scholarly journals Therapeutic Antibody-Induced Vascular Toxicity Due to Off-Target Activation of Nitric Oxide in Cynomolgus Monkeys

2016 ◽  
Vol 151 (2) ◽  
pp. 245-260 ◽  
Author(s):  
Rama Pai ◽  
Ning Ma ◽  
Anu V. Connor ◽  
Dimitry M. Danilenko ◽  
Jacqueline M. Tarrant ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Therapeutic Antibody ◽  
Vascular Toxicity ◽  
Cynomolgus Monkeys ◽  
Target Activation

218 A preclinical study of IMC-002, a fully human therapeutic antibody safely targeting CD47 in cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A237-A237
Author(s):  
Hyeonseok Yoo ◽  
Jeong Kook Kim ◽  
Ji Yea Choi ◽  
Sun Kwang Song ◽  
Jihyun Park ◽  
...  
Keyword(s):  
T Cells ◽  
Cancer Cells ◽  
Solid Tumors ◽  
Therapeutic Antibody ◽  
List Type ◽  
Dependent Manner ◽  
Efficacy And Safety ◽  
Cynomolgus Monkeys ◽  
Hematological Cancers

BackgroundImmunotherapy with immune checkpoint inhibitors such as PD-(L)1 and CTLA-4 blocker has become an important part of cancer treatment. For the cancers resistant to these drugs, however, many other therapeutic targets are being tested to modulate the tumor microenvironment (TME) toward anti-cancer immunity. Due to the functional flexibility, macrophages play an essential role in orchestrating tissue immunity including TME. CD47 is one of the key targets that modulate macrophages, which is often overexpressed on cancer cells.1 When it binds to its receptor, SIRPα, it gives a ‘don’t-eat-me’ signal and inhibits phagocytosis of cancer cells by macrophages.2 IMC-002 is a fully human IgG4 monoclonal antibody targeting human CD47, which has been engineered to possess optimal efficacy and safety profile. IMC-002 does not induce hemagglutination and contains a hinge stabilizing S228P mutation to prevent Fab arm exchange.MethodsA series of in vitro functional assays including ligand binding, cell surface binding and phagocytosis assays were performed. Putative epitopes for IMC-002 were identified using synthetic peptide libraries. In vivo efficacy of IMC-002 was tested in human breast cancer models. Pharmacokinetic parameters and toxicity profiles were assessed in mice and cynomolgus monkeys.ResultsIMC-002 strongly bound to CD47 ligand and to various types of CD47-expressing cancer cells including solid and hematological cancers. IMC-002 also bound to human CD4 T cells and, to a lesser degree, to CD8 T cells, but not to NK or B cells. Interestingly, IMC-002 showed no binding to RBCs which highly express CD47 and thus, did not induce RBC agglutination in vitro. IMC-002 induced phagocytosis of cancer cells by human blood CD14+ monocyte-derived macrophages and strongly suppressed tumor growth in a dose-dependent manner in xenograft animal models. Treating IMC-002 with tumor antigen targeting IgG1 type therapeutics increased phagocytosis compared to single treatment. Epitope mapping analysis revealed that compared to RBC-binding anti-CD47 antibody and a natural ligand, SIRRα-Fc, IMC-002 bound to distinct parts of CD47 antigen, which may be responsible for the cell-selective binding of IMC-002. Consistent with the in vitro data, IMC-002 was well tolerated in cynomolgus monkeys with no adverse effects including hematologic toxicity at doses up to 100 mg/kg. IMC-002 showed a typical pharmacokinetic profile of therapeutic antibody with a half-life of 5–10 days. Given its differential binding profile toward tumor cells vs normal cells such as RBC, preclinical data was thoroughly analyzed to simulate human PK and to come up with the optimal first-in-human dose.ConclusionsPreclinical efficacy and safety profiles of IMC-002 provide a strong rationale for assessing therapeutic potential in clinical studies. Particularly, IMC-002 is expected to be beneficial for hematologic cancer patients because it has been engineered to minimize hematological toxicities such as anemia which is a class effect of the CD47-targeting antibodies. The first-in-human (FIH) study of IMC-002 is ongoing in the US sites. The purpose of the study is to assess the safety and tolerability of IMC-002 and determine the recommended Phase 2 dose (RP2D) of IMC-002 in subjects with metastatic or locally advanced solid tumors and relapsed or refractory lymphomas.Ethics ApprovalAll experimental procedures were performed according to the guidelines of the Institutional Animal Care and Use Committee (IACUC) of the contract research organizations.ReferencesWillingham, S. B. et al. The CD47-signal regulatory protein alpha (SIRPα) interaction is a therapeutictarget for human solid tumors. Proc. Natl Acad. Sci. USA 2012;109:6662–6667.Majeti, R. et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 2009;138:286–299.

Intracranial Delivery of the Nitric Oxide Donor Diethylenetriamine/Nitric Oxide from a Controlled-Release Polymer: Toxicity in Cynomolgus Monkeys

Neurosurgery ◽  
2006 ◽  
Vol 58 (5) ◽  
pp. 952-960 ◽  
Author(s):  
Travis S. Tierney ◽  
Gustavo Pradilla ◽  
Paul P. Wang ◽  
Richard E. Clatterbuck ◽  
Rafael J. Tamargo
Keyword(s):  
Nitric Oxide ◽  
Controlled Release ◽  
Nitric Oxide Donor ◽  
Cynomolgus Monkeys ◽  
Controlled Release Polymer

scholarly journals Mechanism of Vascular Toxicity in Rats Subjected to Treatment with a Tyrosine Kinase Inhibitor

Toxics ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 49
Author(s):  
Claudia Reyes-Goya ◽  
Álvaro Santana-Garrido ◽  
Estefanía Soto-Astacio ◽  
Óscar Aramburu ◽  
Sonia Zambrano ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nadph Oxidase ◽  
Tyrosine Kinase ◽  
Arterial Hypertension ◽  
Tyrosine Kinase Inhibitor ◽  
Vascular Remodeling ◽  
Kinase Inhibitor ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Superoxide Anion Production ◽  
Vascular Toxicity

Sunitinib (Su) is a tyrosine kinase inhibitor with antiangiogenic and antineoplastic effects that is recommended therapy for renal cell carcinoma, gastrointestinal stromal tumors, and pancreatic neuroendocrine tumors. Arterial hypertension is one of the adverse effects observed in the treatment with Su. The aim of this work was to deepen our understanding of the underlying mechanisms involved in the development of this side effect. Studies on endothelial function, vascular remodeling and nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) system were carried out in thoracic aortas from rats treated with Su for three weeks. Animals subjected to Su treatment presented with increased blood pressure and reduced endothelium-dependent vasodilation, the latter being reverted by NADPH oxidase blockade. Furthermore, vascular remodeling and stronger Masson trichrome staining, together with enhanced immunofluorescence signal for collagen 1 alpha 1 (Col1α1), were observed in aortas from treated animals. These results were accompanied by a significant elevation in superoxide anion production and the activity/protein/gene expression of NADPH oxidase isoforms (NOX1, NOX2, and NOX4), which was also prevented by NOX inhibition. Furthermore, a decrease in nitric oxide (NO) levels and endothelial nitric oxide synthase (eNOS) activation was observed in aortas from Su-treated animals. All these results indicate that endothelial dysfunction secondary to changes in vascular remodeling and oxidative stress might be responsible for the typical arterial hypertension that develops following treatment with Su.

Eotaxin and Nitric Oxide Production as Markers of Inflammation in Allergic Cynomolgus Monkeys

1999 ◽  
Vol 120 (3) ◽  
pp. 209-217 ◽  
Author(s):  
Simon S. Young ◽  
Gretchen Ritacco ◽  
Susan Skeans ◽  
Richard W. Chapman
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Production ◽  
Cynomolgus Monkeys ◽  
Oxide Production ◽  
Markers Of Inflammation

Hexachlorobenzene toxicity in the monkey ovary: III. Ultrastructure induced by high (10 mg/kg) dose exposure

1991 ◽  
Vol 49 ◽  
pp. 130-131
Author(s):  
A. Singh ◽  
A. Dykeman ◽  
J. Jarrelf ◽  
D. C. Villeneuve
Keyword(s):  
Present Report ◽  
Reproductive Toxicity ◽  
Control Group ◽  
Primate Model ◽  
Human Follicular Fluid ◽  
Thin Sections ◽  
Cynomolgus Monkeys ◽  
Cacodylate Buffer ◽  
Induction Cycle ◽  
Comprehensive Study

Hexachlorobenzene (HCB), a persistent and mobile organochlorine pesticide, occurs in environment. HCB has been shown to be present in human follicular fluid. An objective of the present report, which is part of a comprehensive study on reproductive toxicity of HCB, was to determine the cytologic effects of the compound on ovarian follicles in a primate model.Materials and Methods. Eight Cynomolgus monkeys were housed under controlled conditions at Animal facility of Health and Welfare, Ottawa. Animals were orally administered gelatin capsules containing HCB mixed with glucose in daily dosages of 0.0 or 10 mg/kg b.w. for 90 days; the former was the control group. On the menstrual period following completion of dosing, the monkeys underwent an induction cycle of superovulation. At necropsy, one-half of an ovary from each animal was diced into ca. 2- to 3-mm cubed specimens that were fixed by immersion in 2.5% glutaraldehyde in 0.1 M cacodylate buffer (pH 7.3). Subsequent procedures followed to obtain thin sections that were examined in a Hitachi H-7000 electron microscope have been described earlier.

Localization of endothelial nitric oxide synthase in the normal and failing human atrial myocardium

1996 ◽  
Vol 54 ◽  
pp. 786-787
Author(s):  
Chi-Ming Wei ◽  
Margarita Bracamonte ◽  
Shi-Wen Jiang ◽  
Richard C. Daly ◽  
Christopher G.A. McGregor ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
Cardiac Tissues ◽  
Mammalian Tissues ◽  
End Stage Heart Failure ◽  
End Stage ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Nitric oxide (NO) is a potent endothelium-derived relaxing factor which also may modulate cardiomyocyte inotropism and growth via increasing cGMP. While endothelial nitric oxide synthase (eNOS) isoforms have been detected in non-human mammalian tissues, expression and localization of eNOS in the normal and failing human myocardium are poorly defined. Therefore, the present study was designed to investigate eNOS in human cardiac tissues in the presence and absence of congestive heart failure (CHF).Normal and failing atrial tissue were obtained from six cardiac donors and six end-stage heart failure patients undergoing primary cardiac transplantation. ENOS protein expression and localization was investigated utilizing Western blot analysis and immunohistochemical staining with the polyclonal rabbit antibody to eNOS (Transduction Laboratories, Lexington, Kentucky).

Nitric Oxide Reduces Pressor Responsiveness During Ovine Hypoadrenocorticism

2001 ◽  
Vol 28 (5-6) ◽  
pp. 459-462
Author(s):  
Pini Orbach ◽  
Charles E Wood ◽  
Maureen Keller-Wood
Keyword(s):  
Nitric Oxide
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