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Raju T.S.,Janssen Research and Development L.L.C. | Lang S.E.,Janssen Research and Development L.L.C.
Current Opinion in Biotechnology | Year: 2014

Terminal sialic acid residues of glycoconjugates exhibit remarkable functional and structural diversity. They affect biological activity, serum half-life and structural stability of glycoproteins. Alternatively, they act as mediators for pathogens to invade host systems. These surface exposed N-glycans are easily accessible for interactions with receptors, enzymes, etc. In contrast, Fc N-glycans of IgGs are sequestered within the two CH2 domains and exhibit high degree of heterogeneity. They are required for antibody effector functions including binding to C1q protein. Biological significance of Fc glycans has been extensively studied and importance of terminal galactose, bisecting GlcNAc and core fucose has been realized. This review focuses on the recent advances in structure and functions of terminal sialic acid residues of Fc glycans. © 2014 Elsevier Ltd.


Shantha Raju T.,Janssen Research and Development LLC | Jordan R.E.,Janssen Research and Development LLC
mAbs | Year: 2012

There are currently~25 recombinant full-length IgGs (rIgGs) in the market that have been approved by regulatory agencies as biotherapeutics to treat various human diseases. Most of these are based on IgG1k framework and are either chimeric, humanized or human antibodies manufactured using either Chinese hamster ovary (CHO) cells or mouse myeloma cells as the expression system. Because CHO and mouse myeloma cells are mammalian cells, rIgGs produced in these cell lines are typically N-glycosylated at the conserved asparagine (Asn) residues in the CH2 domain of the Fc, which is also the case with serum IgGs. The Fc glycans present in these rIgGs are for the most part complex biantennary oligosaccharides with heterogeneity associated with the presence or the absence of several different terminal sugars. The major Fc glycans of rIgGs contain 0 or 1 or 2 (G0, G1 and G2, respectively) terminal galactose residues as non-reducing termini and their relative proportions may vary depending on the cell culture conditions in which they were expressed. Since glycosylation is strongly associated with antibody effector functions and terminal galactosylation may affect some of those functions, a panel of commercially-available therapeutic rIgGs expressed in CHO cells and mouse myeloma cells were examined for their galactosylation patterns. The results suggest that the rIgGs expressed in CHO cells are generally less galactosylated compared with the rIgGs expressed in mouse myeloma cells. Accordingly, rIgGs produced in CHO cells tend to contain higher levels of G0 glycans compared with rIgGs produced in mouse myeloma cell lines. Despite the apparent wide variability in galactose content, adverse events or safety issues have not been associated with specific galactosylation patterns of therapeutic antibodies. Nevertheless, galactosylation may have an effect on the mechanisms of action of some therapeutic antibodies (e.g., effector pathways) and hence further studies to assess effects on product efficacy may be warranted for such antibodies. For antibodies that do not require effector functions for biological activity, however, setting a narrow specification range for galactose content may be unnecessary. © 2012 Landes Bioscience.


Raju T.S.,Janssen Research and Development LLC
Methods in Molecular Biology | Year: 2013

Recombinant monoclonal antibodies (rMAbs) are becoming major human therapeutics to treat lifethreatening diseases such as cancer. These rMAbs are produced using either in vitro cell culture processes or transgenic technology in animals or plants. Glycans present in the Fc region can affect functions of rMAbs. These Fc glycans are heterogeneous and impact binding of rMAbs to Fc gamma receptors (FcγRs) and C1q protein. As a result Fc glycans affect antibody-dependent cellular cytotoxicity and complementdependent cytotoxicity of rMAbs. Thus understanding the glycan heterogeneity is necessary during the development of these rMAbs as human therapeutics. Because of their biological significance, understanding the glycan structure and their impact on the function of antibody molecules is also a regulatory requirement. Glycan mapping by NP-HPLC with fluorescence detection is a sensitive and reproducible method. Labeling of released glycans with anthranilic acid (AA) using reductive amination procedure improves sensitivity of detection. The NP-HPLC method resolves both neutral and sialylated glycans, thus enabling the user to obtain a broad heterogeneity profile of Fc glycans in a single run. Added advantage of the method is that the labeled glycans can be characterized using mass spectrometry and the method is also amenable for LC-MS analysis. © Springer Science+Business Media New York 2013.


Erondu N.,Janssen Research and Development LLC | Desai M.,Janssen Research and Development LLC | Ways K.,Janssen Research and Development LLC | Meininger G.,Janssen Research and Development LLC
Diabetes Care | Year: 2015

OBJECTIVE This study assessed the incidence of serious adverse events of diabetic ketoacidosis (DKA) among patients with type 2 diabetes treated with canagliflozin. RESEARCH DESIGN AND METHODS All serious adverse events of DKA and related events (ketoacidosis, metabolic acidosis, and acidosis) from 17,596 patients from randomized studies of canagliflozin through 11 May 2015 were analyzed. RESULTS Serious adverse events of DKA and related events were reported in 12 patients (0.07%), including 4 (0.07%), 6 (0.11%), and 2 (0.03%) treated with canagliflozin 100 and 300 mg and comparator, respectively; corresponding incidence rates were 0.522, 0.763, and 0.238 per 1,000 patient-years, respectively. Most patients with DKA and related events had a blood glucose >300 mg/dL (16.7 mmol/L) at presentation of DKA,were on insulin, and had DKA-precipitating factors, including some with type 1 diabetes/latent autoimmune diabetes of adulthood. CONCLUSIONS DKA and related events occurred at a low frequency in the canagliflozin type 2 diabetes program, with an incidence consistent with limited existing observational data in the general population with type 2 diabetes. ©2015 by the American Diabetes Association.


Bugelski P.J.,Janssen Research and Development Inc. | Martin P.L.,Janssen Research and Development Inc.
British Journal of Pharmacology | Year: 2012

Monoclonal antibodies (mAbs) and fusion proteins directed towards cell surface targets make an important contribution to the treatment of disease. The purpose of this review was to correlate the clinical and preclinical data on the 15 currently approved mAbs and fusion proteins targeted to the cell surface. The principal sources used to gather data were: the peer reviewed Literature; European Medicines Agency 'Scientific Discussions'; and the US Food and Drug Administration 'Pharmacology/Toxicology Reviews' and package inserts (United States Prescribing Information). Data on the 15 approved biopharmaceuticals were included: abatacept; abciximab; alefacept; alemtuzumab; basiliximab; cetuximab; daclizumab; efalizumab; ipilimumab; muromonab; natalizumab; panitumumab; rituximab; tocilizumab; and trastuzumab. For statistical analysis of concordance, data from these 15 were combined with data on the approved mAbs and fusion proteins directed towards soluble targets. Good concordance with human pharmacodynamics was found for mice receiving surrogates or non-human primates (NHPs) receiving the human pharmaceutical. In contrast, there was poor concordance for human pharmacodynamics in genetically deficient mice and for human adverse effects in all three test systems. No evidence that NHPs have superior predictive value was found. © 2011 The British Pharmacological Society.


Swiecki M.,University of Washington | Swiecki M.,Janssen Research AndDevelopment LLC | Colonna M.,University of Washington
Nature Reviews Immunology | Year: 2015

Plasmacytoid dendritic cells (pDCs) are a unique DC subset that specializes in the production of type I interferons (IFNs). pDCs promote antiviral immune responses and have been implicated in the pathogenesis of autoimmune diseases that are characterized by a type I IFN signature. However, pDCs can also induce tolerogenic immune responses. In this Review, we summarize recent progress in the field of pDC biology, focusing on the molecular mechanisms that regulate the development and functions of pDCs, the pathways involved in their sensing of pathogens and endogenous nucleic acids, their functions at mucosal sites, and their roles in infection, autoimmunity and cancer. © 2015 Macmillan Publishers Limited. All rights reserved.


Fung-Leung W.-P.,Janssen Research and Development L.L.C.
Annals of the New York Academy of Sciences | Year: 2013

Phosphoinositide 3-kinase gamma (PI3Kγ) kinase activity is important for its signaling functions in T cell development, activation, differentiation, and trafficking. Protection of PI3Kγ knockout mice from disease in multiple autoimmune models suggests that targeting PI3Kγ alone, or in combination with PI3Kδ, could be a promising approach to disease therapy. © 2013 New York Academy of Sciences.


Thurmond R.L.,Janssen Research and Development LLC
Frontiers in Pharmacology | Year: 2015

The histamine H4 receptor (H4R) was first noted as a sequence in genomic databases that had features of a class A G-protein coupled receptor. This putative receptor was found to bind histamine consistent with its homology to other histamine receptors and thus became the fourth member of the histamine receptor family. Due to the previous success of drugs that target the H1 and H2 receptors, an effort was made to understand the function of this new receptor and determine if it represented a viable drug target. Taking advantage of the vast literature on the function of histamine, a search for histamine activity that did not appear to be mediated by the other three histamine receptors was undertaken. From this asthma and pruritus emerged as areas of particular interest. Histamine has long been suspected to play a role in the pathogenesis of asthma, but antihistamines that target the H1 and H2 receptors have not been shown to be effective for this condition. The use of selective ligands in animal models of asthma has now potentially filled this gap by showing a role for the H4R in mediating lung function and inflammation. A similar story exists for chronic pruritus associated with conditions such as atopic dermatitis. Antihistamines that target the H1 receptor are effective in reducing acute pruritus, but are ineffective in pruritus experienced by patients with atopic dermatitis. As for asthma, animal models have now suggested a role for the H4R in mediating pruritic responses, with antagonists of the H4R reducing pruritus in a number of different conditions. The anti-pruritic effect of H4R antagonists has recently been shown in human clinical studies, validating the preclinical findings in the animal models. A selective H4R antagonist inhibited histamine-induced pruritus in health volunteers and reduced pruritus in patients with atopic dermatitis. The history to date of the H4R provides an excellent example of the deorphanization of a novel receptor and the translation of this into clinical efficacy in humans. © 2015 Thurmond.


Hu C.,Janssen Research and Development LLC
CPT: Pharmacometrics and Systems Pharmacology | Year: 2014

Exposure-response modeling facilitates effective dosing regimen selection in clinical drug development, where the end points are often disease scores and not physiological variables. Appropriate models need to be consistent with pharmacology and identifiable from the time courses of available data. This article describes a general framework of applying mechanism-based models to various types of clinical end points. Placebo and drug model parameterization, interpretation, and assessment are discussed with a focus on the indirect response models. © 2014 ASCPT All rights reserved 2163-8306/14.


Polidori D.,Janssen Research and Development LLC | Mari A.,National Research Council Italy | Ferrannini E.,University of Pisa
Diabetologia | Year: 2014

Aims/hypothesis: In rodent models of diabetes, treatment with sodium glucose co-transporter 2 (SGLT2) inhibitors improves beta cell function. This analysis assessed the effects of the SGLT2 inhibitor, canagliflozin, on model-based measures of beta cell function in patients with type 2 diabetes. Methods: Data from three Phase 3 studies were analysed, in which: (Study 1) canagliflozin 100 and 300 mg were compared with placebo as monotherapy for 26 weeks; (Study 2) canagliflozin 100 and 300 mg were compared with placebo as add-on to metformin∈+∈sulfonylurea for 26 weeks; or (Study 3) canagliflozin 300 mg was compared with sitagliptin 100 mg as add-on to metformin∈+∈sulfonylurea for 52 weeks. In each study, a subset of patients was given mixed-meal tolerance tests at baseline and study endpoint, and model-based beta cell function parameters were calculated from plasma glucose and C-peptide. Results: In Studies 1 and 2, both canagliflozin doses increased beta cell glucose sensitivity compared with placebo. Placebo-subtracted least squares mean (LSM) (SEM) changes were 23 (9) and 18 (9) pmol min-1 m-2 (mmol/l)-1 with canagliflozin 100 and 300 mg, respectively (p<0.002, Study 1), and 16 (8) and 10 (9) pmol min-1 m-2 (mmol/l)-1 (p<0.02, Study 2). In Study 3, beta cell glucose sensitivity was minimally affected, but the insulin secretion rate at 9 mmol/l glucose increased to similar degrees from baseline with canagliflozin and sitagliptin [LSM (SEM) changes 38 (8) and 28 (9) pmol min-1 m-2, respectively; p<0.05 for both]. Conclusions/interpretation: Treatment with canagliflozin for 6 to 12 months improved model-based measures of beta cell function in three separate Phase 3 studies. Trial registration: Clinicaltrials.gov NCT01081834 (Study 1); NCT01106625 (Study 2); NCT01137812 (Study 3) © 2014 The Author(s).

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