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Raritan, NJ, United States

An observation of visible particulate matter was made during formulation development of a mAb and investigations initiated to understand the colloidal instability of the formulation. It was observed that there was a loss of polysorbate in the IgG formulation and concurrent hydrolysis of polysorbate 80 (PS80) into fatty acid, polyethylene glycol (PEG), and pegylated sorbitan in the presence of mAb A. This observation was confirmed with two other mAb development programs (mAb B and mAb C) that used PS80 and formed particulate, but was absent in any placebo sample tested. Comparative analysis to acid, base and esterase hydrolysis, and exposure to the oxidation reagents Iron(II) and tert-Butyl hydroperoxide demonstrates that the observed reaction is reproduced by a biologic (enzymatic) mechanism. Monooleates of PS80, including the sorbitan and PEG oleates, are hydrolyzed first, showing a slower reaction with higher-order oleates. This leads to a change in the composition of the formulation over time where PS85 becomes the predominant component of the original surfactant remaining in solution. Data suggest that there is a lipid-specific mechanism rather than a general biologic hydrolysis mechanism that hydrolyzes oleate esters of PS80 increasing the risk that colloidal IgG particles will form in mAb drug product. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2268-2277, 2014 © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association. Source

Li M.,Peter MacCallum Cancer Center | Li M.,University of Melbourne | Knight D.A.,Peter MacCallum Cancer Center | Knight D.A.,University of Melbourne | And 4 more authors.
OncoImmunology | Year: 2013

The chemokine CC L2, which is best known for its chemotactic functions, is expressed not only by immune cells, but also by several types of malignant and stromal cells. CC L2 has been shown to exert both pro- and anti-tumor effects. However, recent results demonstrate a main role for CC L2 in tumor progression and metastasis, suggesting that this chemokine may constitute a therapeutic target for anticancer drugs. Mammary carcinoma models, including models of implantable, transgenic, and chemically-induced tumors, were employed in the setting of Ccl2 or Ccr2 knockout mice or CC L2 neutralization with a monoclonal antibody to further investigate the role of the CC L2/CCR 2 signaling axis in tumor progression and metastatic spread. In our implantable tumor models, an anti-CC L2 monoclonal antibody inhibited the growth of primary malignant lesions in a biphasic manner and reduced the number of metastases. However, in Ccl2-/- or Ccr2-/- mice developing implanted or transgenic tumors, the number of pulmonary metastases was increased despite a reduction in the growth rate of primary neoplasms. Transgenic Mtag.Ccl2-/- or Mtag.Ccr2-/- mice also exhibited significantly earlier disease onset. In a chemical carcinogenesis model, anti-CC L2 monoclonal antibody inhibited the growth of established lesions but was ineffective in the tumor induction phase. In contrast to previous studies indicating a role for CC L2 in the establishment of metastases, we have demonstrated that the absence of CC L2/CCR 2-signaling results in increased metastatic disease. Thus, the CC L2/CCR 2 signaling axis appears to play a dual role in mediating early tumor immunosurveillance and sustaining the growth and progression of established neoplasms. Our findings support the use of anti-CC L2 therapies for the treatment of established breast carcinoma, although the complete abrogation of the CC L2 signaling cascade may also limit immunosurveillance and support metastatic spread. © 2013 Landes Bioscience. Source

Reichert J.M.,Reichert Biotechnology Consulting LLC | Beck A.,Pierre Fabre | Lugovskoy A.A.,Merrimack Pharmaceutical Inc. | Wurch T.,Institute Of Recherches Servier | And 2 more authors.
mAbs | Year: 2014

The annual European Antibody Congress (EAC) has traditionally been the key event for updates on critical scientific advances in the antibody field, and 2013 was no exception. Organized by Terrapinn, the well-attended meeting featured presentations on considerations for developing antibodies and antibody-like therapeutics, with separate tracks for antibody-drug conjugates, naked antibodies, and multispecific antibodies or protein scaffolds. The overall focus of the EAC was current approaches to enhance the functionality of therapeutic antibodies or other targeted proteins, with the ultimate goal being improvement of the safety and efficacy of the molecules as treatments for cancer, immune-mediated disorders and other diseases. Roundtable discussion sessions gave participants opportunities to engage in group discussions with industry leaders from companies such as Genmab, Glenmark Pharmaceuticals, MedImmune, Merrimack Pharmaceuticals, and Pierre Fabre. As the 2013 EAC was co-located with the World Biosimilar Congress, participants also received an update on European Medicines Agency guidelines and thoughts on the future direction and development of biosimilar antibodies in the European Union. © 2014 Landes Bioscience. Source

Skibbens R.V.,Lehigh University | Colquhoun J.M.,Lehigh University | Green M.J.,Lehigh University | Molnar C.A.,Lehigh University | And 4 more authors.
PLoS Genetics | Year: 2013

Roberts Syndrome (RBS) and Cornelia de Lange Syndrome (CdLS) are severe developmental maladies that present with nearly an identical suite of multi-spectrum birth defects. Not surprisingly, RBS and CdLS arise from mutations within a single pathway-here involving cohesion. Sister chromatid tethering reactions that comprise cohesion are required for high fidelity chromosome segregation, but cohesin tethers also regulate gene transcription, promote DNA repair, and impact DNA replication. Currently, RBS is thought to arise from elevated levels of apoptosis, mitotic failure, and limited progenitor cell proliferation, while CdLS is thought to arise, instead, from transcription dysregulation. Here, we review new information that implicates RBS gene mutations in altered transcription profiles. We propose that cohesin-dependent transcription dysregulation may extend to other developmental maladies; the diagnoses of which are complicated through multi-functional proteins that manifest a sliding scale of diverse and severe phenotypes. We further review evidence that cohesinopathies are more common than currently posited. © 2013 Skibbens et al. Source

Spriggs F.P.,Pfizer | Crisino R.,Janssen R and D LLC
Bioanalysis | Year: 2015

The 10th annual Applied Pharmaceutical Analysis (APA) conference was held from 8th to 10th September in Cambridge, MA, USA. This year's APA conference focused on three different 'workshops' over the 3 days: Regulated Bioanalysis, Biotransformation, and Discovery. There was a great amount of information discussed by a variety of experts over the 3 days. This included, among other things; speakers from the US FDA discussing statute changes and guidelines, leaders from academic laboratories discussing innovation in bioanalytical tools, and industry scientists discussing current trends in the industry. The conference afforded attendees the opportunity to learn from the speakers during their sessions. In addition, there was ample opportunity for attendees and speakers both to learn from each other through informal interactions. © 2015 Future Science Ltd. Source

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