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MADISON, WI, United States

Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 986.86K | Year: 2009

DESCRIPTION (provided by applicant): The ultimate goal of this project is to develop a new safe AND effective tool for physicians to treat patients with cancer. The EVade Ribonucleases are recombinant variants of mammalian enzymes that are effective in mouse xenograft models of multiple cancer types without exhibiting significant toxicity. While they are effective, Quintessence is interested in increasing the potency of the EVade Ribonucleases to improve clinical outcome. Many of the FDA approved cancer therapies work by very similar mechanisms, including genotoxicity, anti- metabolite and microtubule binding. Newer, targeted therapies are being developed, with a few of these drugs already on the market. We believe an agent with a novel mechanism of action and mild side effect profile, such as an EVade Ribonuclease, is a strong candidate for cancer therapy. In Phase I, the pharmacokinetic profile of the EVade Ribonucleases was changed by conjugation with polyethylene glycol (PEG). These changes resulted in a significant increase (gt20%) in efficacy in vivo at five-fold lower doses than the unmodified Evade Ribonucleases. While benefits of PEG7EVade RNase conjugates has been demonstrated, additional research is necessary to ensure the lead candidate, a conjugate called QBI-206, can be successfully commercialized. The primary goal of the Phase II SBIR grant is to provide data to support the tangible benefits of the conjugate relative to the unconjugated Evade RNase QBI-139. The specific activities for the Phase II grant include: determination of the optimal schedule, a dose response and comparison of antibody formation to an unmodified EVade Ribonuclease. In addition, the side effects of QBI-206 will be compared to an unmodified EVade Ribonuclease (QBI-139) will be determined in a model that provides a direct link to doses to be used in human clinical trials. These activities are all directed to taking QBI-206 into a Phase I human clinical trial. PUBLIC HEALTH RELEVANCE: There is a clear and unfilled need for highly efficacious cancer therapeutics, and our goal is to provide an effective new tool for physicians to treat their patients who have cancer. Cancer is the second most common cause of death in the developed world. On a worldwide basis, cancer is responsible for 12.5% of deaths. New cases of cancer are expected to rise to 16M/year in 2020, up from 11M /yr in 2002. Cancer-related deaths are anticipated to rise from 6.7M to 10M over the same period.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 131.20K | Year: 2006

DESCRIPTION (provided by applicant): Development of technologies enabling early drug absorption profiling for novel drug candidates is one of the crucial issues facing modern drug discovery research. Current approaches are low-throughput and suffer from difficulties with poor reproducibility and poor compatibility with existing instrumentation. To overcome these barriers, we propose to develop a surface plasmon resonance imaging (SPR/)-based microarray assay for drug absorption profiling in a standardized format. The basis for this novel assay is mixture of amphiphilic polymers that can extract membrane proteins and lipids from natural membranes by formation of stable micelle-membrane component complexes (PM-Mem). Such micelles can be effectively immobilized on a SPRi biosensor surface via polymeric tethers. Each SPRi biosensor chip can accommodate multiple spots with biological membrane components extracted from various tissues. This technology provides significant benefits over traditional liposome sensor coatings due to the stability of PM-Mem. The research plan for this Phase I SBIR application includes: 1) optimization of the composition of the polymeric micelles, the extraction procedure from model natural cell membranes using the polymeric micelles, and the immobilization of the PM-Mem on the surface of SPRi biosensor chips; 2) development of a reliable protocol for detecting drug absorption (binding) of different concentrations of a model drug to the SPRi biosensor surface; 3) validation of the principle of our microarray approach by using SPRi biosensor chips coated with PM-Mem formed from the membrane components of model natural membrane preparations (1) to compare binding of single model drug to model cell membranes in two membrane formulations (hybrid bilayers and PM-Mem) and (2) to screen a panel of six drugs with different absorption profiles to establish a correlation between each drug's fraction absorbed (Fa) quotient and its partitioning into the biosensor chip surface. Relevance of the proposed research to the public health: The proposed research is highly relevant to the public health because the methods we propose to develop may provide a break-through in drug discovery research. Using the approaches described in this application may enable researchers to predict quickly, efficiently, and cost-effectively how well the body will likely absorb a potential new drug before animal testing. Our future research plans extend to examining how a potential new drug would be distributed throughout the various tissues in the body.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 170.37K | Year: 2008

The aim of this project is to develop a novel ribonuclease for the treatment of cancer. The molecule will be modified using polyethylene glycol in order to achieve the desired properties.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 157.74K | Year: 2007

DESCRIPTION (provided by applicant): The goal of this project is to develop a safe yet potent antibody-drug conjugate (ADC) by utilizing an EVade(tm) Ribonuclease as the drug. The EVade(tm) Ribonucleases are variants of mammalian enzymes that are effective in mouse xenograft models of multiple cancer types without exhibiting significant toxicity. While they are effective, we are interested in increasing the potency of the EVade(tm) Ribonucleases to improve clinical outcome. Many of the newer, targeted cancer therapies, such as monoclonal antibodies, are approved only in combination with other agents, typically small molecule cytotoxics. Small molecule cytotoxics are potent, but tend to cause serious adverse effects. The combination of the small molecules with the targeted therapies leads to improved efficacy but cancels out any safety benefits of the targeted drugs. We would like to pursue a strategy that would increase the chances of successful treatment without adding toxic side effects. We will conjugate a well characterized antibody reactive against CEA-expresssing cancer cells to a unique cysteine engineered in a potent EVade(tm) Ribonuclease using a variety of linkers. The linkers will be varied in their reactivity towards the antibody (activated ester or hyrdzide) and the ribonuclease (maleimide, thiol, haloacetyl, and 2- pyridyldithio). Some of the linkers can be cleaved in the cell while others will remain stable. The antibody-ribonuclease conjugates will be tested for antigen binding and enzymatic activity. Active conjugates will be tested in vitro (cell proliferation) against CEA-expressing and cell lines not known to express CEA. Promising candidates will then be further screened in a mouse xenograft model with a CEA overexpressing cell line. The ultimate goal of this project is to develop a new safe AND effective tool for physicians to treat patients with cancer. There is a clear and unfilled need for highly efficacious cancer therapeutics, and our goal is to provide an effective new tool for physicians to treat their patients who have cancer. In the year 2003, the National Cancer Institute estimated that 1.3 million Americans will be newly diagnosed with cancer and that more than 1,500 Americans died from cancer each day.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 125.61K | Year: 2007

DESCRIPTION (provided by applicant): 6. Project Summary Abstract The goal of this project is to develop a safe yet potent drug utilizing an EVade(tm) Ribonuclease. The EVade(tm) Ribonucleases are recombinant variants of mammalian enzymes that are effective in mouse xenograft models of multiple cancer types without exhibiting significant toxicity. While they are effective, Quintessence is interested in increasing the potency of the EVade(tm) Ribonucleases to improve clinical outcome. Many of the FDA approved cancer therapies work by very similar mechanisms, including genotoxicity, anti-metabolite and microtubule binding. Newer, targeted therapies are being developed, with a few of these drugs already on the market. We believe an agent with a novel mechanism of action and mild side effect profile, such as an EVade(tm) Ribonuclease, is a strong candidate for cancer therapy. We will change the pharmacokinetic profile of the EVade(tm) Ribonucleases. The EVade(tm) RNase and macromolecules for conjugation were selected because they have shown efficacy in vivo. The initial experiments will produce and characterize the next generation EVade(tm) RNases while the second round will determine the in vivo effects of combining the conjugated EVade(tm) Ribonucleases at various concentrations. The ultimate goal of this project is to develop a new safe AND effective tool for physicians to treat patients with cancer.

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