SBIR-STTR Award

The common cold is a benign disease that also causes ear infections in children and is a leading cause of "attacks" in asthmatic patients. Common cold infections have a great economic impact but are currently treated by OTC remedies intended to alleviate symptoms. Human rhinoviruses cause 70 percent of colds and include >120 different serotypes. This large genetic diversity makes development of a vaccine near impossible. However, about 90 percent of rhinovirus serotypes bind to nasal epithelial cell surface receptor, ICAM- 1. We have developed prototype anti-ICAM-1 antibody fusion constructs that bind to ICAM-1 with high affinity and that prevent rhinovirus infection in cell culture assays. High affinity (low Koff) antibodies are essential for durable protection from infection. This proposal describes a novel method for in vitro affinity enhancement of the antibody through selective amino acid substitutions. The choice of residues to mutate is critical for efficiency and success. Amino acid residues are mutated individually and together to generate E. coli based libraries. Libraries are screened using an "off rate" screening method designed to select for specific, high affinity (low Koff) binding. Once the core antibody has been affinity enhanced, it will be used to generate fusion constructs for clinical evaluation

The common cold is the most prevalent disease affecting humans, and 70% of cases are caused by rhinoviruses (HRV). The majority of HRV serotypes bind ICAM-1 on nasal epithelial cells as the initial step in the infectious cycle: therefore preventing HRV from binding to ICAM-1 should prevent HRV attachment and thereby either prevent or shorten the duration and decrease symptoms of existing colds. A human clinical trial using intranasal administration of an anti-ICAM whole antibody delayed the onset of colds by up to 2 days and decreased symptoms 50% but failed to prevent initial infection, It is now known that the antibody CAM-1 dissociation rate is similar to that of the HRV virion itself indicating that the antibody has no innate advantage in functional affinity over the virus in occupying available receptors. We have generated a tetravalent humanized antibody against ICAM-1 for the prevention and treatment of human rhinovirus (HRV) infections. This protein shows significant functional improvement over the monodonal antibody and it can be produced in bacteria at much lower cost. The goals of the proposed phase II study is to fully characterize the biological, physical and chemical properties of the tetravalent anti-ICAM antibody, optimize the production process, establish quality control assays and to optimize the nasal spray formulation. Result from these studies will support filing of IND to obtain approval from FDA for clinical trials.

Thesaurus Terms:
cell adhesion molecule, common cold, immunologic substance development /preparation, immunopharmacology, rhinovirus biotherapeutic agent, disease /disorder prevention /control, dosage forms, drug screening /evaluation, monoclonal antibody, protein engineering, respiratory epithelium, respiratory virus Escherichia coli, peptide library, protein purification