Antibody therapies for the prevention and treatment of viral infections

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

in humans. 63 MHAA4549A is currently in Phase 2 clinical trials for the treatment of patients hospitalized with severe influenza A infection. 64, 65 VIS410: VIS410 is an engineered human IgG1mAb, which targets the stem (or stalk) region of influenza A HA and has demonstrated binding to both group 1 and group 2 HAs of influenza A viruses. 66 Prophylactic administration of VIS410 resulted in the complete protection of mice from developing acute respiratory distress syndrome against lethal influenza A (H7N9) virus challenge. 67 In a Phase 1 clinical trial, VIS410 was safe and well tolerated and had good relative exposure in both serum and upper respiratory tract. These results support its use as either a single-dose therapeutic or prophylactic for influenza A. 68 VIS410 is currently in a Phase 2a study designed to assess the safety and tolerability of the antibody in subjects with uncomplicated influenza. 69 CR6261: Isolated from combinatorial display libraries that were constructed from human IgM( + ) memory B cells of seasonal influenza vaccinees, antibody CR6261 neutralizes the virus by blocking conformational rearrangements associated with membrane fusion. The antibody is protective in mice when given before and after lethal H5N1 or H1N1 challenge. 5 CR6261 recognizes a highly conserved helical region in the membraneproximal stem of HA1 and HA2. The antibody neutralizes the virus by blocking conformational rearrangements associated with membrane fusion. 70 CR6261 is currently in Phase 2 clinical testing. 71 CR8020: The human mAb CR8020 has broad neutralizing activity against most group 2 viruses, including H3N2 and H7N7, which cause severe human infection. CR8020 was isolated from a B cell of a donor vaccinated against influenza. 72 The crystal structure of Fab CR8020 with the 1968 pandemic H3 HA reveals a highly conserved epitope in the HA stalk distinct from the epitope recognized by the V(H)1-69 group 1 antibodies. 72 CR8020 has been tested in Phase 1/2trials. 73 Structural and computational analyses indicate that CR8020 targets HA residues that are prone to antigenic drift and host selection pressure. Critically, CR8020 escape mutation was seen in certain H7N9 viruses from recent outbreaks. 74 TCN-032: Antibody TCN-032 was isolated from ab IgG( + ) memory B cell of a healthy human subject. The antibody recognizes a previously unknown conformational epitope within the ectodomain of the influenza matrix 2 protein, M2e. 75 This antibody-binding region is highly conserved in influenza A viruses. The region is present in nearly all strains detected to date, including highly pathogenic viruses that infect primarily birds and swine and the 2009 swine-origin H1N1 pandemic strain (S-OIV). In addition, TCN-032 protected mice from lethal challenges with either H5N1 or H1N1 influenza viruses. 75 A Phase 1 clinical study showed that TCN-032 was safe, with no evidence of immune exacerbation based on serum cytokine expression. The trial also showed that the antibody may provide immediate immunity and therapeutic benefit in influenza A infection, with no apparent emergence of resistant virus. 76 Human immunodeficiency virus. Despite decades of intensive effort, an effective HIV vaccine remains a challenge. With recent advances in the identification of broadly neutralizing antibodies from single memory B cells of infected individuals, anti-HIV antibodies are becoming a viable approach for both prophylactic and therapeutic treatment of HIV infectio