IL13 Fused Pseudomonas Exotoxin Targets Various Cancers In Vitro

2021 ◽  
Vol 41 (7) ◽  
pp. 3471-3480
Author(s):  
DAMLA ULUDAĞ ◽  
NIHAL KARAKAŞ
Keyword(s):  
Pseudomonas Exotoxin

scholarly journals Rationally designed chemokine-based toxin targeting the viral G protein-coupled receptor US28 potently inhibits cytomegalovirus infection in vivo

2015 ◽  
Vol 112 (27) ◽  
pp. 8427-8432 ◽  
Author(s):  
Katja Spiess ◽  
Mads G. Jeppesen ◽  
Mikkel Malmgaard-Clausen ◽  
Karen Krzywkowski ◽  
Kalpana Dulal ◽  
...  
Keyword(s):  
G Protein ◽  
Pseudomonas Exotoxin ◽  
Viral Pathogen ◽  
Virus Origin ◽  
Ligand Interactions ◽  
Toxin Protein ◽  
Novel Strategy ◽  
G Protein Coupled

The use of receptor–ligand interactions to direct toxins to kill diseased cells selectively has shown considerable promise for treatment of a number of cancers and, more recently, autoimmune disease. Here we move the fusion toxin protein (FTP) technology beyond cancer/autoimmune therapeutics to target the human viral pathogen, human cytomegalovirus (HCMV), on the basis of its expression of the 7TM G protein-coupled chemokine receptor US28. The virus origin of US28 provides an exceptional chemokine-binding profile with high selectivity and improved binding for the CX3C chemokine, CX3CL1. Moreover, US28 is constitutively internalizing by nature, providing highly effective FTP delivery. We designed a synthetic CX3CL1 variant engineered to have ultra-high affinity for US28 and greater specificity for US28 than the natural sole receptor for CX3CL1, CX3CR1, and we fused the synthetic variant with the cytotoxic domain of Pseudomonas Exotoxin A. This novel strategy of a rationally designed FTP provided unparalleled anti-HCMV efficacy and potency in vitro and in vivo.

scholarly journals Hodgkin lymphoma therapy with interleukin-4 receptor–directed cytotoxin in an infiltrating animal model

Blood ◽  
2005 ◽  
Vol 105 (9) ◽  
pp. 3707-3713 ◽  
Author(s):  
Mariko Kawakami ◽  
Koji Kawakami ◽  
Mitomu Kioi ◽  
Pamela Leland ◽  
Raj K. Puri
Keyword(s):  
Animal Model ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Interleukin 4 ◽  
Spontaneous Metastasis ◽  
Pseudomonas Exotoxin ◽  
Immunodeficient Mice ◽  
Interleukin 4 Receptor ◽  
Lymphoma Therapy

AbstractHodgkin lymphoma represents unique clinicopathologic features because Hodgkin and Reed-Sternberg (H-RS) cells produce a variety of cytokines, express a variety of cytokine receptors, and are surrounded by numerous nonmalignant immunoreactive cells. We found that receptors for interleukin-4 (IL-4R) are highly expressed in H-RS cells. To target interleukin-4 receptor (IL-4R), we used a recombinant protein fusing circularly permuted human IL-4 and Pseudomonas exotoxin termed IL438-37-PE38KDEL, or IL-4 cytotoxin. The cytotoxic effect of IL-4 cytotoxin on H-RS cell lines was determined to be moderate to high in vitro. We developed an infiltrating model of Hodgkin disease (HD) by injecting an adherent population of HD-MyZ cells subcutaneously into the flanks of beige/nude/X-linked immunodeficient mice. The animal model exhibited spontaneous metastasis of H-RS cells to lymph nodes and dissemination to vital organs, including the lungs. Intraperitoneal or intratumoral treatment of these mice with IL-4 cytotoxin resulted in regression of the primary tumor mass and a decrease in the incidence of lymph node metastasis. Mice injected with HD-MyZ cells demonstrated 203% prolonged survival (mean survival, 63 days) compared with control (mean survival, 31 days) when they received systemic IL-4 cytotoxin treatment. Because numerous H-RS cell lines express receptors for IL-4, IL-4 cytotoxin may be a unique agent for the treatment of Hodgkin lymphoma.

Clinical evaluation of intraperitoneal Pseudomonas exotoxin immunoconjugate OVB3-PE in patients with ovarian cancer.

1991 ◽  
Vol 9 (12) ◽  
pp. 2095-2103 ◽  
Author(s):  
By Lee H. Pai ◽  
Michael A. Bookman ◽  
Robert F. Ozols ◽  
Robert C. Young ◽  
John W. Smith ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Peritoneal Fluid ◽  
Serum Levels ◽  
Toxic Encephalopathy ◽  
Human Brain Tissue ◽  
Pseudomonas Exotoxin ◽  
Days Of Therapy ◽  
Transient Elevation ◽  
Fluid Levels

OVB3-PE is an immunotoxin composed of a murine monoclonal antibody reactive with human ovarian cancer and conjugated to Pseudomonas exotoxin (PE). Twenty-three patients with refractory ovarian cancer were treated intraperitoneally (IP) with escalating doses of OVB3-PE to study toxicity, pharmacokinetics, antiimmunotoxin antibody formation, and antitumor response. Dose-limiting CNS toxicity occurred after repeated doses at 5 and 10 micrograms/kg. Other non-dose-limiting toxicities included transient elevation of liver enzymes, fever, and gastrointestinal toxicity. Pharmacokinetics of IP and serum OVB3-PE were determined in 16 patients. Peak peritoneal fluid levels exceeded the in vitro median effective dose at all doses tested. At doses of 1 to 2 micrograms/kg, the immunotoxin concentration in the peritoneal fluid remained constant for up to 8 hours and dropped to negligible levels after 12 hours. At the 5 and 10 micrograms/kg doses, levels remained high for up to 24 hours (greater than 100 ng/mL) and then gradually decreased and became undetectable (less than 4 ng/mL) after 72 hours. Serum levels of OVB3-PE were also analyzed in 16 patients. At doses of 1 micrograms/kg and 2 micrograms/kg, serum levels were not detectable (less than 5 ng/mL). However, after doses of 5 or 10 micrograms/kg, peak serum level occurred at 24 hours after each dose and dropped to negligible levels by 72 hours. Sera from 12 patients were analyzed for anti-PE antibodies and antibodies to mouse immunoglobulin (HAMA). All patients developed antibodies against PE within 14 days of therapy. Domain II of PE appeared to be the most immunogenic portion of the PE molecule. HAMA was detected on day 14 of therapy in nine patients, on day 21 in two, and on day 28 in one patient. No clinical antitumor responses were observed. We conclude that IP OVB3-PE at dose levels of 5 micrograms/kg (x 3) and 10 micrograms/kg (x 2) is accompanied by dose-limiting toxic encephalopathy. Neurologic toxicity is likely to be due to crossreactivity of OVB3 to normal human brain tissue, which was not appreciated during preclinical screening.

scholarly journals Endoprotease PACE4 is Ca2+-dependent and temperature-sensitive and can partly rescue the phenotype of a furin-deficient cell strain

1999 ◽  
Vol 339 (3) ◽  
pp. 639-647 ◽  
Author(s):  
Joseph F. SUCIC ◽  
Joan M. MOEHRING ◽  
Noel M. INOCENCIO ◽  
Jason W. LUCHINI ◽  
Thomas J. MOEHRING
Keyword(s):  
Secretory Pathway ◽  
Protective Antigen ◽  
Chinese Hamster ◽  
Northern Analysis ◽  
Temperature Sensitive ◽  
Exotoxin A ◽  
Wild Type ◽  
Pseudomonas Exotoxin ◽  
Pseudomonas Exotoxin A

PACE4 is a member of the eukaryotic subtilisin-like endoprotease family. The expression of human PACE4 in RPE.40 cells (furin-null mutants derived from Chinese hamster ovary K1 cells) resulted in the rescue of a number of wild-type characteristics, including sensitivity to Sindbis virus and the ability to process the low-density-lipoprotein receptor-related protein. Expression of PACE4 in these cells failed to restore wild-type sensitivity to Pseudomonas exotoxin A. Co-expression of human PACE4 in these cells with either a secreted form of the human insulin pro-receptor or the precursor form of von Willebrand factor resulted in both proproteins being processed; RPE.40 cells were unable to process either precursor protein in the absence of co-expressed PACE4. Northern analysis demonstrated that untransfected RPE.40 cells express mRNA species for four PACE4 isoforms, suggesting that any endogenous PACE4 proteins produced by these cells are either non-functional or sequestered in a compartment outside of the secretory pathway. In experiments in vitro, PACE4 processed diphtheria toxin and anthrax toxin protective antigen, but not Pseudomonas exotoxin A. The activity of PACE4 in vitro was Ca2+-dependent and, unlike furin, was sensitive to temperature changes between 22 and 37 °C. RPE.40 cells stably expressing human PACE4 secreted an endoprotease with the same Ca2+ dependence and temperature sensitivity as that observed in membrane fractions of these cells assayed in vitro. These results, in conjunction with other published work, demonstrate that PACE4 is an endoprotease with more stringent substrate specificity and more limited operating parameters than furin.

scholarly journals In Vitro Evaluation of Vegf-Pseudomonas Exotoxin: A Conjugated on Tumor Cells

2017 ◽  
Vol 6 (1) ◽  
pp. 144
Author(s):  
Morteza Karimipoor ◽  
Jahangir Langari ◽  
Majid Golkar ◽  
Hossein Khanahmad ◽  
Sirous Zeinali ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Exotoxin A ◽  
Pseudomonas Exotoxin ◽  
In Vitro Evaluation ◽  
Pseudomonas Exotoxin A

Biological activity of a transforming growth factor-alpha-Pseudomonas exotoxin fusion protein in vitro and in vivo

1991 ◽  
Vol 7 (3) ◽  
pp. 203-207 ◽  
Author(s):  
David C. Heimbrook ◽  
Steven M. Stirdivant ◽  
Janet D. Ahern ◽  
Nancy L. Balishin ◽  
Denis R. Patrick ◽  
...  
Keyword(s):  
Biological Activity ◽  
Growth Factor ◽  
Fusion Protein ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Alpha ◽  
Pseudomonas Exotoxin ◽  
Factor Alpha
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