Savonenko A.V.,Johns Hopkins University |
Melnikova T.,Johns Hopkins University |
Hiatt A.,Mapp Biopharmaceutical, Inc. |
Li T.,Johns Hopkins University |
And 4 more authors.
Neuropsychopharmacology | Year: 2012
Over the past three decades, significant progress has been made in understanding the neurobiology of Alzheimer's disease. In recent years, the first attempts to implement novel mechanism-based treatments brought rather disappointing results, with low, if any, drug efficacy and significant side effects. A discrepancy between our expectations based on preclinical models and the results of clinical trials calls for a revision of our theoretical views and questions every stage of translationfrom how we model the disease to how we run clinical trials. In the following sections, we will use some specific examples of the therapeutics from acetylcholinesterase inhibitors to recent anti-AΒ immunization and γ-secretase inhibition to discuss whether preclinical studies could predict the limitations in efficacy and side effects that we were so disappointed to observe in recent clinical trials. We discuss ways to improve both the predictive validity of mouse models and the translation of knowledge between preclinical and clinical stages of drug development. © 2012 American College of Neuropsychopharmacology. All rights reserved. Source
Murin C.D.,Scripps Research Institute |
Fusco M.L.,Scripps Research Institute |
Bornholdt Z.A.,Scripps Research Institute |
Qiu X.,Public Health Agency of Canada |
And 6 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2014
Ebola virus (EBOV) and related filoviruses cause severe hemorrhagic fever, with up to 90% lethality, and no treatments are approved for human use. Multiple recent outbreaks of EBOV and the likelihood of future human exposure highlight the need for pre- and postexposure treatments. Monoclonal antibody (mAb) cocktails are particularly attractive candidates due to their proven postexposure efficacy in nonhuman primate models of EBOV infection. Two candidate cocktails, MB-003 and ZMAb, have been extensively evaluated in both in vitro and in vivo studies. Recently, these two therapeutics have been combined into a new cocktail named ZMapp, which showed increased efficacy and has been given compassionately to some human patients. Epitope information and mechanism of action are currently unknown for most of the component mAbs. Here we provide single-particle EM reconstructions of every mAb in the ZMapp cocktail, as well as additional antibodies from MB-003 and ZMAb. Our results illuminate key and recurring sites of vulnerability on the EBOV glycoprotein and provide a structural rationale for the efficacy of ZMapp. Interestingly, two of its components recognize overlapping epitopes and compete with each other for binding. Going forward, this work now provides a basis for strategic selection of next-generation antibody cocktails against Ebola and related viruses and a model for predicting the impact of ZMapp on potential escape mutations in ongoing or future Ebola outbreaks. Source
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 224.99K | Year: 2014
DESCRIPTION (provided by applicant): Glioblastoma is the most common primary brain tumor in adults. While many patients achieve disease remission following treatment with surgical resection, radiation therapy and chemotherapy, this remission is brief andinvariably followed by tumor recurrence and progression. The failure to offer durable therapies to patients with glioblastoma reflects the complex nature of this cancer. Targeted therapies involving monoclonal antibodies (mAbs) have had remarkable successin various diseases including cancer. Unfortunately, the current targeted therapy for glioblastoma, bevacizumab, has had disappointing clinical results. There is a clear need for alternative targeted therapies for glioblastoma that can potentially improveoverall survival of newly diagnosed patients. This proposal is intended to further develop an antibody against a cancer-specific antigen that has shown promising clinical results in humans. We will be exploring the possibility that the non-fucosylated
Agency: Department of Defense | Branch: Army | Program: SBIR | Phase: Phase I | Award Amount: 99.95K | Year: 2014
Ricin is a category B toxin due to its ease of acquisition, dissemination, and the high potential for morbidity and mortality after exposure. There are currently no methods of preventing or treating ricin exposure this represents a major unmet need for protection of civilians and warfighters. Because of their excellent safety profile and efficacy, mAbs are a rapidly growing class of therapeutic drugs with a regulatory track record superior to small molecules. The Mapp team, in collaboration with Dr. Nicholas Mantis (Wadsworth Institute, Albany, NY) has identified a highly potent humanized anti-ricin mAb, hPB10. The potency of this mAb is superior to any mAb previously described. In this work effort we propose to increase the serum-half life of hPB10 and establish proof-of-concept in rodent models with a long range objective of developing a safe, effective and long-acting mAb (> 6 months of protection from a single dose) product for ricin intoxication. The envisioned injectable product will be for use in humans both prior to (e.g. by first responders or military personnel entering a contaminated zone) and/or after ricin exposure.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 600.00K | Year: 2010
DESCRIPTION (provided by applicant): The National Institutes of Health has deemed the development of therapeutics against potential bioterrorism agents as a national research priority. There is a particular need for antidotes against the toxin ricin (NIAID, 2004); the Centers for Disease Control estimates that 500 micrograms of ricin is a lethal dose in humans exposed via injection or inhalation. Ricin, a Category B Select Agent, was weaponized by the U.S. and other countries during World War II and has been used as an agent of bioterrorism (Maman and Yehezkelli, 2005; Stone, 2002). This toxin has been used in assassinations, and it was recently uncovered in a number of government facilities, including a South Carolina postal facility and in envelopes delivered to offices of the U.S. Senate (Hulse, 2004; Schier et al., 2007). Because of ricin's toxicity and ease of preparation from the castor bean (Ricinus communis), have mounted a concerted effort by public health officials and defense agencies to develop countermeasures for protecting civilian and military populations. There are currently no drugs available for preventing or treating intoxication with ricin. Passive immunization with antibodies has been shown to be effective against a wide variety of toxins (Casadevall, 2002). Because of their excellent safety profile and efficacy, monoclonal antibodies (mAbs), are a rapidly growing class of therapeutic drugs. A highly potent murine anti-ricin mAb, GD12, (Neal et al., 2009) has been identified by one of the investigators (Dr. Mantis) and shown to protect mice when administered prior to systemic or mucosal ricin challenge. The Long Range Objective of this project is to develop a safe and effective mAb product for ricin intoxication. The envisioned injectable product will be for use in humans prior to and/or after ricin exposure. PUBLIC HEALTH RELEVANCE: The efforts in this proposal will help in the development of a drug for preventing and/or treating intoxication with ricin, a potential biowarfare agent, for which no treatment currently exists.