ACE2 Antibody

Development of a humanized ACE2 blockade
antibody for COVID-19 immunotherapy

A. Coronavirus disease 2019 (COVID-19)

A1. Although highly effective vaccines are available, there is still unmet urgent need to develop targeted therapy for COVID-19. COVID-19 is an emerging infectious disease caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1, 2, 3, 4, 5, 6, 7, 8. COVID-19 is currently still a global pandemic 9, 10. The clinical spectrum of SARS-CoV-2 infection appears to be wide, ranging from asymptomatic infection, mild upper respiratory tract illness, severe viral pneumonia, to respiratory failure and death 7, 11, 12. The wonderful news is that the FDA has approved several vaccines and these vaccines are highly effective. However, a large population has not been vaccinated. Furthermore, it is clear now that the virus mutates quickly and the current vaccines are less effective for the virus variants (e.g., the Delta variant). Therefore, non-vaccine treatment options are still needed. There is currently an urgent need for the development of a SARS-CoV-2 immunotherapy.
A2. SARS-2-S and ACE2 interaction controls SARS-CoV-2 infection of humans.
The SARS-CoV-2 genome varies from 29.8 kb to 29.9 kb. There are 10 open reading frames with the 5’ two-thirds of the genome consisting of orf1a/b which encodes orf1ab polyproteins. The 3’ one third of the genome encodes genes for structural proteins including surface spike (S or SARS-2-S), envelope (E), membrane (M), and nucleocapsid N proteins. Experimental data of SARS-CoV-2 viral protein structures indicate that the spike protein SARS-2-S binds to the ACE2 receptor on human cells with high affinity to mediate SARS-CoV-2 entry into host cells 13, 14. Functional studies using pseudovirus containing SARS-2-S protein and authentic SARS-CoV-2 isolates from human patients determined that SARS-2-S binds to ACE2 on human cells to enter the host cells to replicate in humans 15. The SARS-2-S protein and the interactions between SARS-2-S and ACE2 are thus key determinants of human infection and COVID-19 pathogenesis, and provide the molecular basis for the development of targeted therapies to block SARS-2-S and ACE2 interactions.
A3. ACE2 blockade immunotherapy is a more effective immunotherapy for COVID-19.
A3.1. Emerging SARS-CoV2 variant outbreak limits the efficacy of SARS-CoV-2 antibody blockade immunotherapy: As of January 4, 2021, there are 2,678 SARS-CoV-2 genome sequence depositions in the NCBI GEO Database 6, 16, 17. A systemic alignment analysis of the SARS-CoV-2 genome sequences deposited in the database revealed that there are more than 156 total variants 16. The distinct variants consist of 46 missense, 52 synonymous, 2 insertion, 1 deletion, and 14 non-coding alleles. These variants will likely affect the efficacy of a specific SARS-CoV-2 neutralization antibody in patients with variant SARS-CoV-2. The recent new SARS-CoV2 variant outbreak in the UK18 and the current Delta variant spreading in the US further highlight the limitations of SARS-CoV-2 neutralization/blockade immunotherapy since the SARS-CoV-2-specific neutralization antibodies may lose affinity for the variants.
A3.2. ACE2 blockade immunotherapy is a more effective immunotherapy for blocking SARS-CoV-2 infection of humans: The above findings suggest that ACE2 blockade immunotherapy using an ACE2-specific monoclonal antibody is potentially a more effective approach to block SARS-CoV-2 entry into human target cells since ACE2 is the receptor for all SARS-CoV-2 variants and ACE2 blockade immunotherapy should block all SARS-CoV-2 variants, including the present and future variants. Another advantage of ACE2 blockade over SARS-CoV-2 blockade is the ration of virus load vs ACE2 receptor level. It is likely that virus load can be very high in human COVID-19 patients whereas the ACE2 receptor is restricted in specific cell types. The recent breakthrough in antibody-based immune checkpoint blockade cancer immunotherapy provides a strong rationale to explore ACE2 blockade immunotherapy over SARS-CoV-2/SARS-2-S blockade. Program death ligand 1 (PD-L1) is expressed on the surfaces of tumor cells and immune suppressive immune cells. Its receptor PD-1 is expressed on activated T cells. PD-L1 binds to PD-1 to inhibit T cell activation, which leads to tumor immune evasion and progression. Due in part to the less abundance of PD-1 as compared to PD-L1, anti-PD-1 antibody blockade immunotherapy is very effective in reversing T cell activation induced by PD-L1 to suppress tumor progression, and FDA-approved agents for cancer immunotherapy are almost all anti-PD-1 antibodies. By parallel, ACE2 conceptually mimics PD-1 and SARS-2-S conceptually mimics PD-L1. In summary, ACE2 blockade immunotherapy is a more effective therapy than the SARS-CoV-2/SARS-2-S blockade immunotherapy.

B. Chemedimmune is developing an ACE2 neutralization monoclonal antibody for SARS-CoV-2 immunotherapy.

We have developed a first-in-class ACE2 neutralization monoclonal antibody that can effectively block SARS-2-S binding with minimal effect on ACE2 enzyme activity. Therefore, it blocks the ACE2/Spike protein interaction while maintaining ACE2 normal functional activity. Therefore, it is a potentially safe agent to use as an immunotherapy against COVID-19.

C. Current development status

The goal is to move the humanized ACE2 blockade antibody to clinical trials.


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