Antibody therapies for the prevention and treatment of viral infections

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

Human cytomegalovirus. HCMV is a member of the herpes family. Like other members of this family, HCMV can establish lifelong latent infection in its host, with occasional reactivation. 43 Infection is in general asymptomatic, but can cause serious disease in people whose immune systems are compromised, such as transplant recipients and AIDS patients with HIV infection. Furthermore, children infected with HCMV in utero are at risk for serious birth defects. They may even experience delayed hearing loss and deafness despite being asymptomatic at birth. 43 After several decades of effort, an effective vaccine against HCMV infection remains elusive. 44 Typical adult therapy for HCMV infection is with antivirals such as ganciclovir, foscarnet, and cidofovir. 45 For children who are suspected to have been infected in utero, treatment with Ganciclovir may prevent developmental problems and loss of hearing. 46 Women with primary infection during pregnancy, a risk factor for congenital HCMV infection and disease (cHCMV), may be treated with HCMV immunoglobulin as a way to reduce the cHCMV risk. 47 Polyclonal preparations of antibodies (IVIGs) are an alternative for antiviral medications that have serious limitations. For example, IVIGs are difficult to standardize and less effective. In contrast, mAbs specifically targeting key epitopes should provide an advantage in efficacy. Multiple HCMV targeting mAbs being developed are in various stages of preclinical and clinical trials. 48, 49 HCMV is a complex virus with multiple antigens, including glycoprotein B (gB) and the gHp entameric complex. 43, 50 The vast majority of antibodies generated against HCMV target its gB antigen. The gB targeting antibodies alone may not have strong neutralizing ability to control HCMV infection and reactivation. 51 Recent studies have demonstrated that the pentameric gH complex is the primary target for neutralizing antiviral antibodies, 50 and as result most recently developed mAbs target the virus' pentameric complex. 51 The use of a combination of mAbs has several advantages, including enhanced efficacy and decreased development of viral resistance. At least two of the HCMV targeting antibodies in clinical trials are combinations of two mAbs. 48, 49 CSJ148: CSJ148 is a combination of two anti-HCMV human mAbs -LJP538, which binds to the viral gB protein and LJP539, which binds to the viral gH pentameric complex. 48 LJP538, also known as 7H3, and LJP539, as 4I22, were isolated from EBV immortalized B cells from HCMV-immune human donors as described. 52, 53 Results from clinical trials show CSJ148 and its component mAbs were safe and well tolerated, with pharmacokinetics as expected for human immunoglobulin. 48 Phase 2 clinical trials of CSJ148 in stem cell transplant patients are ongoing. 54 RG7667: RG7667 is a combination of two mAbs, MCMV5322A and MCMV3068A. 49 MCMV5322A is an affinity-matured version of MSL-109 that binds a neutralizing epitope on HCMVgH/gL. 55 MSL-109 is a human mAb isolated from spleen cells of a HCMV seropositive individual. In the late 1990s, MSL-109, known by several other names including Protovir, SDZ 89-109, SDZ MSL-109, and Sevirumab, was developed by Sandoz in several clinical trials as a therapy for HCMV infection. 56 Development was discontinued after MSL-109 failed to demonstrate improved outcomes in the treatment of HCMV retinitis in AIDS patients and prevention of HCMV infection after hematopoietic stem cell transplantation. 56 In