Antibody therapies for the prevention and treatment of viral infections

Salazar, Georgina; Zhang, Ningyan; Fu, Tong-Ming; An, Zhiqiang

addition to the activities in developing MSL-109 as a therapy, the antibody was a subject for a series of mechanistic studies, Fig. 4 Representation of the combination of proteomics and high-throughput sequencing approaches to isolation of relevant mAbs from human donors. Analysis of nucleic acids from B cells combined with proteomic analysis of antibodies in serum provides a deeper understanding of the humoral response to viral infection and vaccinations. The diagram was generated based on a combination of publications 17, 18, 38, 39 including some that defined the mechanism by which HCMV escapes neutralization by MSL-109 57 . The other component of RG7667, MCMV3068A, binds the pentameric gH complex. MCMV3068A was isolated from a mouse hybridoma and subsequently humanized. 49 RG7667 is developed by Genentech as a treatment to prevent HCMV infection in utero and in solid organ and hematopoietic stem cell transplant recipients. Phase 1 studies of RG7667 showed to be safe and well-tolerated and had a favorable pharmacokinetic and immunogenicity profile. The study supports further development of RG7667 as a therapy for the prevention and treatment of HCMV infection in susceptible populations. 49 In a Phase 2 trial in high-risk kidney transplant recipients, RG7667 was well tolerated, numerically reduced the incidence of HCMV infection within 12 and 24 weeks post-transplantation; it was statistically significant for delaying time to HCMV viremia, and was associated with few cases of HCMV disease compared to placebo. 58 Influenza. Influenza virus infections are common and usually cause only mild illness. Typical therapy involves respiratory precautions and medication such as oseltamivir (Tamiflu), that inhibit the influenza protein neuraminidase involved in release of virus particles. However, development of resistance to neuraminidase inhibitors is a problem. 59 Influenza viruses have a unique flexibility which tolerates small errors, resulting in a change of viral structure known as "antigenic drift" that allows escape of the immune response. 60 The seasonal flu vaccine protects against the influenza viruses that are predicted to be most common during the upcoming season. However, the vaccine is not always effective, due to mismatch of the predicted strains with the actual circulating flu strains. A universal flu vaccine with long-term effectiveness remains elusive. 61 Occasionally influenza virus makes a major change that preserves its virulence, as in the case of the 2009 pandemic H1N1 strain. 34 The large antigenic drift renders the seasonal flu vaccine of little efficacy. As a result of the rapid development of antibody isolation and engineering technologies, passive immunization with broadly neutralizing antibodies is becoming an increasingly viable approach to address the immediate health threat of an influenza pandemic while vaccines are being developed. MHAA4549A: MAb MHAA4549A, also known as 39.29, was cloned from a single-human plasmablast cell isolated from an influenza vaccinated donor. MHAA4549A binds a highly conserved epitope on the stalk of influenza A HA and blocks the HAmediated membrane fusion in the endosome, and is capable of neutralizing all known human influenza A strains. 62 In two Phase 1 clinical trials, MHAA4549A was safe and well tolerated up to a single intravenous dose of 10,800 mg. The mAb demonstrates linear serum pharmacokinetics consistent with those of a human IgG1 antibody lacking known endogenous targets