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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.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 240.22K | Year: 2016

Summarty Abstract Vectored immunoprophylaxis or antibody gene transfer for infectious disease is a promising new strategy to provide protection against high risk infectious agents supplementing vaccine and passive immunization efforts It has been demonstrated to be effective against HIV and Dengue virus in animal models and there is currently an ongoing human trial for HIV prevention in high risk individuals with an adeno associated viral vector AAV delivering the gene for a broadly neutralizing HIV antibody We propose to expand these efforts to the filoviruses starting with the Ebolavirus Zaire EBOV EBOV causes severe hemorrhagic fever with a high mortality between and depending on the virus Although the recent EBOV epidemic appears to be waning the outbreak was classified by the WHO as andquot an international public health emergency andquot In addition Ebolavirus is a potential bioterrorism agent Category A While recent reports suggest optimism for an Ebola vaccine these are early trials with much work to be done to prove efficacy and to characterize the onset of protection and durability Passive immunization has shown great promise against EBOV in a therapeutic setting however production capabilities are not yet available for protection of a large segment of the population and passive immunization requires repeated administration if used in a prophylactic setting As such there is an ongoing need for increasing the repertoire of immunoprotectants such as vectored antibodies Project Narrative We will use mAb G gene transfer to compare the expression patterns from both AAV and plasmid based systems and to assess efficacy in a live virus challenge model in mice compared to the native murine G mAb The results will provide the basis for a definitive investigation during which time the plasmid and AAV approaches will be evaluated head to head and in combination in non human primates


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 3.00M | Year: 2011

DESCRIPTION (provided by applicant): The National Institutes of Health considers the development of therapeutics against potential bioterrorism agents a national research priority. There is a particular need for immunotherapeutics against Ebola virus (a Category A agent). Because of Ebola's lethality and reports that it has been weaponized, public health officials and defense agencies have mounted a concerted effort to encourage development of countermeasures for protecting civilian and military populations. There are currently no drugs available for preventing or treating Ebola virus infection. Passive immunization with antibodies has been shown to be effective against a wide variety of viruses. Because of their excellent safety profile and efficacy, monoclonal antibodies (mAbs) are a rapidly growing class of therapeutic drugs. Mapp has been developing MB-2003, a mAb based anti-Ebola product. The current configuration of MB-2003 consists of 3 mAbs that individually and in combination have been shown to provide significant prophylactic and therapeutic protection in mice. As a result of completion of the Phase 1 activities, the MB-2003 cocktail has also been shown to provide 100% protection in macaques against a highly lethal challenge. This is the first time antibodies have been shown to protect primates against Ebola - previous experiments with polyclonal or monoclonal antibodies have failed to provide any protection. Because of the rapid onset and high lethality of Ebola virus, we anticipate the MB-2003 product will be administered intravenously as a pre-exposure and/or post-exposure prophylactic. The Specific Aims of this proposal are: Specific Aim 1. Determine the final MB-2003 product configuration. Tests in the macaque model will determine whether the final MB-2003 configuration will be one, two, or three mAbs. Dose ranging studies will be performed to identify the protective dose, and time course experiments will determine the therapeutic window for MB-2003. Specific Aim 2. Finalize the MB-2003 liquid formulation. An optimal liquid formulation for the mAb(s) selected in Aim 1 will be identified in collaboration with Formatech (Andover, MA). Specific Aim 3. Complete IND-enabling testing and submit an IND. MB-2003 will be manufactured and formulated under current Good Manufacturing Practices (cGMP). All IND- enabling pharmacology, toxicology, and Chemistry, Manufacturing and Controls (CMC) studies will be performed, with a final goal of filing an IND to support a Phase 1 human safety trial. PUBLIC HEALTH RELEVANCE: The efforts in this proposal will help in the development of a drug for preventing and/or treating Ebola virus infection, a potential biowarfare agent, for which no treatment currently exists.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 299.99K | Year: 2012

DESCRIPTION (provided by applicant): Clostridium difficile associated disease (CDI) is an important cause of morbidity in hospital and nursing home patients, and is being increasingly recognized as an important cause of mortality. Estimates put the economic burden of CDI at 1-3 billion dollars in the U.S. alone. The overall goal of this project is to develop an anti-toxin humn monoclonal antibody product for prevention and/or treatment of C. difficile infection. Due to specificity, stability, safety, and the specific targeting of toxins (as opposed to selective pressre on the bacterium), a mAb product is ideal for prevention and treatment of the diseases caused by C. difficile. Antibodies are the only category of FDA-approved therapeutic that specifically neutralize toxins. We have isolated a panel of neutralizing human monoclonal antibodies (mAbs) that recognize the toxins of C. difficile. In terms of their neutralizing potency in vitro, these mAbs are superior to mAbs previously reported that are in clinical development [1]. Preliminary testing in vivo has demonstrated protection in the hamster model that was superior to vancomycin. We will produce each of our human mAbs against C. difficile toxins A and B (TcdA, TcdB) in a scalable production system that can provide antibodies for therapeutic or prophylactic indications. Each mAb, as well as the combination of mAbs, will be evaluated for effectiveness in preventing and treating C. difficile infection in the hamster model to select the lead mAb cocktail for continued development. Specific Aim #1. Produce quantities of each anti-TcdA and anti-TcdB human mAb for in vitro characterization and animal testing in a novel manufacturing system. Human anti-TcdA and anti-TcdB mAbs have been generated using transgenic mice containing human immunoglobulin loci (HuMab-Mouse(r)). Three anti-TcdA and three anti-TcdB mAbs have been developed under license by Mapp. The mAbs all exhibited potent neutralizing activity and have subsequently been produced in a scalable plant-basedsystem. Combined, these mAbs are potent immunoprotectants in the hamster challenge model. Specific Aim #2. Evaluate individual mAbs and combinations of mAbs in vivo for prevention and treatment of CDI. MAbs produced in Specific Aim #1 will be compared in the hamster model of C. difficile infection. The anti-TcdA mAbs will first be evaluated individually to determine the baseline of protection. Only anti-TcdA has been observed to provide significant protection alone, whereas anti-TcdB may extend the durationand effectiveness of anti-TcdA protection [1]. The best anti- TcdA mAb will then be further tested in combination with each anti-TcdB mAb to determine the synergistic potential of mAb pairs. The best mAb pair will be selected for further development in pre-clinical and clinical protocols largely funded by a Phase II SBIR grant. PUBLIC HEALTH RELEVANCE: The efforts in this proposal will help in the development of a drug product for preventing and/or treating Clostridium difficile infection (CDI), acause of significant morbidity and mortality in hospitals and nursing homes. The economic cost of CDI has been conservatively estimated at 1-3 billion per year in the U.S. The recent characterization of an epidemic C. difficile strain with increased virulence and antibiotic resistance has made the development of alternative therapies even more pressing.


Grant
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


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 2.31M | Year: 2014

DESCRIPTION provided by applicant Staphylococcal enterotoxin B SEB Category B agent a toxin that commonly causes classic food poisoning and can cause a non menstrual toxic shock syndrome TSS has been studied as a potential biological warfare agent Importantly SEB is derived from common readily accessible bacteria is relatively easily produced and can be delivered in a stable aerosol form SEB exhibits severe toxicity by the inhalation route once inhaled it causes widespread systemic damage multi organ system failure and even shock and death at microgram doses Clearly an SEB attack would be devastating to civilian populations as well as on the battlefield during times of war Currently there are no preventatives or therapeutics available against SEB Monoclonal antibodies mAbs are a class of FDA approved biologics that can potently neutralize toxins Because of their stability specificity versatility and low potential for immunogenicity mAbs are ideal for biodefense related countermeasures As a result of successful completion of our Phase efforts we have identified a highly potent mAb that protects mice from systemic and aerosol challenge Further in this proposal we are combining forces with Integrated Biotherapeutics Gaithersburg MD whose team has identified an additional anti SEB mAb via separate NIAID funding Together we will determine which of the two mAbs is the most appropriate for continued development resulting in cost savings for NIH The Long Range Objective of this project is to develop a safe and effective immunoprotectant product for SEB We expect the initial indication will be for pre and post exposure prophylaxis The Specific Aims and Milestones of this proposal are Aim Produce the two candidate mAbs using a Nicotiana benthamiana based rapid antibody manufacturing platform RAMP Aim Evaluate the pre and post exposure efficacy of the two mAbs in non human primates against aerosolized SEB The most efficacious mAb to be designated MB SEB will be chosen for continued development Aim Complete Investigational New Drug IND enabling studies to prepare for clinical evaluation of MB SEB in accordance with regulatory requirements Using RAMP mAb produced under Good Manufacturing Practice GMP the studies necessary pharmacology and toxicology chemistry manufacturing and control data to submit an IND application will be performed to support a Phase safety trial PUBLIC HEALTH RELEVANCE The efforts in this proposal will help in the development of a drug for preventing and treating exposure to SEB a highly potent toxin that is a significant biological warfare threat to public and military safety


Grant
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.


Grant
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.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 228.76K | Year: 2015

DESCRIPTION provided by applicant Pseudomonas aeruginosa PA an opportunistic Gram negative bacterium is one of the leading nosocomial pathogens worldwide PA is responsible for localized infections of a variety of organ systems including respiratory urinary gastrointestinal skin eye ear and joints and also systemic infections in susceptible individuals Because PA is highly adaptable to survive in common environments mechanical ventilators intravenous lines urinary and dialysis catheters pacemakers and endoscopes can all be potential reservoirs for PA infections Despite the widespread presence and growing significance of PA and the increasing rates of antibiotic treatment failure no efficient and marketable vaccine is currently available Recent advances in the development of anti PA monoclonal antibodies mAbs have offered the possibility that passive immunotherapy may be a viable clinical modality We are examining the treatment effectiveness of a combination of mAbs that can target two common PA LPS serotypes in one formulation using animal models infected with two virulent PA strains The results will provide the basis for pre clinical development of a combination PA therapy with an optimized glycosylation profile The proposed work scope will allow us to determine whether using plant derived manufacturing techniques could enhance manufacturing productivity whether manipulating glycosylation can achieve enhanced potency against bacterial challenge in two mouse models and the effectiveness of using a cocktail of two mAbs to target two common PA serotypes PUBLIC HEALTH RELEVANCE We are developing two IgM monoclonal antibodies for the treatment of Pseudomonas aeruginosa infections The antibody manufacturing system involves plant based production and glycol engineering The goal is to develop a PA therapy using a cocktail of two mAbs to target two common PA serotypes


Patent
Icon Genetics GmbH and Mapp Biopharmaceutical, Inc. | Date: 2012-09-27

Disclosed herein are GNGN and G1/G2 antibodies that recognize and bind various FcRs and C1q. Also disclosed herein are glycan-optiminzed antibodies, predominantly of the GNGN or G1/G2 glycoform, with enhanced Fc receptor binding achieved through CHO, Nicotiana benthamiana and yeast manufacturing systems. Nucleic acids encoding these antibodies, as well as expression vectors and host cells including these nucleic acids are also disclosed herein. Methods and pharmaceutical compositions including the monoclonal antibodies are provided herein for the prevention and/or therapeutic treatment of viral infections, cancers and inflammatory diseases.

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