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Boyce, VA, United States

Choi M.Y.,University of California at San Diego | Widhopf G.F.,University of California at San Diego | Wu C.C.N.,University of California at San Diego | Cui B.,University of California at San Diego | And 7 more authors.
Clinical Lymphoma, Myeloma and Leukemia

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncoembryonic antigen. Because of its expression on the cell surface of leukemia cells from patients with chronic lymphocytic leukemia (CLL), but not on normal B-cells or other postpartum tissues, ROR1 is an attractive candidate for targeted therapies. UC-961 is a first-in-class humanized monoclonal antibody that binds the extracellular domain of ROR1. In this article we outline some of the preclinical studies leading to an investigational new drug designation, enabling clinical studies in patients with CLL. © 2015 The Authors. Source

On February 3-4, 2009, a DIA Workshop was held to review and discuss comparability challenges and issues for biotechnology-derived pharmaceuticals. The workshop was held in the Washington, DC, area and was attended by representatives from the FDA and biotech and pharmaceutical industries. The expectation was to develop a consensus on which data are necessary to provide assurance of comparability for manufacturing changes made to biotechnology products during different stages of development or postmarketing. Numerous case studies were reviewed and discussed to build on best practices and recognize successful approaches to comparability. Copyright © 2010 Drug Information Association, Inc. All rights reserved. Source

Kornbrust D.,Preclinsight | Cavagnaro J.,Access Bio | Levin A.,Miragen Therapeutics | Foy J.,Celgene | And 3 more authors.
Nucleic Acid Therapeutics

This document summarizes the current consensus opinion of the Exaggerated Pharmacology (EP) Subcommittee of the Oligonucleotide Safety Working Group on the appropriate strategies to assess potential adverse effects caused by an "exaggerated" degree of the intended pharmacologic activity of an oligonucleotide (ON). The Subcommittee focused its discussions primarily on the ON subclasses that impact expression of "host" (i.e., human gene products - antisense, small interfering RNAs, and related ONs that target messenger RNA), with later and more limited discussions on aptamer, immunostimulatory, and microRNA subclasses. It is expected that many of these principles will be relevant to other subclasses but will need to be carefully considered as those development programs advance towards clinical trials. The recommendations may also serve as a frame of reference when designing Good Laboratory Practice safety studies with ONs, with regard to the study design elements that address assessment of EP. It is also hoped that these recommendations will establish a foundation for discussion with regulatory agencies on this subject. © Mary Ann Liebert, Inc. Source

Alton E.W.,Imperial College London | Boushey H.A.,University of California at San Francisco | Garn H.,Sterna Biologicals | Green F.H.,University of Calgary | And 12 more authors.
Nucleic Acid Therapeutics

Oligonucleotides (ONs) are an emerging class of drugs being developed for the treatment of a wide variety of diseases including the treatment of respiratory diseases by the inhalation route. As a class, their toxicity on human lungs has not been fully characterized, and predictive toxicity biomarkers have not been identified. To that end, identification of sensitive methods and biomarkers that can detect toxicity in humans before any long term and/or irreversible side effects occur would be helpful. In light of the public's greater interests, the Inhalation Subcommittee of the Oligonucleotide Safety Working Group (OSWG) held expert panel discussions focusing on the potential toxicity of inhaled ONs and assessing the strengths and weaknesses of different monitoring techniques for use during the clinical evaluation of inhaled ON candidates. This white paper summarizes the key discussions and captures the panelists' perspectives and recommendations which, we propose, could be used as a framework to guide both industry and regulatory scientists in future clinical research to characterize and monitor the short and long term lung response to inhaled ONs. © Copyright 2012, Mary Ann Liebert, Inc. 2012. Source

Ivens I.A.,Bayer AG | Achanzar W.,Bristol Myers Squibb | Baumann A.,Bayer AG | Brandli-Baiocco A.,Roche Holding AG | And 12 more authors.
Toxicologic Pathology

PEGylation (the covalent binding of one or more polyethylene glycol molecules to another molecule) is a technology frequently used to improve the half-life and other pharmaceutical or pharmacological properties of proteins, peptides, and aptamers. To date, 11 PEGylated biopharmaceuticals have been approved and there is indication that many more are in nonclinical or clinical development. Adverse effects seen with those in toxicology studies are mostly related to the active part of the drug molecule and not to polyethylene glycol (PEG). In 5 of the 11 approved and 10 of the 17 PEGylated biopharmaceuticals in a 2013 industry survey presented here, cellular vacuolation is histologically observed in toxicology studies in certain organs and tissues. No other effects attributed to PEG alone have been reported. Importantly, vacuolation, which occurs mainly in phagocytes, has not been linked with changes in organ function in these toxicology studies. This article was authored through collaborative efforts of industry toxicologists/nonclinical scientists to address the nonclinical safety of large PEG molecules (>10 kilo Dalton) in PEGylated biopharmaceuticals. The impact of the PEG molecule on overall nonclinical safety assessments of PEGylated biopharmaceuticals is discussed, and toxicological information from a 2013 industry survey on PEGylated biopharmaceuticals under development is summarized. Results will contribute to the database of toxicological information publicly available for PEG and PEGylated biopharmaceuticals. © 2015 by The Author(s). Source

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