A Dose-Escalating Phase I Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of Intravenous OPL-CCL2-LPM in Patients With IgA Nephropathy

The purpose of this study is to evaluate the safety of several dose levels of CCL2-LPM in patients with IgA Nephropathy who have high levels of protein in the urine.

开始日期2009-03-01

申办/合作机构

Osprey Pharmaceuticals USA, Inc.

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2011-01-01·Recent patents on inflammation & allergy drug discovery

Anti-Inflammatory Approaches that Target the Chemokine Network

Review

作者: Wilson, Susan E. ; McDonald, John R. ; Finck, Barbara K. ; McIntosh, Laura M.

Chemokine-ligand/receptor axes play pivotal roles in a myriad of inflammatory, allergic and autoimmune diseases, as well as in the promotion of tumor growth and metastasis. Upon insult, tissue resident cells (and cancer cells in general) release a defined set of inflammatory chemokines that are responsible for the recruitment of activated pathological leukocytes. Recruited leukocytes synthesize and release a host of inflammatory mediators such as chemokines, cytokines, reactive oxygen and nitrogen species, and proteinases. These agents are responsible for the maintenance and amplification of inflammatory responses, and are directly responsible for secondary tissue damage, promotion of autoimmunity, fibrosis and tissue remodelling. Many cancers are associated with the expression of chemokine ligands that co-opt leukocytes such as tumor associated macrophages which in turn provide mediators including growth factors, chemokines and proteinases that promote angiogenesis, tumor growth, and cancer metastasis. Here, we discuss the relevant patents, development and the mechanism of action of a range of therapeutic and potential therapeutic agents that specifically target the chemokine ligand and receptor network. The main approaches that will be highlighted here are antagonism, cell depletion and the relatively unexplored fields of anti-sense, gene and stem cell therapies.

2009-11-01·Recent patents on inflammation & allergy drug discovery

Selective Chemokine Receptor-Targeted Depletion of Pathological Cells as A Therapeutic Strategy for Inflammatory, Allergic and Autoimmune Diseases

Review

作者: McDonald, John R

Targeting cell surface antigens or receptors with lytic monoclonal antibodies and specific ligand-directed fusion proteins in order to eliminate cancer cells has been in development for at least forty years. More recently, leukocyte populations known to drive a host of allergic, autoimmune and inflammatory diseases have been targeted. For fusion protein constructs, a number of different classes of cellular toxins have been fused to a variety of ligands such as monoclonal antibodies, growth factors and cytokines. Although there has been great clinical success using these biologics, there are some limitations. The target antigens are often expressed on normal cells leading to side effects. More recently, several groups have explored the use of chemokine receptor ligands and antibodies to target leukocytes and cancer cells. There are a number of inducible chemokine receptors that are only up-regulated in inflammation and their expression is relatively restricted to pathological cells. This confers another degree of specificity on biologics that are composed of chemokine receptor targeting agents. This review discusses articles, recent patents and patent applications that explore the selective depletion of pathological cells by targeting chemokine receptors with chemokine ligands, monoclonal antibodies and different bispecific constructs as a therapeutic strategy for allergic, autoimmune and inflammatory diseases.

2009-01-06·Clinical and experimental immunology3区 · 医学

Selective CCR2-targeted macrophage depletion ameliorates experimental mesangioproliferative glomerulonephritis

3区 · 医学

Article

作者: McDonald, J R ; Barnes, J L ; McIntosh, L M ; Barnes, V L

Summary:

The CCL2/CCR2 chemokine/receptor axis directs the chemotaxis of infiltrating monocytes/macrophages and T cells and plays a pivotal role in tissue damage and fibrosis in kidney diseases. The eradication of the activated leucocytes should diminish the production of inflammatory mediators, limit tissue damage and ameliorate disease. A recombinant fusion protein (OPL-CCL2-LPM) comprised of the human CCL2 (monocyte chemoattractant protein-1) chemokine fused to a truncated form of the enzymatically active A1 domain of Shigella dysenteriae holotoxin (SA1) has been developed. The CCL2 portion binds specifically to CCR2-bearing leucocytes and the fusion protein enters the cells, where the SA1 moiety inhibits protein synthesis resulting in cell death. The compound was tested in a model of anti-thymocyte serum (ATS)-induced mesangioproliferative glomerulonephritis (ATS-GN). Male rats were injected with ATS on day 0 and treated intravenously with vehicle, 50 or 100 µg/kg of OPL-CCL2-LPM Q2D from days 2, 4, 6 and 8. Urine and blood were collected on days 0, 5 and 9. Animals were sacrificed on day 9. No treatment-related effects on body weight or signs of clinical toxicity were observed. Urine protein levels were decreased in treated animals. At the highest dose, histopathological analyses of kidney sections revealed maximum reductions of 36, 31, 30 and 24% for macrophage count, glomerular lesions, α-smooth muscle actin and fibronectin respectively. These results indicate a significant protective effect of OPL-CCL2-LPM in this model of nephritis.

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2021-03-16

·BioSpace

Barbara K. Finck, M.D., Appointed to ReForm Biologics Board of Directors

March 16, 2021 11:00 UTC Brings 25 years of preclinical and clinical drug development experience to ReForm WOBURN, Mass.--(BUSINESS WIRE)-- ReForm Biologics, a company developing a new generation of bio-innovative biologic medicines to improve patient access, safety and convenience, today announced the appointment of Barbara Finck, M.D., to its Board of Directors. Dr. Finck is currently the acting Chief Medical Officer at Coherus BioSciences. “Dr. Finck’s experience in the successful clinical development of groundbreaking therapies such as Ditropan-XL® and Enbrel® will be invaluable to ReForm Biologics as we pivot to the in-house development of our own bio-innovative medicines,” said Jim Sherblom, Chairman of the Board. “Barbara’s unwavering commitment to the development of therapies that improve and extend human lives will help guide the development of biologics that can be more easily and safely administered to patients living with debilitating illnesses. We look forward to working with Barbara as we build our clinical capabilities at ReForm.” “Biologics have changed the way we treat disease but they generally require in-clinic intravenous infusions that are inconvenient and often difficult to administer to fragile patients, particularly children who have smaller veins,” said Dr. Finck. “ReForm’s ability to reformulate biologics provides the opportunity to deliver these proven therapies in the clinic or at home through subcutaneous injections that could be safe, more convenient and encourage better compliance. I look forward to working with the ReForm team to improve patient care by making biologics more accessible for patients.” Dr. Finck is a board certified rheumatologist with more than 25 years of preclinical and clinical drug development experience in academic and biopharmaceutical settings. Dr. Finck, whose drug development activities have spanned multiple therapeutic areas, started her pharmaceutical career at ALZA as medical director for early clinical development of Ditropan-XL®, to treat spasms of the bladder. She subsequently held senior level positions at a half-dozen innovative biopharmaceutical companies. At Immunex (later acquired by Amgen), she was lead medical director for the Phase III clinical development of Enbrel® in rheumatoid arthritis and juvenile idiopathic arthritis. At Eos Biotechology, she was VP of Clinical Development. In addition, she was on the executive teams at PDL Biopharma (VP, Clinical Development), Osprey Pharmaceuticals USA, Inc. (Senior VP, Research and Development, and Chief Medical Officer), and NKT Therapeutics, Inc. (Chief Medical Officer). In her role as the Chief Medical Officer at Coherus, she was instrumental in the development and approval of UDENYCA®, a biosimilar pegfilgrastim. About ReForm Biologics ReForm Biologics creates gentler therapies for fragile patients, including pediatric patients, by using our proprietary technology to transform intravenous drugs into subcutaneous injections, to reduce adverse reactions, and to improve drug stability. Our goal is to enhance comfort, convenience, safety and compliance so that patients living with debilitating diseases can experience a better life while treating their medical conditions. For more information, visit . View source version on businesswire.com: Contacts Rob Kloppenburg Shoreline Biotech Communications (617) 930-5595 Source: ReForm Biologics View this news release online at:

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