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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.


Cowden J.M.,Janssen Research and Development L.L.C. | Cowden J.M.,Takeda California | Yu F.,Janssen Research and Development L.L.C. | Banie H.,Janssen Research and Development L.L.C. | 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.


Ghaderi D.,Sialix Inc. | Zhang M.,Sialix Inc. | Hurtado-Ziola N.,Sialix Inc. | Varki A.,University of California at San Diego
Biotechnology and Genetic Engineering Reviews | Year: 2012

One of the fastest growing fields in the pharmaceutical industry is the market for therapeutic glycoproteins. Today, these molecules play a major role in the treatment of various diseases, and include several protein classes, i.e., clotting factors, hormones, cytokines, antisera, enzymes, enzyme inhibitors, Ig-Fc-Fusion proteins, and monoclonal antibodies. Optimal glycosylation is critical for therapeutic glycoproteins, as glycans can influence their yield, immunogenicity and efficacy, which impact the costs and success of such treatments. While several mammalian cell expression systems currently used can produce therapeutic glycoproteins that are mostly decorated with human-like glycans, they can differ from human glycans by presenting two structures at the terminal and therefore most exposed position. First, natural human N-glycans are lacking the terminal Galα1-3Gal (alpha-Gal) modification; and second, they do not contain the non-human sialic acid N-glycolylneuraminic acid (Neu5Gc). All humans spontaneously express antibodies against both of these glycan structures, risking increased immunogenicity of biotherapeutics carrying such non-human glycan epitopes. However, in striking contrast to the alpha-Gal epitope, exogenous Neu5Gc can be metabolically incorporated into human cells and presented on expressed glycoproteins in several possible epitopes. Recent work has demonstrated that this non-human sialic acid is found in widely varying amounts on biotherapeutic glycoproteins approved for treatment of various medical conditions. Neu5Gc on glycans of these medical agents likely originates from the production process involving the non-human mammalian cell lines and/or the addition of animalderived tissue culture supplements. Further studies are needed to fully understand the impact of Neu5Gc in biotherapeutic agents. Similar concerns apply to human cells prepared for allo- or auto- transplantation, that have been grown in animal-derived tissue culture supplements.


Trademark
Sialix Inc. | Date: 2010-05-05

Diagnostic kits consisting primarily of monoclonal antibodies, buffers, and reagents for use in disease testing.


Trademark
Sialix Inc. | Date: 2011-05-17

Biochemicals, namely, monoclonal antibodies for in vitro scientific or research use; Diagnostic kits consisting primarily of monoclonal antibodies, buffers, and reagents to monitor toxicity of drugs; Laboratory chemicals, namely, an antibody reagent used for the detection of antigens in cell and tissue analysis for in vitro diagnostic use. Diagnostic kits consisting primarily of monoclonal antibodies, buffers, and reagents for use in disease testing.


Trademark
Sialix Inc. | Date: 2012-01-31

Biochemicals, namely, monoclonal antibodies for in vitro scientific or research use; Diagnostic kits consisting primarily of monoclonal antibodies, buffers, and reagents to monitor toxicity of drugs; Laboratory chemicals, namely, an antibody reagent used for the detection of antigens in cell and tissue analysis for in vitro diagnostic use.


Patent
The Regents Of The University Of California and Sialix Inc. | Date: 2014-01-01

The invention provides sialylated glycans and antibodies that specifically bind to them. The inventions compositions and methods for using them are useful for early detection and diagnosis of cancer.


Patent
Sialix Inc | Date: 2013-10-10

The present invention provides glycan-interacting antibodies useful in the treatment and prevention of human disease, including cancer. Such glycan-interacting antibodies include monoclonal antibodies, derivatives and fragments thereof as well as compositions and kits comprising them.


Trademark
Sialix Inc. | Date: 2014-06-09

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 in vitro scientific or research use. 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
Sialix Inc. | Date: 2014-06-09

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 in vitro scientific or research use. 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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