Recombinant antibodies with engineered human IgG1 Fc domains have been developed to resist viral Fc receptor capture, enhancing immune targeting of virus-infected cells. These antibodies maintain normal host receptor affinity, potentially improving therapeutic outcomes against HCMV and related viruses.
Human cytomegalovirus (HCMV) infection poses significant health risks, particularly to the very young, elderly, and immunocompromised individuals. Despite over five decades of vaccine development efforts, the most advanced vaccine candidates have demonstrated limited efficacy, with protection often correlating with high levels of non-neutralizing antibodies.
HCMV’s ability to evade the immune system complicates vaccine development, as the virus can persist in a latent state and reactivate, leading to widespread infection. The virus employs multiple strategies to evade immune responses, including the expression of viral Fc receptors (vFcyRs) that interfere with antibody functions such as antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis. These vFcyRs, such as gp34 and gp68, bind to the Fc region of antibodies, reducing their efficacy in mediating immune responses.
This immune evasion results in ineffective prevention of viral spread, even in individuals with robust antibody responses. Consequently, there is a pressing need for novel therapeutic approaches that can enhance the neutralization of cell-to-cell viral spread and improve the clearance of infected cells by the immune system.
Recombinant antibodies with engineered human IgG1 Fc domains have been developed to enhance immune responses against viral infections such as those caused by human cytomegalovirus (HCMV) and herpes simplex viruses. These antibodies have been specifically modified to reduce their affinity for viral Fc receptors, which are typically exploited by viruses to evade the immune system.
The modifications involve specific amino acid substitutions at positions R255, H268, E294, Q311, K334, and S337, according to the EU numbering system. These changes significantly decrease the binding affinity to viral receptors like gp34 and gp68, while maintaining normal interactions with host receptors such as CD16A and FcRn. This design aims to prevent viral capture of antibodies, thereby enhancing the immune system’s ability to target and eliminate virus-infected cells, potentially leading to better therapeutic outcomes for infections caused by HCMV and related viruses.
The differentiation of this technology lies in its ability to selectively reduce viral receptor binding without compromising the antibody’s interaction with host immune receptors. This selective binding is crucial because it allows the antibodies to evade viral mechanisms that typically neutralize immune responses. By maintaining normal affinity for host receptors, the engineered antibodies can effectively engage immune effector functions such as antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis.
This targeted approach not only enhances the therapeutic potential of the antibodies against viral infections but also minimizes the risk of off-target effects, making it a promising strategy for improving the efficacy of antibody-based therapies against viruses that utilize Fc receptor-mediated immune evasion tactics.
https://patents.google.com/patent/WO2023108117A2/en?oq=+PCT%2fUS2022%2f081258