Nonclinical investigation of the potential of MHAA4549A, an anti-influenza A therapeutic antibody, to mediate antibody-dependent enhancement.

Antibody-dependent enhancement (ADE) of infection and disease is a theoretical safety risk for antiviral antibodies against seasonal viruses with antigenic drift, such as influenza. ADE of infection may occur if virus-specific antibodies at subtherapeutic, nonneutralizing concentrations facilitate virus uptake, thus potentially enhancing virus replication. In contrast, ADE of disease reflects exacerbation of viral disease severity through viral replication-dependent or -independent mechanisms. Because of the theoretical concern of ADE, nonclinical safety assessment of therapeutic anti-influenza antibodies includes a thorough evaluation of ADE potential. The current set of studies was conducted to investigate the potential of MHAA4549A-a broadly specific, neutralizing, therapeutic anti-influenza A antibody-to elicit ADE of infection and disease of influenza H3N2 A/Aichi/2/68 (X31) across a broad dose range. Assessment of ADE was based on totality of results from both in vitro and mouse influenza studies with integration across study endpoints. In vitro studies demonstrated that MHAA4549A can mediate increased X31 entry into human and murine monocytic cells, but increased uptake did not result in enhanced viral replication or release under physiologic conditions. In a mouse model of X31 infection, intravenous administration of MHAA4549A resulted in delayed body weight recovery, but no exacerbation in orthogonal endpoints including mortality, lung viral titers or genomes, lung weights, or severity of influenza pneumonia. Overall, the totality of nonclinical data did not demonstrate any clear indication of ADE of infection at nonneutralizing concentrations, suggesting a low risk for MHAA4549A to cause enhanced influenza A-mediated disease at subtherapeutic doses.