SUNNYVALE, CA, United States
SUNNYVALE, CA, United States

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Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.98K | Year: 2016

DESCRIPTION provided by applicant Memantine an aminoadamantane is approved to treat moderate to severe Alzheimerandapos s disease in the US and Europe Memantine selectively inhibits abnormally active N methyl D aspartate type glutamate receptor NMDAR channels while preserving normal glutamate activity and physiological neuronal function Lipton Lipton a b Pathological NMDA receptor activity is further down regulated by S nitrosylation of cysteine residues located on the N terminus or extracellular domain Taking advantage of these insights we have developed a series of bifunctional antagonists nitromemantines that not only preferentially bind to the open channel state but also selectively target NO to a second modulatory site using the memantine pharmacophore as a homing motif Our data suggest that some of these memantine analogs have good potency while maintaining selectivity for persistently open NMDAR channels Most importantly they appear to have greater neuroprotective properties than memantine in both in vitro and in vivo animal models Our results provide structural guidance to further optimize and then identify a potential development candidate with an optimal profile to maximize neuroprotective effects PRI owns and the PI is a co inventor on the original nitromemantine patents Wang Recent work from the laboratory of our collaborator and co inventor Prof Stuart Lipton demonstrates the unique superiority of one of our nitromemantines YQW amino diethyl nitrateadamantane versus memantine to rescue protect synapses Talantova This compound preferentially and uniquely modulates pathogenic extrasynaptic NMDARs versus synaptic NMDARs Phase I seeks to identify a development candidate based on our promising dual targeted lead compound Phase II will support translational IND enabling studies The achievement of this milestone will generate a proprietary first in class disease modifying drug for Alzheimerandapos s disease PUBLIC HEALTH RELEVANCE Alzheimerandapos s disease AD is a devastating form of dementia whose incidence is increasing due to an aging population The FDA approved drug memantine is arguably the best available therapeutic for AD We have synthesized improved memantine like drugs and have demonstrated their effectiveness in cell culture and in an animal model Development of these memantine analogs will result in a best in class disease modifying treatment for AD


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.98K | Year: 2016

DESCRIPTION provided by applicant Osteoclasts OC are key mediators of erosive bone diseases including tumor associated osteolytic lesions as well as rheumatoid arthritis RA other forms of arthritis and osteoporosis Indeed OC are the only cells known to degrade bone Osteoclastogenesis begins with differentiation of monocytes into OC precursor cells OCP which subsequently differentiate into multinucleated OC with bone resorption activity Chiu Studies with antibodies Mensah and knock out in models Yagi demonstrate an absolute requirement for the Dendritic Cell Specific TrAnsMembrane Protein DC STAMP for the fusion of OCP to generate fully active OC Anti DC STAMP monoclonal antibodies attenuate the fusogenic process reducing the number of active OC Mensah thus providing a unique approach to erosive bone diseases Our Phase goal is to identify and characterize a human monoclonal anti DC STAMP antibody humAb as a therapy for erosive bone diseases We will construct a panel of humanized versions of DC STAMP specific mouse mAb A then express purify and characterize the candidate humAbs to be rank ordered using an in vitro assays of binding and osteoclastogenesis The functional activity of the top anti DC STAMP humAb will then be evaluated in a mouse model to explore application for multiple myeloma associated bone erosion Successful identification of a DC STAMP humAb will merit submission of a Phase application to fund IND enabling studies PUBLIC HEALTH RELEVANCE Skeletal metastases occur in multiple myeloma and other malignancies Current treatments are moderately effective yet fail to stop degradation of bone tissue and loss of joint function We have identified a monoclonal antibody that targets the master controller of bone loss in these diseases Besides its novel mechanism anti DC STAMP antibody therapy offers advantage safety due to highly specific nature of targeting and requirement for less frequent dosing With further development this antibody will greatly improve the therapeutic options for erosive bone diseases


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.66K | Year: 2016

Abstract Inflammatory Bowel Disease IBD including primarily Crohnandapos s disease CD and ulcerative colitis UC is a chronic debilitating condition with no effective treatment The economic impact is disproportionally high because it affects primarily young individuals years old and the characteristic periods of remission and relapse necessitate frequent hospitalizations Furthermore some of patients with total bowel involvement will have colectomy and of patients with CD require some type of surgical intervention during their lifetime Symptoms like bloody diarrhea abdominal pain general malaise and fever significantly compromise quality of life IBD affects million Americans with annual healthcare costs approaching $ billion Current therapies anti inflammatory drugs immunosuppressants antibiotics and drugs for symptomatic relief are only modestly effective and often cause unacceptable adverse events particularly with long term use A new generation of biologics targets pathways of immune activation to block proinflammatory signaling All seven biologics showing clinical benefits in IBD are monoclonal antibodies including TNF integrin and IL blockers Mucosal healing and long term remission occur in only a minority of patients Significantly rare but life threatening conditions including increased risk for serious infections non Hodgkinandapos s lymphoma and melanoma have been associated with chronic exposure to anti TNF therapies The pharmaceutical management of IBD despite the revolutionizing use of biological therapies remains problematic Recent data support the hypothesis that melanin concentrating hormone MCH is a crucial link in inflammatory events affecting the mucosa Results from four animal models support a pivotal role for MCH signaling in IBD Both MCH and MCH receptor MCHR expression levels are elevated in biopsies of inflamed mucosa from IBD patients relative to non involved mucosa from the same patients A polyclonal rabbit anti MCH antibody attenuates chronic colitis and fibrosis in two animal models of colitis Further supporting a role for MCH in IBD MCH knock out mice are protected from experimental colitis induced by trinitrobenzene sulfonic acid TNBS During this Phase I project we will identify and characterize a neutralizing anti MCH human monoclonal antibody humAb Evaluation in both in vitro cellular and in vivo rodent models will be carried out We are optimistic that this work will result in a new therapeutic for CD and UC This biological therapy will reduce inflammation fibrosis and prolong periods of remission among patients suffering from IBD Narrative Inflammatory bowel disease IBD involves chronic inflammation of all or part of the colon IBD can be painful and debilitating necessitating frequent surgeries in many cases and sometimes leads to life threatening complications Current treatments are only modestly effective We have developed a new therapeutic that has the potential to reduce inflammation and tissue damage in this intractable disease


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.98K | Year: 2016

DESCRIPTION provided by applicant The anemia of chronic disease ACD anemia of inflammation is commonly observed in chronic inflammatory states and may hinder patient recovery and survival Induction of hepcidin mediated by IL leads to iron limited erythropoiesis and anemia Gardenghi Iron homeostasis reviewed by Ganz depends on regulated absorption and transport of dietary iron by means of the iron transport protein ferroportin and its regulatory peptide hepcidin All iron releasing cells including enterocytes macrophages and hepatocytes contain ferroportin Ferroportin activity is controlled by hepcidin Upon binding hepcidin ferroportin is internalized and degraded Fig When hepcidin concentrations are high ferroportin degradation exceeds its rate of synthesis and ferroportin is lost from cell membranes Without ferroportin macrophages fail to release iron recycled from senescent erythrocytes and hepatocytes retain stored iron Ongoing erythropoiesis depletes extracellular iron within hours Conversely when hepcidin concentrations are low ferroportin synthesis exceeds its degradation ferroportin re accumulates in cell membranes and increased amounts of iron flow from iron exporting cells into the extracellular fluid In ACD excessive hepcidin prevents iron mobilization for erythropoiesis Recently an erythroid factor erythroferrone ERFE was discovered to down regulate hepcidin in response to erythropoietic stimuli The size and composition of ERFE will lead to a short plasma half life and will limit its chronic use Therefore in this Phase I project we will construct a fusion protein containing ERFE fused to the human IgG Fc domain Fc fusion proteins have extended plasma half lives due to recycling by the FcRN receptor We will verify that the Fc fusions are active by measuring hepcidin down regulation in vitro evaluate the ability of ERFE Fc to increase serum iron levels in mice In addition we will carry out preliminary pharmacokinetic experiments to determine plasma half life Phase will focus on obtaining the preclinical data necessary for submission of an IND We expect ERFE Fc to address the unmet need of a rational therapy for the anemia of chronic disease PUBLIC HEALTH RELEVANCE The anemia of chronic disease ACD anemia of inflammation is associated with infectious inflammatory or neoplastic disease While often mild ACD complicates recovery of the patient We have identified an approach to treat ACD by targeting an iron metabolism pathway This therapeutic will allow rapid recovery from anemia with a convenient treatment regimen


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.98K | Year: 2015

DESCRIPTION provided by applicant Monoclonal antibody for autoimmune disease Abstract B cells play a major role in the pathogenesis of many autoimmune disorders including rheumatoid arthritis RA systemic lupus erythematosus SLE multiple sclerosis and type I diabetes mellitus as indicated by the efficacy of B cell targeted therapies like rituximab in thes diseases Unfortunately current therapies are predicated on B cell depletion which is problematic from a safety standpoint Due to immunosuppression existing standard of care therapies generate adverse effects notably opportunistic infections resulting from long term severe B cell depletion Recently an alternative approach involving the targeting of CD the transducer subunit of the B cell receptor BCR has been described Unlike anti CD mAbs the protective effects of CD targeted mAbs do not require cell depletion rather they act by inducing an unresponsive or anergic state in which B cells physically relocate and are unavailable to participate in immune response generation In the murine MRL lpr model of SLE anti CD antibodies were potently immunosuppressive and effective at decreasing inflammation and improving survival Li In a collagen induced arthritis model of rheumatoid arthritis anti CD antibodies delayed the onset of arthritis and decreased arthritis scores by inducing anergy with transient reversible B cell redistribution Hardy Based on these studies Phase work will identify and characterize a potent anti CD human monoclonal antibody Unlike other B cell targeted biologics that induce B cell death by ADCC complement fixation or survival factor starvation mediated cell death this approach will induce a transient state of polyclonal B cell anergy We expect this second generation immunosuppressive therapeutic to be significantly safer than existing B cell targeted antibodies PUBLIC HEALTH RELEVANCE Autoimmune diseases as a group impose a major health burden While most autoimmune diseases are individually rare in the aggregate they affect of Americans and can be life threatening Current treatments are moderately effective yet carry a heavy risk of adverse effects We have identified a monoclonal antibody specific to B cells which shows efficacy in animal models of rheumatoid arthritis and systemic lupus erythematosus This antibody therapy is safer than competing approaches because its effects are transient and can be quickly reversed if necessary With further development this antibody will greatly improve the therapeutic options for autoimmune diseases


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.98K | Year: 2015

DESCRIPTION provided by applicant Netherton syndrome NS is one of the most severe heritable skin disorders of neonates with life threatening symptoms that result from a defective skin barrier Severe complications in infants include recurrent bacterial infections dehydration and failure to thrive In adults NS is a chronic debilitating condition with no effective treatmet Current therapies anti inflammatory drugs immunosuppressants antibiotics and drugs for symptomatic relief are only modestly effective and often cause unacceptable adverse events particularly with long term use Recently the cause of NS was identified as mutations in an epidermal protease inhibitor LEKTI At neutral pH in the deep stratum corneum SC LEKTI binds and inhibits Kallikrein KLK In normal epidermis LEKTI inhibits KLK through a pH dependent interaction In the superficial SC where the pH is this complex dissociates permitting KLK to proteolytically activate additional epidermal kallikreins KLK and KLK as well as elastase ELA These proteases degrade corneodesmosomal proteins leading to shedding of superficial cells Recent data from human genetic studies animal models and siRNA knockdown of LEKTI in organotypic human tissue culture establish unregulated KLK activity as the underlying cause of NS An inhibitory antibody to KLK can provide an effective treatment for NS by blocking the KLK protease cascade in the SC During this Phase I project we will identify an inhibitory anti KLH human monoclonal antibody humAb We will evaluate inhibitory activity in vitro using an organotypic human skin culture model This work has the potential to result in a new therapeutic for NS by alleviating the life threatening skin barrier deficits in the newborn and reducing skin irritation and inflammation in adults This humAb may also be effective against other dermatological disorders including atopic dermatitis that involve activated KLK PUBLIC HEALTH RELEVANCE Netherton syndrome NS is one of the most severe heritable skin disorders of neonates with life threatening symptoms that result from a defective skin barrier In adults NS is a chronic debilitating condition with no effective treatment There are o approved treatments for NS with current therapies directed only on relief of symptoms We have identified a monoclonal antibody that targets the underlying cause of premature skin shedding in NS This antibody will provide the first specifically targeted mechanism based treatment for NS


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.62K | Year: 2015

DESCRIPTION provided by applicant Novel NMDA Receptor Antagonists for Beta Cell Rescue Abstract Type diabetes mellitus T DM is rapidly becoming the most common chronic disease in the US with more than of the adult population affected and million new cases per year Fundamentally T DM involves beta cell dysfunction and poor control of blood glucose levels resulting in hyperglycemia Impaired insulin secretion is accompanied by a decrease in beta cell mass an increase in apoptosis of beta cells and a reduced functional capacity of the remaining cells A disease modifying treatment would not only promote insulin secretion but also reduce apoptosis and increase proliferation of beta cells Recent data from animal models and Phase clinical studies in humans suggest that NMDA receptors NMDAR inhibit insulin release and promote beta cell death and that NMDAR antagonists act as insulin secretagogues and can increase beta cell mass Although further mechanistic studies are required to fully understand the function of NMDARs in beta cells NMDARs may act as part of a negative feedback loop in pancreatic islets to ensure that insulin is not released in an excessive manner at high blood glucose concentrations The lack of extreme blood glucose lowering effects with high dose and long term exposure to NMDAR antagonists suggests that such treatment is unlikely to lead to life threatening hypoglycemia such as is seen with sulfonylurea treatment The larger islet cell mass observed in diabetic mice upon long term treatment with a high dose versus a low dose of NMDAR antagonists also indicates that inhibition of NMDARs could maintain the number of beta cells in diabetes These data suggest that NMDAR antagonists may be useful to reduce or even reverse progression of human diabetes Memantine an aminoadamantane selectively inhibits abnormally active NMDAR channels while preserving normal activity and physiological neuronal function Memantine has been approved for the treatment of moderate to severe Alzheimerandapos s disease for over years Pathological NMDA receptor activity is further down regulated by S nitrosylation of specific cysteine residues Taking advantage of these insights PRI has developed a proprietary series of bifunctional antagonists called nitromemantines that not only preferentially bind to the open channel state but also selectively target NO to a second modulatory site on the NMDAR using the memantine pharmacophore as a homing motif During this Phase I study we will evaluate our lead nitromemantine YQW for its activity in vitro and in an animal model of T DM Successful achievement of these milestones will provide a proprietary first in class disease modifying drug for T DM PUBLIC HEALTH RELEVANCE Type diabetes mellitus T DM affects over million people worldwide and its incidence is increasing T DM is associated with an increased risk of disease of the eye kidney and cardiovascular system Current treatments do not alter the long term course of the disease We have developed a new class of drugs that bind to a receptor that is critical for normal function and maintenance of normal numbers of pancreatic beta cells the cells that secrete insulin We will evaluate these new compounds as potential treatments for T DM


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 223.80K | Year: 2015

DESCRIPTION provided by applicant Idiopathic pulmonary fibrosis IPF is a chronic fatal lung disease characterized by rapid progressive loss of pulmonary function IPF is a major health problem as it affects more than typically middle aged people in the USA Quality of life rapidly deteriorates due to dyspnea and IPF associated symptoms such as pulmonary hypertension and heart failure The year mortality rate for IPF is greater than many malignancies including bladder cancer colon cancer and multiple myeloma A major need exists for effective therapeutics IPF is characterized by increased collagen deposition fibrosis by an excessive number of myofibroblasts in the lung interstitium Inappropriate proliferation and function of fibroblasts alveolar epithelial cells and embedded mesenchymal stem cells play key roles in the pathogenesis of the disease Although the molecular mechanisms that underlie this idiopathic disease have been obscure recent progress has been made Of key importance has been the identification of Wnt signaling as necessary for fibrosis in a wide variety of fibrotic diseases including IPF This is consistent with Wnt signaling playing a key regulatory role in normal wound healing tissue repair and regeneration fibrotic disease in the lung results from aberrant repair regeneration in which alveolar type AT epithelial progenitor cells stop functioning midway through repair Attenuation of Wnt signaling decreases pulmonary fibrosis in several mouse models of IPF A unifying treatment hypothesis for fibrotic disease suggests that attenuating pathologically high levels of Wnt signaling but preserving sufficient signaling will allow repair to resume We have developed a biologically active monoclonal Ab mAb that binds to the E E domains of Wnt co receptor LRP to reduce Wnt signaling by direct competition The mAb also downregulates LRP expression through endocytosis Our anti LRP mAb likely works in part by competing with the pro fibrotic Wnts that activate canonical Wnt signaling and decreasing the ability of LRP to act as a co receptor for PDGF BB CTGF and TGF mediated signaling This mAb is expected to be biologically active in a wide range of conditions it has already been shown to exert significant biological activity in mouse models of diabetic retinopathy and choroidal neovascularization We have constructed humanized versions of this mAb that bind LRP to attenuate Wnt signaling We propose to demonstrate that a humanized anti LRP mAb will sufficiently antagonize Wnt signaling in pulmonary fibrosis to inhibit progression of fibrosis of IPF and restore the cellular and extracellular milieu to permit homeostatic repair Our anti LRP humAb is postulated to be a first in class rationally designed therapy to reduce fibrosis in IPF and may be useful in other fibrotic diseases affecting the skin liver and kidney associated with aberrant Wnt signaling PUBLIC HEALTH RELEVANCE Idiopathic pulmonary fibrosis IPF is a devastating progressive and ultimately fatal lung disease We have created a rationally targeted antibody as a potential therapeutic for IPF


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 955.59K | Year: 2015

DESCRIPTION provided by applicant Antibody Membrane Switch AMS technology for optimized antibody engineering Abstract Generation of high productivity cell lines remains a major bottleneck in therapeutic antibody development Conventional cell line development depends on gene amplification methodologies using dihydrofolate reductase DHFR or glutamine synthetase GS Higher productivity is associated with an increased gene copy number However lack of selection pressure under the conditions of large scale manufacturing leads to clonal instability We have developed a novel method for cell line development Antibody Membrane Switch AMS technology that does not rely on gene amplification This FACS based high throughput method is facilitated by cell surface antibody expression to rapidly and efficiently isolate high producing cells The switch between membrane expression and secretion is achieved by alternative splicing and specific DNA recombination The antibody of interest is initially displayed on the cell surface to facilitate FACS Isolated high producing cells are then seamlessly transformed into production cells after removing the membrane anchoring domain sequence via a DNA recombinase AMS technology has been applied in a number of antibody cell line development projects which typically last months The top manufacturing cell lines exhibit very high specific productivity of pg cell day resulting in production titers of g L in day batch culture In Phase I studies the underlying AMS methods were reduce to practice Furthermore we have optimized the AMS process using two biosimilar antibodies In Phase II these optimized methods will be applied to screening of CHO surface displayed antibody libraries An affinity maturation library and a na ve human antibody library will be constructed and utilized to screen by FACS for therapeutic antibody candidates The screening will be carried out with soluble antigen for high affinity binding or antigen e g GPCR presenting cells for desired bio activities The isolated positive cells will be transformed into antibody production cells by DNA recombinase to remove the membrane anchorage This successful application of AMS technology will permit the discovery of antibodies to be seamlessly linked to downstream cell line development providing the basis for rapid facile cell line production directly from a novel antibody discovery platform Phase I R AI A PUBLIC HEALTH RELEVANCE Therapeutic antibodies are expensive in part due to the costly time consuming steps involved in the development of stable high expressing cell lines for production We describe a novel cell line development method that utilizes alternative splicing of a membrane anchored Fc domain and fluorescence activated cell sorting FACS to rapidly identify antibody production cell lines with greatly reduced time and cost The same platform will be optimized to screen affinity maturation or synthetic antibody libraries and thereby facilitating seamless transformation into production cell lines


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.78K | Year: 2015

DESCRIPTION provided by applicant Diabetic nephropathy DN is the most common cause of end stage renal disease ESRD in the world and affects about of type I diabetes patients and of patients with type II diabetes Clinical DN evolves in a sequence of stages initially with increases in glomerular filtration rate GFR and intraglomerular capillary pressure glomerular hypertrophy and microalbuminuria Poor glycemic control further exacerbates the disease progression to proteinuria nodular glomerulosclerosis and tubulointerstitial injury and a decline in GFR which can eventually lead to ESRD The development of DN is thought to result from the cumulative interactions among multiple metabolic and hemodynamic factors which activate intracellular signaling pathways that trigger the production of cytokines and growth factors leading to fibrotic renal disease Although TGF undoubtedly contributes to renal fibrosis therapeutic attempts to neutralize it are potentially problematical due to the pleiotropic some beneficial effects of TGF in normal tissues Moreover there are other pro fibrotic agents implicated in DN that represent novel therapeutic targets One such target is marinobufagenin MBG a cardiotonic steroid that has been implicated as a mediator of fibrosis in renal and cardiac diseases The E monoclonal antibody mAb produced by a murine hybridoma neutralizes MBG and has anti fibrotic activity in various in vitro assays and in rodent models of renal and cardiac fibrosis The overall goal of this projec is to develop a humanized E mAb hu E as a therapy for diabetic nephropathy The murine E has been cloned expressed in mammalian cells and its biological activity confirmed The first aim is to humanize E and if necessary use affinity maturation technology to increase its binding affinity and specificity for MBG A CHO cell line stably expressing hu E will be developed Finally E will be evaluated in a mouse model of DN induced by streptozotocin treatment of mutant mice deficient in endothelial nitric oxide synthase The results of this study will establish the feasibility of future preclinical and clinical development of hu E as a novel therapy for DN and possibly other fibrotic diseases PUBLIC HEALTH RELEVANCE Marinobufagenin MBG is a cardiotonic steroid that has been implicated as a mediator of fibrosis in renal and cardiac diseases The goal of this project is to develop a completely human antibody that neutralizes MBG for diabetic nephropathy and possibly other fibrotic diseases

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