymatically produced superoxide in complicated biological fluids like serum.</a>

Evaluation of Potent Isoquinoline-Based Thiosemicarbazone Antiproliferatives Against Solid Tumor Models

2019 ◽  
Author(s):  
Daniel Sun ◽  
Soumya Poddar ◽  
Roy D. Pan ◽  
Juno Van Valkenburgh ◽  
Ethan Rosser ◽  
...  
Keyword(s):  
Solid Tumor ◽  
Small Cell Lung Carcinoma ◽  
Single Agent ◽  
Resistance Mechanisms ◽  
Tumor Models ◽  
Cell Lung Carcinoma ◽  
Adaptive Resistance ◽  
Cancer Models ◽  
Nanomolar Range

The lead compound, an ⍺-N-heterocyclic carboxaldehyde thiosemicarbazone <b>HCT-13</b>, was highly potent against a panel of pancreatic, small cell lung carcinoma, and prostate cancer models, with IC<sub>90</sub> values in the low-to-mid nanomolar range.<b> </b>We show that the cytotoxicity of <b>HCT-13</b> is copper-dependent, that it acts as a copper ionophore, induces production of reactive oxygen species (ROS), and promotes mitochondrial dysfunction and S-phase arrest. Lastly, DNA damage response/replication stress response (DDR/RSR) pathways, specifically Ataxia-Telangiectasia Mutated (ATM) and Rad3-related protein kinase (ATR), were identified as actionable adaptive resistance mechanisms following <b>HCT-13 </b>treatment. Taken together, <b>HCT-13 </b>is potent against solid tumor models and warrants <i>in vivo</i> evaluation against aggressive tumor models, either as a single agent or as part of a combination therapy.

Supramolecular Enhancement of Aminoxyl ORCA Contrast Agents

2019 ◽  
Author(s):  
Hamilton Lee ◽  
Jenica Lumata ◽  
Michael A. Luzuriaga ◽  
Candace Benjamin ◽  
Olivia Brohlin ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Side Effects ◽  
Magnetic Resonance ◽  
Tobacco Mosaic Virus ◽  
Contrast Agents ◽  
Single Molecule ◽  
Organic Radical ◽  
Resonance Imaging ◽  
Physiological Conditions

<div><div><div><p>Many contrast agents for magnetic resonance imaging are based on gadolinium, however side effects limit their use in some patients. Organic radical contrast agents (ORCAs) are potential alternatives, but are reduced rapidly in physiological conditions and have low relaxivities as single molecule contrast agents. Herein, we use a supramolecular strategy where cucurbit[8]uril binds with nanomolar affinities to ORCAs and protects them against biological reductants to create a stable radical in vivo. We further over came the weak contrast by conjugating this complex on the surface of a self-assembled biomacromolecule derived from the tobacco mosaic virus.</p></div></div></div>

THE ROLE OF POLYETHYLENIMINE IN ENHANCING PERFORMANCE OF GLUTAMATE BIOSENSORS

2018 ◽  
Vol 8 (3) ◽  
pp. 36-41
Author(s):  
Diep Do Thi Hong ◽  
Duong Le Phuoc ◽  
Hoai Nguyen Thi ◽  
Serra Pier Andrea ◽  
Rocchitta Gaia
Keyword(s):  
First Generation ◽  
Good Reproducibility ◽  
Complex Matrices ◽  
Long Term Stability ◽  
In Vitro Characterization ◽  
Glutamate Oxidase

Background: The first biosensor was constructed more than fifty years ago. It was composed of the biorecognition element and transducer. The first-generation enzyme biosensors play important role in monitoring neurotransmitter and determine small quantities of substances in complex matrices of the samples Glutamate is important biochemicals involved in energetic metabolism and neurotransmission. Therefore, biosensors requires the development a new approach exhibiting high sensibility, good reproducibility and longterm stability. The first-generation enzyme biosensors play important role in monitoring neurotransmitter and determine small quantities of substances in complex matrices of the samples. The aims of this work: To find out which concentration of polyethylenimine (PEI) exhibiting the most high sensibility, good reproducibility and long-term stability. Methods: We designed and developed glutamate biosensor using different concentration of PEI ranging from 0% to 5% at Day 1 and Day 8. Results: After Glutamate biosensors in-vitro characterization, several PEI concentrations, ranging from 0.5% to 1% seem to be the best in terms of VMAX, the KM; while PEI content ranging from 0.5% to 1% resulted stable, PEI 1% displayed an excellent stability. Conclusions: In the result, PEI 1% perfomed high sensibility, good stability and blocking interference. Furthermore, we expect to develop and characterize an implantable biosensor capable of detecting glutamate, glucose in vivo. Key words: Glutamate biosensors, PEi (Polyethylenimine) enhances glutamate oxidase, glutamate oxidase biosensors

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