John M. Delaney
Amgen
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Publication
Featured researches published by John M. Delaney.
Nature Immunology | 2000
Gang Yu; Tom Boone; John M. Delaney; Nessa Hawkins; Michael Kelley; Meena Ramakrishnan; Susan McCabe; Wanrong Qiu; Masayo Kornuc; Xing-Zhong Xia; Jane Guo; Marina Stolina; William J. Boyle; Ildiko Sarosi; Hailing Hsu; Giorgio Senaldi; Lars Eyde Theill
We report that the tumor neurosis factor homolog APRIL (a proliferation-inducing ligand) stimulates in vitro proliferation of primary B and T cells and increases spleen weight due to accumulation of B cells in vivo. APRIL functions via binding to BCMA (B cell maturation antigen) and TACI (transmembrane activator and CAML-interactor) and competes with TALL-1 (also called BLyS or BAFF) for receptor binding. Soluble BCMA and TACI specifically prevent binding of APRIL and block APRIL-stimulated proliferation of primary B cells. BCMA-Fc also inhibits production of antibodies against keyhole limpet hemocyanin and Pneumovax in mice, indicating that APRIL and/or TALL-1 signaling via BCMA and/or TACI are required for generation of humoral immunity. Thus, APRIL–TALL-1 and BCMA-TACI form a two ligands–two receptors pathway involved in stimulation of B and T cell function.
Journal of Biological Chemistry | 1997
Shuqian Jing; Yanbin Yu; Mei Fang; Zheng Hu; Paige Holst; Thomas C. Boone; John M. Delaney; Henry Schultz; Renping Zhou; Gary M. Fox
The receptor for glial cell line-derived neurotrophic factor (GDNF) consists of GFRα-1 and Ret. Neurturin is a GDNF-related neurotrophin whose receptor is presently unknown. Here we report that neurturin can bind to either GFRα-1 or GFRα-2, a novel receptor related to GFRα-1. Both GFRα-1 and GFRα-2 mediate neurturin-induced Ret phosphorylation. GDNF can also bind to either GFRα-1 or GFRα-2, and activate Ret in the presence of either binding receptor. Although both ligands interact with both receptors, cells expressing GFRα-1 bind GDNF more efficiently than neurturin, while cells expressing GFRα-2 bind neurturin preferentially. Cross-linking and Ret activation data also suggest that while there is cross-talk, GFRα-1 is the primary receptor for GDNF and GFRα-2 exhibits a preference for neurturin. We have also cloned a cDNA that apparently codes for a third member of the GFRα receptor family. This putative receptor, designated GFRα-3, is closely related in amino acid sequence and is nearly identical in the spacing of its cysteine residues to both GFRα-1 and GFRα-2. Analysis of the tissue distribution of GFRα-1, GFRα-2, GFRα-3, and Ret by Northern blot reveals overlapping but distinct patterns of expression. Consistent with a role in GDNF function, the GFRαs and Ret are expressed in many of the same tissues, suggesting that GFRαs mediate the action of GDNF family ligands in vivo.
Protein Science | 2010
Jane Carter; Jue Zhang; Thien-Lan Dang; Haruki Hasegawa; Janet D. Cheng; Irene Gianan; Jason W. O'Neill; Martin Wolfson; Sophia Siu; Sheldon Qu; David Park Meininger; Helen Y. Kim; John M. Delaney; Christopher Mehlin
The expression levels of five secreted target interleukins (IL‐11, 15, 17B, 32, and IL23 p19 subunit) were tested with three different fusion partners in 2936E cells. When fused to the N‐terminus, human serum albumin (HSA) was found to enhance the expression of both IL‐17B and IL‐15, cytokines which did not express at measurable levels on their own. Although the crystallizable fragment of an antibody (Fc) was also an effective fusion partner for IL‐17B, Fc did not increase expression of IL‐15. Fc was superior to HSA for the expression of the p19 subunit of IL‐23, but no partner led to measurable levels of IL‐32γ secretion. Glutathione S‐transferase (GST) did not enhance the expression of any target and suppressed the production of IL‐11, a cytokine which expressed robustly both on its own and when fused to HSA or Fc. Cleavage of the fusion partner was not always possible. The use of HSA or Fc as N‐terminal fusions can be an effective technique to express difficult proteins, especially for applications in which the fusion partner need not be removed.
Current Pharmaceutical Biotechnology | 2010
Jue Zhang; Jane Carter; Sophia Siu; Jason W. O'Neill; Andrew H. Gates; John M. Delaney; Christopher Mehlin
The expression of proteins which do not express well on their own can be enhanced by linking them to human serum albumin (HSA) or antibody crystallizable fragment (Fc). The constructs shown here are designed to secrete the proteins after transient transfection of mammalian cell lines. The fusion partners are appended to the N-terminus of the proteins and contain a linker designed to be proteolytically cleaved. Transient transfection and purification protocols are provided as well as experimental results with five interleukins.
Arthritis & Rheumatism | 2015
Ming Zhang; Gang Yu; Brian Mingtung Chan; Joshua T. Pearson; Palaniswami Rathanaswami; John M. Delaney; Ai Ching Lim; John Babcook; Hailing Hsu; Marc A. Gavin
Systemic lupus erythematosus (SLE) is a complex autoimmune disease that is driven in part by chronic B and T lymphocyte hyperresponsiveness to self antigens. A deficiency of interleukin‐21 (IL‐21) or IL‐21 receptor (IL‐21R) in mice dramatically reduces inflammation and B and T cell activation in models of autoimmunity, including SLE. However, whether IL‐21 is essential for the maintenance and amplification of preestablished inflammation has not been widely examined in various animal models. The purpose of this study was to examine the impact of novel mouse IL‐21R neutralizing antibodies on recall responses to antigen challenge and on disease progression in the (NZB × NZW)F1 (NZB/NZW) mouse model of SLE.
Journal of Biological Chemistry | 2016
Ruwanthi N. Gunawardane; Preston Fordstrom; Derek E. Piper; Stephanie Masterman; Sophia Siu; Dongming Liu; Michael Brown; Mei Lu; Jie Tang; Richard Zhang; Janet D. Cheng; Andrew H. Gates; David Park Meininger; Joyce Chi Yee Chan; Tim Carlson; Nigel Walker; Margrit Schwarz; John M. Delaney; Mingyue Zhou
Drug discovery opportunities where loss-of-function alleles of a target gene link to a disease-relevant phenotype often require an agonism approach to up-regulate or re-establish the activity of the target gene. Antibody therapy is increasingly recognized as a favored drug modality due to multiple desirable pharmacological properties. However, agonistic antibodies that enhance the activities of the target enzymes are rarely developed because the discovery of agonistic antibodies remains elusive. Here we report an innovative scheme of discovery and characterization of human antibodies capable of binding to and agonizing a circulating enzyme lecithin cholesterol acyltransferase (LCAT). Utilizing a modified human LCAT protein with enhanced enzymatic activity as an immunogen, we generated fully human monoclonal antibodies using the XenoMouseTM platform. One of the resultant agonistic antibodies, 27C3, binds to and substantially enhances the activity of LCAT from humans and cynomolgus macaques. X-ray crystallographic analysis of the 2.45 Å LCAT-27C3 complex shows that 27C3 binding does not induce notable structural changes in LCAT. A single administration of 27C3 to cynomolgus monkeys led to a rapid increase of plasma LCAT enzymatic activity and a 35% increase of the high density lipoprotein cholesterol that was observed up to 32 days after 27C3 administration. Thus, this novel scheme of immunization in conjunction with high throughput screening may represent an effective strategy for discovering agonistic antibodies against other enzyme targets. 27C3 and other agonistic human anti-human LCAT monoclonal antibodies described herein hold potential for therapeutic development for the treatment of dyslipidemia and cardiovascular disease.
Journal of Biological Chemistry | 1997
Xuhong Sunny Wang; Katrina Diener; Carl L. Manthey; Shen-Wu Wang; Bradley Rosenzweig; Jeffrey Bray; John M. Delaney; Craig N. Cole; Po-Ying Chan-Hui; Nathan B. Mantlo; Henri Lichenstein; Mark M. Zukowski; Zhengbin Yao
Journal of Experimental Medicine | 2000
Xing-Zhong Xia; James J. S. Treanor; Giorgio Senaldi; Sanjay D. Khare; Tom Boone; Michael J. Kelley; Lars Eyde Theill; Anne Colombero; Irina Solovyev; Frances Lee; Susan McCabe; Robin Elliott; Kent Miner; Nessa Hawkins; Jane Guo; Marina Stolina; Gang Yu; Judy Wang; John M. Delaney; Shi-Yuan Meng; William J. Boyle; Hailing Hsu
International Immunology | 2000
Steven Kiyoshi Yoshinaga; Ming Zhang; Jeanne Pistillo; Tom Horan; Sanjay D. Khare; Kent Miner; Michael Sonnenberg; Tom Boone; David Brankow; Tianang Dai; John M. Delaney; Hong Han; Ariela Hui; Tadahiko Kohno; Raffi Manoukian; John S. Whoriskey; Marco A. Coccia
Biochemistry | 1998
Robert Rosenfeld; Lisa Zeni; Andrew A. Welcher; Linda O. Narhi; Clarence Hale; Julie Marasco; John M. Delaney; Thomas Gleason; John S. Philo; Viswanathan Katta; John O. Hui; Jamie Baumgartner; Melissa Graham; Kevin Lee Stark; William Karbon