Molecular Targeting Technologies, Inc. and National Health Research Institutes | Date: 2017-03-29
Dipicolylamine compounds of Formula (I) set forth herein. Also disclosed are pharmaceutical compositions containing metal ions and these compounds. Further disclosed is a method for treating a condition associated with cells containing inside-out phosphatidylserine, with these compounds
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase II | Award Amount: 836.32K | Year: 2011
DESCRIPTION (provided by applicant): Current human rabies virus (RV) vaccines are effective if administered in an appropriate and timely manner and therefore, RV infection is a vaccine-preventable disease. However, immunization protocols are complex, requiring multiple doses over a period of weeks and in some cases months. High costs and the lack of compliance associated with current vaccines, and the re-emergence and emergence of rabies and rabies- related viruses, helps to keep rabies a global health threat. The World Health Organization estimates RV kills over 55,000 people per year and over 15 million people receive post-exposure prophylaxis (PEP) after exposure to potentially infected animals. Rabies is ranked seventh in important infectious diseases since it often occurs in children. In addition, current vaccines are based on the inactivation of live RV, however, live RV was recently discovered in a production lot of vaccine, resulting in an international vaccine recall and shortage indicating intrinsically safe human RV vaccines are needed. Taken together, the development of novel pre- and post-exposure vaccines is necessary to combat this global health issue. Our overall goal is to develop new human RV vaccines that are safe, inexpensive and effectiveas pre- and post-exposure vaccines for both industrialized and developing countries. Since pre-exposure vaccination is reserved only for those at-risk populations, such as laboratory workers and veterinarians, PEP is the worldwide standard for human rabies prevention. We hypothesize that a matrix (M) gene-deleted RV, which renders the virus replication-deficient, will make excellent an RV PEP. Among other attributes, M-gene deleted RV vaccines elicit immune responses similar to that from live RV vaccines,which are more potent and different from inactivated vaccines. Importantly, these replication-deficient viruses are also very safe even in T- and B- cell immune-deficient mice and in non-human primates. The M gene-deleted RV emerged as our most promising vaccine vector identified during Phase I studies in conjunction with our other preliminary immunogenicity and protection data in mice non-human primates. We believe M-gene deleted RVs will benefit PEP vaccination reducing the number of inoculations from thecurrent standard regimen of five doses of active and one dose of passive immunization to a one- or two-dose immunization protocol. Three Aims are proposed to achieve our overall goal. Aim I is directed towards preparing a research master seed of the M gene-deleted RV using protocols developed during Phase I to recover and propagate M gene-deleted RVs on Vero cells (a pharmaceutically acceptable cell substrate). Aim II is directed towards assessing the safety and toxicity of the M gene-deleted RV by studying its biodistribution, histopathology, genetic stability, thermal stability and neurovirulence in mice. Aim III is to further evaluate immunogenicity our vaccine vector, and to define or establish a new acceptable potency assay for the replication-deficient virus vaccine by correlating focus forming units (ffu) to the well-defined NIH potency test of RV vaccine-induced immunity and protection. In summary, this Phase II study should finalize pre-clinical testing of the M gene-deleted RV and support the development of a one- to two-dose RV vaccine. Achieving these Aims will bring us closer to saving lives and reducing the cost of human RV prevention in both industrialized and developing countries. PUBLIC HEALTH RELEVANCE: The goal of this applicationis to develop safe and effective alternatives to the current human rabies post- exposure prophylaxis. The development of treatment that relies on only one to two doses of vaccine instead of five or six inoculations will greatly enhance the effectiveness ofrabies virus prevention, save lives and reduced costs in developing and developed countries.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 222.58K | Year: 2014
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase II | Award Amount: 2.51M | Year: 2012
DESCRIPTION (provided by applicant): According to the NIAID fact sheet on Botulism, the extreme toxicity of botulinum neurotoxins (BoNT) and the ease of production, transport, and delivery make this an agent of extreme bioterrorism concern. Nonetheless, although there are major vaccine development initiatives ongoing, there currently is no approved Botulinum toxin vaccine available. Advances in Botulinum research have designated the optimal target for vaccine development to be the non-toxic carboxyterminal half of the toxin heavy chain (HC50). In fact, an immediate research goal for NIAID is listed as the development of a HC50 fragment vaccine against botulinum. Building upon the encouraging data from the phase I proof of concept study of this project,the overall phase II project goal is to develop a new, trivalent botulinum vaccine against the most common serotypes A, B and E. Three Aims are proposed for the further development of this novel trivalent BoNT vaccine as follows: Specific Aim 1: Vaccine vector construction and recovery. i) plasmid constructions, ii) demonstration of cell surface expression of the BoNT HC50, and iii) re-recovery of recombinant RVs from cDNA on Vero. Specific Aim 2. Vaccine vector characterization i) purification, inactivation, and in vitro characterization of the RV virions, ii) analysis of mouse immune responses to the vaccine using ELISA, in vitro neutralization assays, and in vivo protection of mice against a single challenge with BoNT or multiple BoNT challenge dependenton the used vaccine(s) for immunization. Specific Aim 3: Development of Pilot Production and Purification Processes. The overall goal of this aim is to translate the production process of our vaccine from a research setting to one suitable for pilot scalevaccine manufacture. PUBLIC HEALTH RELEVANCE: This research project is directly relevant to public health in that it is directed towards the development of a safe and effective vaccine for Botulinum neurotoxin. Botulinum toxin posesa major bioweapon threat because of its extreme potency andlethality and its ease of production and transport. A current investigational botulinum- toxoid vaccine requires multiple boosts to generate titers that are not very high, highlighting the need for an improved botulinum toxin vaccine. It is unclear if the current Botulinum vaccine protects at all as indicated by the disclaimer on the CDC vaccine consent form: ..., but other personal protective measures are still required. You should think of personal protectivemeasures as the only protective measure against any of these bacteria (sic) toxins at this time.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 224.44K | Year: 2012
DESCRIPTION (provided by applicant): Although a rapid and accurate diagnosis is crucial to the management of patients suspected of bacterial infection, the currently available radiopharmaceuticals are not capable of distinguishing between sterile inflammation and bacterial infections. Our goal is to develop an infection-specific PET/SPECT radiopharmaceutical for eventual use in clinical practice. In Phase I, we will evaluate two independent approaches. In a covalent approach, we will conjugate a radionuclide chelator for PET/SPECT imaging with a Zn-DPA targeting moiety that is known to selectively target the negatively charged bacterial envelope, to provide a novel small molecule nuclear imaging agent. In an alternative, non-covalent radiolabeling approach,we will use streptavidin (SA) as a linker between the biotinylated Zn-DPA targeting motif and a biotinylated chelator to form an imaging agent which may have improved bacterial lesion accumulation over the covalent approach due to: (i) its slower pharmacokinetics because of increased size, and (ii) its potential to bind up to three DPA groups for affinity enhancement. Our Specific Aims include: 1) Synthesize and characterize DOTA- DPA-(1 Zn) for the covalent conjugation approach, DOTA/SA/DPA-(1 Zn) for thenon-covalent approach and radiolabel the DOTA containing agents with the PET isotope 68Ga, as well as the SPECT isotope 111In. 2) Serum stability assays and in vitro evaluation of the covalent [68Ga /111In-DOTA-DPA-(1 Zn)] and non- covalent [68Ga/111In-DOTA/SA/DPA-(1 Zn)] agents to S. pyogenes. Specific binding to bacteria will be evaluated by measuring binding to bacteria with increasing concentrations of unlabeled DOTA-DPA-Zn. Thereafter, labeled bacteria will be evaluated in 37o C serum environments to determine the stability of both radionuclide within the chelate and the stability of both agents to the bacteria. 3) Evaluate the covalent and non-covalent approaches in infection and inflammation mouse models for evidence of specific accumulations. SKH1 hairless mice will be injected in the thigh with live S. pyogenes to provide the bacterial infection model or lipopolysaccharide to provide the inflammation model. We will evaluate the agents radiolabeled with 68Ga as well as 111In in the mouse models usingsmall animal PET and SPECT/CT cameras respectively. In all cases, the location and extent of infection will be monitored by co-injecting PSVue(R) 794 (a fluorescent bacteria targeting probe) and imaging on a small animal optical camera. Agents will be evaluated for their pharmacokinetics, their accumulation in the target, their target thigh/contralateral normal thigh accumulation, evidence of specific infection imaging and sensitivity of detection. At sacrifice, full biodistributions of each radiolabel willbe done to supplement the imaging results. Key benchmarks for Phase I will be to obtain using either 68Ga/ 111In-DOTA- DPA-Zn or 68Ga/111In-DOTA/SA/DPA-Zn an infected thigh/normal thigh ratio of greater than 5 within a 10 h (68Ga) or 24 h (111In) period,obtain a statistically higher accumulation in the infected thighs compared to the inflammation thighs, and obtain an estimate of the lower limits of detection in the infection model. PUBLIC HEALTH RELEVANCE: Bacterial infection is one of the major causes of morbidity and mortality not only in developing countries but globally. Early diagnosis of infection and an ability to distinguish between bacterial infection and sterile inflammation is critical to the effective management of these patients. However, despite the efforts of many international imaging groups, there is currently no validated bacterial imaging agent that can distinguish infection from sterile inflammation. Obviously, the development of such an agent would greatly advance our ability todetect, localize, and quantify infections, to prescribe the appropriate treatment and to follow the patient throughout the treatment. In this project we propose to evaluate two novel approaches aimed at developing a new radiopharmaceutical which would allow noninvasive imaging of bacterial infections with the sensitivity that nuclear imaging approaches promise and would also allow infectious and inflammatory abscesses to be distinguished.
National Health Research Institute and Molecular Targeting Technologies, Inc. | Date: 2015-05-14
Dipicolylamine compounds of Formula (I) set forth herein. Also disclosed are pharmaceutical compositions containing metal ions and these compounds. Further disclosed is a method for treating a condition associated with cells containing inside-out phosphatidylserine, with these compounds.
Molecular Targeting Technologies, Inc. | Date: 2013-11-21
The invention provides novel multi-modality probes for pathologic cell tracking which allow labeling of dying cells with new probes and tracking them via non-invasive imaging techniques to diagnose ocular diseases, determine disease progression and evaluate effectiveness of treatment. The molecular probes of the invention can be topically, locally, or systemically administered for diagnosing and monitoring improvement or progression of any ocular diseases.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 219.94K | Year: 2013
DESCRIPTION: Tracing neuronal connections with lipophilic carbocyanine dyes has revolutionized neuroanatomical tract tracing and is an essential feature to understand development of brain connections in both control and mutant mice in particular since multiple colors of dyes can be used. More recently, lipophilic dyes have also gained ground in labeling blood vessels by directly staining the endothelial cell membranes upon contact. A persistent problem that blocks even wider use of these extremely successful dyes is their limited combination with other procedures such as immunostaining or detailed histology that requires dehydration for embedding, since the dye molecules are not permanently bound to the membranes and can either leak out or be easily washedaway by lipophilic solvents or detergents. Attempts to overcome these problems have thus far been at best partially successful. Therefore, to broaden even further the use of carbocyanine lipophilic dyes we propose to develop fixable carbocyanine dyes thatcan be bonded to lysine groups in membrane bound proteins thereby retaining the dyes in the membranes even after the lipid bilayers has been removed with detergents or organic solvents. We plan to optimize the use of these dyes by developing a protocol that allows combination of multiple distinct fluorophores to maximize the information gained from a given model organism. Specifically, our Specific Aims are: (1) Synthesize four spectrally distinct fixable lipophilic dyes, three for nerve tract tracing andone or blood vessel labeling, that are compatible with standard fixation techniques used in tissue processing and immunocytochemistry protocols. Dyes synthesized will feature an aromatic N-hydroxysuccinimide ester group to provide covalent anchoring to membrane proteins. (2) Evaluate fixable dyes in standardized test systems in fixed tissue using processing techniques needed for high resolution histology at the light microscope level. In this aim we will characteriz how long these dyes are retained in tissue after treatment with organic solvents and detergents and how washing out progresses over time. We will also characterize the conditions under which these dyes can be best combined with each other and with immunochemistry and/or staining for dying cells.(3) Create test products to market each dye alone or in combination to the research community. We will develop test products to be sent to 5-10 collaborators in the neuroscience community along with the published protocol developed in SA2. Combined, thesethree aims will provide novel reagents useful for studies related to breaches in the blood-brain barrier such as tumors, trauma and neurodegenerative diseases as well as normal development. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Studying the normal and diseased brain with fluorescence imaging techniques requires probes with improved performance. We will generate high performance fluorescent dyes for membrane labeling of nerve tracts and blood vessels compatible with long-term tissuepreservation techniques and other known fluorescent cell markers. The possible multicolor labeling will provide detailed knowledge of the developing brain and disease models such as brain tumors, fetal alcohol syndrome, neurodegenerative diseases, traumaor other disruptions of the blood-brain barrier.
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.82K | Year: 2015
DESCRIPTION provided by applicant Although antitumor agents have resulted in significant survival benefits for cancer patients several agents have serious cardiovascular toxic side effects Anthracyclines are commonly used antineoplastic drugs with demonstrated clinical utility However their effectiveness is limited by well established dose dependent risk of acute and chronic cardiotoxicity and congestive heart failure In current clinical practice several methods are used to noninvasively monitor left ventricle ejection fraction LVEF and to assess the impairment of cardiac function by chemotherapy Unfortunately regardless of methodology a decrease in LVEF is a relatively late manifestation of progressive subclinical myocardial damage and abnormal observations are made when cardiac damage has already occurred Despite routine monitoring of LVEF some patients still develop severe LV dysfunction Therefore a non invasive method for detection of myocardial injury before irreversible left ventricular dysfunction has occurred would be of great clinical significance providing the opportunity for timely intervention Our long term goal is to develop an SPECT imaging probe that will detect cancer treatment induced cardiotoxicity earlier than methods detecting left ventricle dysfunction To address this significant unmet medical need we propose a Phase I proof of concept study to show our that novel innovative molecular probe mTc Duramycin which has been demonstrated to image apoptotic necrotic cells in vivo will be able to detect doxorubicin Dox induced cardiotoxicity in a rat model Duramycin is a amino acid peptide that binds to phosphatidylethanolamine PE with relatively high affinity and provides an innovative tool for the targeting of PE molecules exposed on target cells and tissues Duramycin is characterized by multiple thioether crosslinking and uncommon amino acids derived from posttranslational modifications The overall structure of Duramycin assumes a compact cyclic configuration with a single binding pocket that specifically interacts with the glycerophosphoethanolamine head group of PE Two aims are proposed to achieve our proof of concept study Specific Aim is directed towards establishing the ability of mTc Duramycin to image Dox induced cardiotoxicity in an acute rat model Specific Aim is directed towards demonstrating the ability of mTc Duramycin imaging to detect Dox induced cardiotoxicity at an earlier time point than the onset of LV dysfunction in a chronic Dox induced cardiotoxicity rat model In summary this phase I SBIR project is intended to confirm the hypothesis that mTc Duramycin will detect Dox induced cardiotoxicity by in vivo SPECT imaging prior to the onset of left ventricle dysfunction as measured by echocardiography PUBLIC HEALTH RELEVANCE Although doxorubicin toxicity is a direct result of cancer therapy it is nonetheless a key concern and topic of research for the NHLBI Our research project is directly relevant to public health and would advance diagnostic capability of the cardiologist to detect cancer therapy induced cardiac toxicity in the clinic and for research
Molecular Targeting Technologies, Inc. | Date: 2013-06-04
Embodiments provide dual modality probes for imaging phosphatidylserine (PS) exposure and other anionic membrane surfaces. In various embodiments, the probes were constructed by utilizing a) the high selectivity of synthetic zinc (II) dipicolylamine coordination complexes (Zn-DPA) for targeting externalized PS which over-expresses in apoptotic and necrotic cells, b) a near-infrared (NIR) dye for optical imaging, and c) a widely used clinically approved radionuclide for PET (or SPECT) imaging. A variety of linking elements were incorporated into the probes between the Zn-DPA and radionuclide motif to modulate the pharmacokinetics. The in vitro and in vivo data of radiolabeled dipicolylamine probes demonstrated their utilities for imaging PS exposure with multiple imaging modalities.