AZD7442 demonstrates prophylactic and therapeutic efficacy in non-human primates and extended half-life in humans

Abstract

Despite the success of SARS-CoV-2 vaccines, there remains a need for more prevention and treatment options for individuals remaining at risk of COVID-19. Monoclonal antibodies (mAbs) against the viral spike protein have potential to both prevent and treat COVID-19, and reduce the risk of severe disease and death. Here, we describe AZD7442, a combination of two mAbs, AZD8895 (tixagevimab) and AZD1061 (cilgavimab), that simultaneously bind to distinct non-overlapping epitopes on the spike protein receptor binding domain to potently neutralize SARS-CoV-2. Initially isolated from individuals with prior SARS-CoV-2 infection, the two mAbs were designed to extend their half-lives and abrogate effector functions. The AZD7442 mAbs individually prevent the spike protein from binding to angiotensin-converting enzyme 2 receptor, blocking virus cell entry. Together, these two mAbs create a higher barrier to viral escape and a wider breadth of coverage, neutralizing all known SARS-CoV-2 variants of concern. In a non-human primate model of SARS-CoV-2 infection, prophylactic AZD7442 administration prevented infection, while therapeutic administration accelerated virus clearance from lung. In an ongoing Phase I study in healthy participants (NCT04507256), 300 mg intramuscular AZD7442 provided SARS-CoV-2 serum geometric mean neutralizing titers >10-fold above those of convalescent sera for >=3 months, which remained 3-fold above those of convalescent sera 9 months post-AZD7442 administration. Approximately 1-2% of serum AZD7442 levels were detected in nasal mucosa, a site of SARS-CoV-2 infection. Extrapolation of the time course of serum AZD7442 concentrations suggests AZD7442 may provide up to 12 months of protection and benefit individuals at high-risk of COVID-19.

COVID-19 and Solid Organ Transplantation: Role of Anti-SARS-CoV-2 Monoclonal Antibodies

“…A subset of patients with the acute decompensated fulminant disease, who are unable to be fully vaccinated pre-transplant, patients who require retransplantation, and patients with various auto-immune disorders on pre-transplant immunosuppression would be at higher risk of acquiring community-onset COVID-19 immediate post-transplantation, especially in the setting of high rates of community prevalence. Even though vaccinated, household or other close contacts can have very mild or asymptomatic SARS-CoV-2 infection, it can be transmitted to a susceptible host [40]. A subset of SOTRs will not have a significant immunological response even after multiple doses of vaccination [10, 11 ••, 12].…”

“…pdf. Accessed October 20, 2021] [40]. Synergy with emergent oral anti-viral agents like molnupiravir may offer another outpatient treatment modality in the future in certain pre-determined patients with multiple risk factors and/ or suspected high viral loads.…”

A combination of two human neutralizing antibodies prevents SARS-CoV-2 infection in rhesus macaques

“…However, a similar protective titer against SARS-CoV-2 was identified in NHPs for a combination of another combination of two neutralizing human mAbs in clinical development -AZD7442 (Loo et al, 2021). Future studies are needed to determine if the lower serum neutralizing antibody protective titer for COVID-19 vaccines relative to that achieved by passive mAb transfer is due to targeting of multiple epitopes on the SARS-CoV-2 S, different anatomical distribution of antibody responses, a contribution of Fc-mediated effector functions in the polyclonal response, or complementary mechanisms of protection that are mediated by vaccineinduced T cells.…”

“…A threshold for virological protection in BAL fluid and NP secretions was estimated to be equal to or higher than 6,000 for serum neutralizing antibody titer (NT 50 ), since antibody levels above these thresholds conferred full protection in 83% to 93% of challenged NHPs. This quantitative determination of a neutralizing titer as a direct mechanistic correlate of protection has implications for estimating the durability of protection conferred by passive immunization with antibodies (Loo et al, 2021) or active immunization with vaccines. The failure to achieve serum neutralizing titers above this threshold likely explains the lack of limited efficacy observed in most clinical trials of COVID-19 convalescent plasma (Begin et al, 2021;Bradfute et al, 2020;Janiaud et al, 2021).…”

“…Currently available antibody therapeutics that have received EUA from the FDA were approved for post-exposure treatment, not for pre-exposure prophylaxis (FDA, 2020(FDA, , 2021a. Prophylaxis with passive antibody therapy could be important as an option for individuals at high risk of disease from SARS-CoV-2 infection who cannot be adequately vaccinated, including immunocompromised individuals or others who respond poorly to vaccination (AstraZeneca, 2021;Loo et al, 2021).…”