The goal of this project is to create a human recombinant polyclonal antibody (HRPA) therapy against C. difficile associated disease (CDAD). Over the last several decades, C. difficile has become the most important cause of nosocomial diarrhea in the U.S., Canada and Europe. Previously first-line antibiotic treatments are increasingly ineffective against emerging antibiotic-resistant strains and the mortality rate from CDAD is rising. New treatment options are desperately needed. The HRPA therapy for CDAD proposed here will consist of several antibodies targeting multiple antigens and epitopes of the disease organism. Development of an HRPA therapy is a complex, multi-stage process. The phase I goal is to create a small but viable library of human antibodies against C. difficile to demonstrate the feasibility of creating a more complete library in a phase II study for testing in animals. The phase I specific aims for this project are: 1. to recruit subjects from three groups of potential donors with known or likely exposure to C. difficile, obtain blood samples and isolate the plasma cells in order to clone the antibody genes; 2. to generate a test library of cloned and expressed antibodies using a subset of the plasma cells obtained from each donor; 3. to optimize and carry out an ELISA-based screen for antibodies recognizing C. difficile proteins in culture supernatant, bacterial lysate and toxins; and 4. to analyze the antibody library generated in aim 3 and determine whether additional screening will be required for the Phase II study. Following a successful Phase I, the goals of a Phase II study would be: 1. to analyze the antibody-epitope interactions of antibodies obtained in Phase I; 2. to perform large scale expression and purification of C. difficile antibodies; and 3. to carry out a series of animal studies to examine the effectiveness of several antibody cocktails in an animal model of CDAD. Following the successful completion of animal trials, Excelimmune will seek to bring a CDAD therapeutic product to market through strategic partnerships with larger biopharmaceutical companies.
Public Health Relevance: C. difficile associated disease (CDAD) is a growing public health problem due to the rise of highly virulent, antibiotic resistant strains. According to the CDC, approximately 3 million cases of CDAD occur annually, with mortality rates of approximately 1-2.5%, and these numbers are on the rise. The overall goal of this project is to develop a novel therapeutic for CDAD, based on the use of cloned human antibodies that will effectively treat the disease and prevent the rise of resistant strains.
Public Health Relevance Statement: Project Narrative C. difficile associated disease (CDAD) is a growing public health problem due to the rise of highly virulent, antibiotic resistant strains. According to the CDC, approximately 3 million cases of CDAD occur annually, with mortality rates of approximately 1-2.5%, and these numbers are on the rise. The overall goal of this project is to develop a novel therapeutic for CDAD, based on the use of cloned human antibodies that will effectively treat the disease and prevent the rise of resistant strains.
Project Terms: ATGN; Animal Model; Animal Models and Related Studies; Animals; Antibiotic Agents; Antibiotic Drugs; Antibiotic Resistance; Antibiotic Therapy; Antibiotic Treatment; Antibiotics; Antibodies; Antibody Repertoire; Antibody Therapy; Antigenic Determinants; Antigens; Binding; Binding (Molecular Function); Binding Determinants; Biologic Products; Biological Agent; Biological Products; Blood Plasma Cell; Blood Sample; Blood Serum; Blood specimen; C. difficile; C.difficile; CDC; Canada; Cell Isolation; Cell Segregation; Cell Separation; Cell Separation Technology; Centers for Disease Control; Centers for Disease Control (U.S.); Centers for Disease Control and Prevention; Centers for Disease Control and Prevention (U.S.); Clinical Trials, Phase II; Clostridium; Clostridium difficile; Complex; Deposit; Deposition; Diarrhea; Disease; Disorder; Donor Screening; Donor Selection; ELISA; Effectiveness; Enzyme-Linked Immunosorbent Assay; Epitopes; Europe; Exposure to; Generations; Genes; Goals; Human; Human Cloning; Human Development; Human Engineering; Human, General; ITX; Immune response; Immunoglobulin V; Immunoglobulin Variable Region; Immunologically Directed Therapy; Immunotherapeutic agent; Immunotherapy; Individual; Infectious Diseases / Treatment, General; Libraries; Man (Taxonomy); Man, Modern; Marketing; Membrane Proteins; Membrane-Associated Proteins; Miscellaneous Antibiotic; Molecular Interaction; Mortality; Mortality Vital Statistics; Organism; Phase; Phase 2 Clinical Trials; Phase II Clinical Trials; Plasma Cells; Plasmacytes; Pressure; Pressure- physical agent; Process; Proteins; Public Health; Recombinants; Recruitment Activity; Refractory; Research; Resistance; Resistance to antibiotics; Resistance, Antibiotic; Resistant to antibiotics; Screening procedure; Selection Criteria; Series; Serum; Sorting - Cell Movement; Staging; Surface; Surface Proteins; System; System, LOINC Axis 4; Testing; Therapeutic; Toxin; Treatment of Infectious Diseases; United States Centers for Disease Control; United States Centers for Disease Control and Prevention; Validation; Variable Region; Variable Region, Ig; Virulent; abstracting; animal efficacy; antibiotic resistant; bacterial immunostimulant; bacterial lysate; base; biopharmaceutical; biotherapeutic agent; cell sorting; disease/disorder; efficacy trial; gene product; host response; immune therapy; immunogen; immunologic preparation; immunoresponse; immunotherapeutics; interest; living system; model organism; new therapeutics; next generation therapeutics; novel; novel therapeutics; pathogen; peripheral blood; phase 2 study; phase 2 trial; phase II trial; plasmocyte; polyclonal antibody; polyclonal human antibody; pressure; prevent; preventing; protocol, phase II; public health medicine (field); recruit; resistant; resistant strain; screening; screenings; sorting; study, phase II; success; treatment of bacterial diseases; treatment of bacterial infectious disease
