Antibody therapies for the prevention and treatment of viral infections

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

and blocks entry of HIV-1, is also being tested in clinical trials. 100 In another approach, bispecific Abs that combine the HIV-1 inhibitory activity of ibalizumab with that of anti-gp120 bNAbs were constructed for passive immunization to prevent HIV-1 infection. 101, 102 Respiratory syncytial virus Palivizumab, motavizumab, and motavizumab-YTE: In 1998, the FDA approved palivizumab, which binds to the F glycoprotein of the RSV for prophylaxis in children susceptible to severe disease. 103, 104 Motavizumab is an affinity matured derivative of palivizumab, tenfold more potent than palivizumab in F glycoprotein binding. 103, 105 In Phase 3 clinical trials, motavizumab recipients had a 26% relative reduction in RSV hospitalization compared with palivizumab recipients, and motavizumab was superior to palivizumab for reduction of RSV-specific outpatient lower respiratory tract infections (MALRIs, 50% relative reduction). 106 A half-life extended derivative of the antibody, known as motavizumab-YTE (motavizumab with amino-acid substitutions M252Y/S254T/T256E [YTE]), an Fc-modified anti-RSV mAb was also tested in Phase 1 trials. 107 Clearance of motavizumab-YTE was significantly lower (71 to 86%) and the half-life was two to fourfold longer than that of motavizumab in healthy participants. 107 The sustained serum concentrations of motavizumab-YTE were fully functional, as shown by RSV neutralizing activity that persisted for 240 days with motavizumab-YTE versus 90 days postdose for motavizumab. 107 Despite the improvements of motavizumab and motavizumab-YTE over palivizumab, the clinical benefits were considered incremental and they have not been approved for clinical use. MEDI8897, REGN2222, and ALX-0171: MEDI8897, which is 100fold more potent than palivizumab in vitro, is derived from D25 108 a mAb isolated from a B cell of a human donor targeting the 110 Not an IgG1 antibody, ALX-0171 is a single-domain camelid-derived antibody, or nanobody, targeting the RSV-F protein. Due to small size of the nanobody, ALX-0171 is being tested as a therapeutic by inhalation in Phase 2 in infants (aged 1-24 months) who were hospitalized with an RSV infection. 111 Ebola, Zika, rabies, and HBV. An outbreak of Ebola in West Africa between 2014 and 2015 affected 28,652 people and led to more than 11,325 deaths. 112 The lessons learned from the handling of that high mortality rate epidemic contribute to the call for taking innovative counter measures against emerging infectious diseases, including the use of mAbs. For example, an experimental mAb cocktail ZMapp was given special approval for compassionate use during the fast-moving epidemic. ZMapp is a combination of three mAbs (c13C6, c2G4, c4G7) optimized from two previous antibody cocktails (ZMab and MB-0033). 113 ZMapp showed protective efficacy in a rhesus macaques challenge model. 113 However, a randomized, controlled human trial of ZMapp plus the current standard of care did not meet the statistical threshold set for improved efficacy as compared with the current standard of care alone (NCT02363322) [114] [115] [116] . Efforts to isolate potent neutralizing antibodies against Ebola are ongoing. For example, potent neutralizing antibodies targeting the Ebola virus surface glycoprotein (EBOV GP) were isolated through sequential immunization of rhesus macaques and antigenspecific single B-cell sorting. 117 Similarly, potent neutralizing antibodies targeting the Ebola EBOV GP were isolated from the periphe