Potent High-Affinity Antibodies for Treatment and Prophylaxis of Respiratory Syncytial Virus Derived from B Cells of Infected Patients

• Published in: The Journal of immunology (1950) Vol. 183; no. 10; pp. 6338 - 6345
• Main Authors: Collarini, Ellen J, Lee, F. Eun-Hyung, Foord, Orit, Park, Minha, Sperinde, Gizette, Wu, Hai, Harriman, William D, Carroll, Stephen F, Ellsworth, Stote L, Anderson, Larry J, Tripp, Ralph A, Walsh, Edward E, Keyt, Bruce A, Kauvar, Lawrence M
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.11.2009
• Subjects: Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - metabolism; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Antibodies, Viral - immunology; Antibodies, Viral - therapeutic use; Antibody Affinity - immunology; Antigens, Viral - immunology; Antigens, Viral - metabolism; B-Lymphocytes - immunology; B-Lymphocytes - virology; Cell Line; Humans; Mice; Neutralization Tests; Palivizumab; Recombinant Proteins - immunology; Respiratory Syncytial Virus Infections - prevention & control; Respiratory Syncytial Virus Infections - therapy; Respiratory Syncytial Virus, Human - immunology; Transfection; Viral Fusion Proteins - immunology; Viral Load - drug effects; Viral Load - immunology
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.0901373

Native human Abs represent attractive drug candidates; however, the low frequency of B cells expressing high-quality Abs has posed a barrier to discovery. Using a novel single-cell phenotyping technology, we have overcome this barrier to discover human Abs targeting the conserved but poorly immunogenic central motif of respiratory syncytial virus (RSV) G protein. For the entire cohort of 24 subjects with recent RSV infection, B cells producing Abs meeting these stringent specificity criteria were rare, <10 per million. Several of the newly cloned Abs bind to the RSV G protein central conserved motif with very high affinity (Kd 1–24 pM). Two of the Abs were characterized in detail and compared with palivizumab, a humanized mAb against the RSV F protein. Relative to palivizumab, the anti-G Abs showed improved viral neutralization potency in vitro and enhanced reduction of infectious virus in a prophylaxis mouse model. Furthermore, in a mouse model for postinfection treatment, both anti-G Abs were significantly more effective than palivizumab at reducing viral load. The combination of activity in mouse models for both prophylaxis and treatment makes these high-affinity human-derived Abs promising candidates for human clinical testing.