SBIR-STTR Award

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

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 (>20%) 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.

Thesaurus Terms:
(Sp-4-2)-Diamminedichloroplatinum; 1-(2-Oxo-4-Amino-1,2-Dihydropyrimidin-1-Yl)-2-Deoxy-2,2-Difluororibose; 2',2'-Dfdc; 2',2'-Difluoro-2'-Deoxycytidine; 2',2'-Difluorodeoxycytidine; 2'-Deoxy-2'-Difluorocytidine; 2'deoxy-2',2'-Difluorocytidine; 2,2 Difluorodexoycytidine; Adverse Effects; Amino Acid Substitution; Animals; Anti-Cancer Agents; Anti-Tumor Agents; Anti-Tumor Drugs; Antibodies; Antibody Formation; Antibody Production; Antibody Response; Antineoplastic Agents; Antineoplastic Drugs; Antineoplastics; Antiproliferative Agents; Antiproliferative Drugs; Assay; Binding; Binding (Molecular Function); Bioassay; Biochemical; Biologic Assays; Biological Assay; Blood Plasma; Blood Serum; Cddp; Cancer Drug; Cancer Patient; Cancer Treatment; Cancers; Carcinoma, Non-Small-Cell Lung; Cause Of Death; Cessation Of Life; Chemistry; Chemotherapeutic Agents, Neoplastic Disease; Chromatography, High Performance Liquid; Chromatography, High Pressure Liquid; Chromatography, High Speed Liquid; Cis-Diammine-Dichloroplatinum; Cis-Diamminedichloridoplatinum; Cis-Diamminedichloro Platinum (Ii); Cis-Dichloroammine Platinum (Ii); Cis-Platinous Diamine Dichloride; Cis-Platinum Ii; Cis-Platinum Ii Diamine Dichloride; Cisplatin; Cisplatina; Cisplatinum; Clinic; Clinical; Clinical Trials; Clinical Trials, Phase I; Clinical Trials, Unspecified; Commit; Common Rat Strains; Complex; Compliance Behavior; Cysplatyna; Ddp; Data; Death; Detection; Development; Development And Research; Dichlorodiammineplatinum; Difluorodeoxycytidine; Dose; Drug Kinetics; Drugs; Elisa; Early-Stage Clinical Trials; Ensure; Enzyme-Linked Immunosorbent Assay; Enzymes; Erlotinib; Evaluation; Exhibits; Fda; Fda Approved; Family Suidae; Financial Support; Food And Drug Administration; Food And Drug Administration (U.S.); Gamma Globulin, 7s; Gastrointestinal Tract, Pancreas; Gene Products, Rna; Generalized Growth; Genital System, Male, Prostate; Goals; Government; Grant; Growth; Hplc; Hand; High Pressure Liquid Chromatography; Histopathology; Human; Human Prostate; Human Prostate Gland; Human, General; Igg; Immune Response; Immunoglobulin G; In Vitro; Investigational New Drug Application; Kidney; Killings; Lead; Left; Link; Liver; Macrogols; Malignant Cell; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant Neoplasms; Malignant Tumor; Mammals, Mice; Mammals, Rats; Mammals, Rodents; Man (Taxonomy); Man, Modern; Marketing; Mass Spectrum; Mass Spectrum Analysis; Measures; Medication; Methods; Mice; Micro-Tubule; Microtubules; Modeling; Molecular Interaction; Murine; Mus; N-Debenzoyl-N-(Tert-Butoxycarbonyl)-10-Deacetyltaxol; Nsclc; Nsclc - Non-Small Cell Lung Cancer; New Agents; Non-Small Cell Lung Cancer; Non-Small-Cell Lung Carcinoma; Nucleases, Rna; Organ; Outcome; Ovarian; Peg; Pancreas; Pancreatic; Pancreatic Rnase; Pancreatic Ribonuclease; Patient Compliance; Patient Cooperation; Patients; Pb Element; Peptide Fingerprinting; Peptide Mapping; Performance; Persons; Peyrone's Chloride; Peyrone's Salt; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Preparations; Pharmaceuticals; Pharmacokinetics; Pharmacologic Substance; Pharmacological Substance; Phase; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Photometry/Spectrum Analysis, Mass; Physicians; Pigs; Plasma; Platinum Diamminodichloride; Platinum, Diaminedichloro-, Cis- (8ci); Platinum, Diamminedichloro-, (Sp-4-2)-; Polyethylene Glycols; Polyethylene Oxide; Polyethyleneoxide; Polyoxyethylenes; Procedures; Production; Program Development; Programs (Pt); Programs [publication Type]; Prostate; Prostate Gland; Prostatic Gland; Proteins; Protocols, Treatment; Qualifying; R & D; R&D; Rgm; Rna; Rna, Non-Polyadenylated; Rnase; Rnase A; Rnase I; Rat; Rattus; Recombinants; Regimen; Relative; Relative (Related Person); Research; Research Resources; Resources; Reticuloendothelial System, Serum, Plasma; Ribonuclease A; Ribonuclease Family Protein; Ribonuclease I; Ribonucleases; Ribonucleic Acid; Rodent; Rodentia; Rodentias; Sbir; Sbirs (R43/44); Sched; Sampling; Schedule; Science Of Chemistry; Screening Procedure; Serum; Serum, Plasma; Small Business Innovation Research; Small Business Innovation Research Grant; Spectrometry, Mass; Spectroscopy, Mass; Spectrum Analyses, Mass; Spectrum Analysis, Mass; Structure; Suidae; Swine; Tarceva; Taxotere; Therapeutic; Tissue Growth; Toxic Effect; Toxicities; Toxicology; Treatment Compliance; Treatment Protocols; Treatment Regimen; Treatment Schedule; Treatment Side Effects; Tumor-Specific Treatment Agents; Usfda; United States Food And Drug Administration; Urinary System, Kidney; Variant; Variation; Work; Xenograft Model; Antibody Biosynthesis; Anticancer Agent; Anticancer Drug; Anticancer Therapy; Base; Body System, Hepatic; Cancer Cell; Cancer Therapy; Cancer Type; Candidate Selection; Cis Dichlorodiammineplatinum; Cis Platinum Compound; Cis-Diaminedichloroplatinum; Cis-Diamminedichloroplatinum; Cis-Diamminedichloroplatinum(Ii); Cis-Dichlorodiammineplatinum(Ii); Cis-Platinum; Clinical Investigation; Commercial Application; Commercialization; Compliance Cooperation; Cost; Dfdc; Dfdcyd; Docetaxel; Docetaxol; Drug Efficacy; Drug/Agent; Effective Therapy; Gemcitabine; Gene Product; Genotoxicity; Heavy Metal Pb; Heavy Metal Lead; Host Response; Immunogenicity; Immunoglobulin Biosynthesis; Immunoresponse; Improved; In Vivo; Inhibitor; Inhibitor/Antagonist; Interest; Malignancy; Neoplasm/Cancer; Nonsmall Cell Lung Cancer; Novel; Ontogeny; Organ System, Hepatic; Patient Adherence; Phase 1 Study; Phase 1 Trial; Phase I Trial; Porcine; Programs; Protein Folding; Protocol, Phase I; Public Health Relevance; Renal; Research And Development; Response; Scale Up; Screening; Screenings; Side Effect; Small Molecule; Suid; Therapeutic Protein; Therapy Adverse Effect; Therapy Compliance; Therapy Cooperation; Tool; Treatment Adverse Effect; Tumor Growth