INFECTIOUS DISEASE 2017 © The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. A highly potent extended half-life antibody as a potential RSV vaccine surrogate for all infants Qing Zhu, 1 * † Jason S. McLellan, 2† Nicole L. Kallewaard, 1 Nancy D. Ulbrandt, 1 Susan Palaszynski, 1 Jing Zhang, 1 Brian Moldt, 1 Anis Khan, 3 Catherine Svabek, 1 Josephine M. McAuliffe, 1 Daniel Wrapp, 2 Nita K. Patel, 1 Kimberly E. Cook, 4 Bettina W. M. Richter, 1 Patricia C. Ryan, 5 Andy Q. Yuan, 4 JoAnn A. Suzich 1 * Prevention of respiratory syncytial virus (RSV) illness in all infants is a major public health priority. However, no vaccine is currently available to protect this vulnerable population. Palivizumab, the only approved agent for RSV prophylaxis, is limited to high-risk infants, and the cost associated with the requirement for dosing throughout the RSV season makes its use impractical for all infants. We describe the development of a monoclonal antibody as potential RSV prophylaxis for all infants with a single intramuscular dose. MEDI8897*, a highly potent human antibody, was opti- mized from antibody D25, which targets the prefusion conformation of the RSV fusion (F) protein. Crystallographic analysis of Fab in complex with RSV F from subtypes A and B reveals that MEDI8897* binds a highly conserved epitope. MEDI8897* neutralizes a diverse panel of RSV A and B strains with >50-fold higher activity than palivizumab. At similar serum concentrations, prophylactic administration of MEDI8897* was ninefold more potent than palivizumab at re- ducing pulmonary viral loads by >3 logs in cotton rats infected with either RSV A or B subtypes. MEDI8897 was gen- erated by the introduction of triple amino acid substitutions (YTE) into the Fc domain of MEDI8897*, which led to more than threefold increased half-life in cynomolgus monkeys compared to non-YTE antibody. Considering the pharma- cokinetics of palivizumab in infants, which necessitates five monthly doses for protection during an RSV season, the high potency and extended half-life of MEDI8897 support its development as a cost-effective option to protect all infants from RSV disease with once-per-RSV-season dosing in the clinic. INTRODUCTION Respiratory syncytial virus (RSV) is the most prevalent cause of viral lower respiratory tract disease among infants and young children worldwide (1–4). RSV circulates seasonally in temperate regions, usually between late fall and early spring. In developing countries, it is among the leading causes of infant death (2). Although deaths due to RSV are rare in the developed world, it is a significant cause of infant hospital- ization and is also responsible for a large outpatient health care burden (1, 4, 5). In addition to acute disease, RSV lower respiratory infections in infancy have been associated with long-term wheezing and asthma ( 6–10). There is no licensed vaccine available for RSV despite 50 years of research and development. One reason for this lack of progress is that the highest rates of RSV hospitalization are in infants ≤2 months of age (11, 12) when the ability to elicit strong anti-RSV responses may be com- promised by the presence of maternal antibodies and the immaturity of the infant immune system. In addition, there are concerns that nonlive vaccine compositions could result in vaccine-enhanced RSV disease similar to what was observed with a formalin-inactivated vaccine candidate administered to seronegative infants in the 1960s (13). Live-attenuated RSV vaccines and chimeric viruses expressing RSV antigens (14, 15) are not considered a risk for inducing enhanced disease; however, achieving a proper balance between attenuation (safety) and immunogenicity, as well as genetic stability, has been difficult. To date, these types of vac- cines have been either over- or underattenuated when tested in infants (16, 17). An alternative approach to RSV prevention is passive immuno- prophylaxis with neutralizing antibody. RSV encodes 11 proteins, in- cluding the fusion (F) and attachment (G) surface glycoproteins that are targets for virus-neutralizing antibodies. The mature F protein is a trimer of heterodimers consisting of disulfide-linked F1 and F2 subunits. This highly conserved protein exists on the surface of virions in a pre- fusion conformation that drives an irreversible conformational change that brings the viral and host cell membranes together as it adopts a stable postfusion conformation (18). Preventing this conformational change from occurring blocks viral entry, and most of the neutralizing activity detected in a human immunoglobulin (IgG) preparation capable of pro- tecting at-risk infants from RSV disease was found to be directed against the prefusion conformation of RSV F (19). Palivizumab, a humanized monoclonal antibody (mAb) directed against a neutralizing epitope found on both the pre- and postfusion forms of the RSV F protein, is effective in preventing RSV hospitaliza- tion in infants and children at highest risk for serious disease (that is, premature infants, children with chronic lung disease of prematurity, or children with congenital heart disease) (20). This antibody is administered at a dose of 15 mg/kg body weight by intramuscular injection once a month throughout the RSV season. The current cost of this mAb prophylaxis, along with the inconvenience of once-a- month injections, makes immunoprophylaxis with palivizumab un- feasible for healthy infants who nonetheless would benefit from RSV prevention. Since the licensure of palivizumab almost 20 years ago, new methods of antibody generation have led to identification of broadly neutralizing mAbs targeting the prefusion form of the RSV F protein that are much more potent than palivizumab (21, 22). Technologies have also been invented to extend the serum half-lives of antibodies (23–25), and 1 Department of Infectious Disease, MedImmune LLC, One MedImmune Way, Gaithers- burg, MD 20878, USA. 2 Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, 7200 Vail Building, Hanover, NH 03755, USA. 3 Department of Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, MedImmune LLC, One MedImmune Way, Gaithersburg, MD 20878, USA. 4 Department of Antibody Dis- covery and Protein Engineering, MedImmune LLC, One MedImmune Way, Gaithers- burg, MD 20878, USA. 5 Biologics Safety Assessment, MedImmune LLC, One MedImmune Way, Gaithersburg, MD 20878, USA. †These authors contributed equally to this work. *Corresponding author. Email: suzichj@medimmune.com (J.A.S.); zhuq@medimmune. com (Q.Z.) SCIENCE TRANSLATIONAL MEDICINE | RESEARCH ARTICLE Zhu et al., Sci. Transl. 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