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Ghaderi D.,University of California at San Diego | Ghaderi D.,Sialix Inc. | Taylor R.E.,University of California at San Diego | Padler-Karavani V.,University of California at San Diego | And 2 more authors.
Nature Biotechnology | Year: 2010

Recombinant glycoprotein therapeutics produced in nonhuman mammalian cell lines and/or with animal serum are often modified with the nonhuman sialic acid N-glycolylneuraminic acid (Neu5Gc; refs. 1,2). This documented contamination has generally been ignored in drug development because healthy individuals were not thought to react to Neu5Gc (ref. 2). However, recent findings indicate that all humans have Neu5Gc-specific antibodies, sometimes at high levels. Working with two monoclonal antibodies in clinical use, we demonstrate the presence of covalently bound Neu5Gc in cetuximab (Erbitux) but not panitumumab (Vectibix). Anti-Neu5Gc antibodies from healthy humans interact with cetuximab in a Neu5Gc-specific manner and generate immune complexes in vitro. Mice with a human-like defect in Neu5Gc synthesis generate antibodies to Neu5Gc after injection with cetuximab, and circulating anti-Neu5Gc antibodies can promote drug clearance. Finally, we show that the Neu5Gc content of cultured human and nonhuman cell lines and their secreted glycoproteins can be reduced by adding a human sialic acid to the culture medium. Our findings may be relevant to improving the half-life, efficacy and immunogenicity of glycoprotein therapeutics. © 2010 Nature America, Inc. All rights reserved. Source


Cowden J.M.,Janssen Research and Development LLC | Cowden J.M.,Takeda California | Yu F.,Janssen Research and Development LLC | Banie H.,Janssen Research and Development LLC | And 9 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Objective The histamine H4 receptor (H4R) has been shown to drive inflammatory responses in models of asthma, colitis and dermatitis, and in these models it appears to affect both innate and adaptive immune responses. In this study, we used both H4R-deficient mice and a specific H4R antagonist, JNJ 28307474, to investigate the involvement of the H4R in mouse arthritis models. Methods H 4R-deficient mice and wild-type mice administered the H4R antagonist were studied in models of collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis (CIA). The impact on Th17 cells was assessed by restimulation of inguinal lymphocytes in the disease or immunisation models and with in vitro stimulation of whole blood. Results Both H4R-deficient mice and mice treated with the H4R antagonist exhibited reduced arthritis disease severity in both CAIA and CIA models. This was evident from the reduction in disease score and in joint histology. In the CIA model, treatment with the H4R antagonist reduced the number of interleukin (IL)-17 positive cells in the lymph node and the total production of IL-17. Th17 cell development in vivo was reduced in H4R-deficient mice or in mice treated with an H4R antagonist. Finally, treatment of both mouse and human blood with an H4R antagonist reduced the production of IL-17 when cells were stimulated in vitro. Conclusions These results implicate the H4R in disease progression in arthritis and in the production of IL-17 from Th17 cells. This work supports future clinical exploration of H 4R antagonists for the treatment of rheumatoid arthritis. Source


Cowden J.M.,Janssen Research and Development LLC | Yu F.,Janssen Research and Development LLC | Challapalli M.,Janssen Research and Development LLC | Huang J.-F.,La Jolla BioConsulting | And 7 more authors.
Inflammation Research | Year: 2013

Objective: Antagonism of the histamine H4 receptor (H 4R) has been shown to be anti-inflammatory in a number of preclinical disease models, however the exact mechanisms behind this are still being uncovered. In vitro, the receptor interacts with TLR and impacts inflammatory mediator production from a number of different cell types. Here it is shown that this interaction also occurs in vivo. Materials and methods: Wild-type and H4R deficient BALB/c mice received an i.p. injection of LPS in PBS in conjunction with p.o. JNJ 7777120 or JNJ 28307474 (H4R antagonists). Two hours later blood was collected and TNF was measured. Results: Two different H4R antagonists inhibited LPS-induced TNF production in mice and this production was also reduced in H4R-deficient mice. The TNF mRNA analysis showed that the major source of the cytokine was the liver and not blood, and that the H4R antagonist only reduced the expression levels in the liver. Depletion or inactivation of macrophages reduced the TNF levels and eliminated the H4R sensitivity. Treatment with an H 4R antagonist also reduced LPS-induced liver injury and blocked LPS-enhanced lung inflammation in mice. Conclusion: The data support an interaction between H4R and TLR activation in vivo that can drive inflammatory responses. © 2013 The Author(s). Source


Trademark
Siamab Therapeutics and Sialix Inc. | Date: 2016-02-16

Biochemicals, namely, monoclonal antibodies for in vitro scientific or research use; Diagnostic kits consisting of monoclonal antibodies, buffers, and reagents to monitor toxicity of drugs; Laboratory chemicals, namely, antibody reagents used for the detection of antigens in cell and tissue analysis for in vitro diagnostic use. Medical, biological and pharmaceutical preparations for scientific, research, medical or pharmaceutical use, namely, monoclonal antibodies for treating cancer, immune disorders, inflammation, neoplasms, rare diseases, genetic diseases, inborn error of metabolism and auto-immune diseases. Scientific research; scientific research in the fields of biochemicals, namely, monoclonal antibodies; scientific research in the fields of diagnostic kits, consisting of monoclonal antibodies, buffers, and reagents to monitor toxicity of drugs; scientific research in the field of laboratory chemicals, namely, antibody reagents used for the detection of antigens in cell and tissue analysis for in vitro diagnostic use.


Trademark
Siamab Therapeutics and Sialix Inc. | Date: 2016-02-16

Biochemicals, namely, monoclonal antibodies for in vitro scientific or research use; Diagnostic kits consisting of monoclonal antibodies, buffers, and reagents to monitor toxicity of drugs; Laboratory chemicals, namely, antibody reagents used for the detection of antigens in cell and tissue analysis for in vitro diagnostic use. Medical, biological and pharmaceutical preparations for scientific, research, medical or pharmaceutical use, namely, monoclonal antibodies for treating cancer, immune disorders, inflammation, neoplasms, rare diseases, genetic diseases, inborn error of metabolism and auto-immune diseases. Scientific research; scientific research in the fields of biochemicals, namely, monoclonal antibodies; scientific research in the fields of diagnostic kits, consisting of monoclonal antibodies, buffers, and reagents to monitor toxicity of drugs; scientific research in the field of laboratory chemicals, namely, antibody reagents used for the detection of antigens in cell and tissue analysis for in vitro diagnostic use.

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