Researchers in the Republic of Korea (South Korea), The Netherlands, and South Africa have demonstrated the potential of the monoclonal antibody CT-P59 as an effective therapeutic for coronavirus disease 2019 (COVID-19) caused by the South African B.1.351 variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Soo-Young Lee from Celltrion Inc., in Incheon and colleagues, found that although the antibody exhibited reduced antiviral activity against the B.1.351 variant in vitro, it demonstrated potent antiviral activity in ferrets when administered at clinically relevant doses.
A therapeutic dosage of CT-P59 significantly decreased viral load and infectious viral titer in both the upper and lower respiratory tracts of the animals, compared with untreated controls.
“Overall, considering that ferrets were administered with clinically relevant doses of CT-P59, it is expected CT-P59 would maintain its efficacy with patients infected with the South African variant,” writes the team.
A pre-print version of the research paper is available on the bioRxiv* server, while the article undergoes peer review.
Morbidity and mortality rates on the rise again
The recent emergence of novel SARS-CoV-2 variants poses further threats to global public health during the ongoing COVID-19 pandemic, with morbidity and mortality rates now on the rise again in many countries.
The B.1.1.7 variant that was first identified in the UK and found to contain the N501Y mutation in the viral spike protein has now spread to more than 100 countries.
The spike protein mediates the initial stage of the SARS-CoV-2 infection process by attaching to the host cell receptor angiotensin-converting enzyme 2 (ACE2) via its receptor-binding domain (RBD).
In addition to N501Y, the B.1.351 variant of concern that was first identified in South Africa contains eight more mutations in the spike protein, namely, L18F, D80A, D215G, Δ242-244, K417N, E484K, D614G, and A701V.
Since quickly becoming the dominant SARS-CoV-2 strain in South Africa, B.1.351 has now spread to neighboring nations in Africa, some countries in Europe, and the United States.
Similarly, the P.1 variant that was first detected in Brazil and shares several mutations with B.1.351 has spread to several other countries in South America.
Some vaccines and therapeutics show reduced activity against the variants
Worryingly, studies have shown that some of the vaccines and therapeutics developed to protect against COVID-19 exhibit compromised activity against the new variants compared with the original wild-type virus.
Neutralization assays of serum from vaccinees have shown that two mRNA-based vaccines maintained activity against the UK variant (B.1.1.7) but showed an approximately 10-fold reduction in activity against the South African (B.1.351) variant.
The monoclonal antibody LY-CoV555 has also been shown to maintain activity against the UK variant, but not against B.1.351 since it cannot bind to a triple mutation in (K417N/E484K/N501Y) found in the spike RBD of this strain.
What did the researchers do?
Lee and colleagues have recently developed a monoclonal antibody – CT-P59 – that binds to the SARS-CoV-2 spike RBD and shows potent in vitro and in vivo activity against the original wild-type virus.
To assess whether CT-P59 is also effective against the UK and South African variants, the team performed both in vitro binding and neutralization assays with live viruses and pseudoviruses and in vivo experiments in ferrets.
The team found that CTP59 showed similar neutralizing activity against the B.1.1.7 variant in vitro as it did against the wild-type virus.
However, compared with the wild-type and UK variant, binding affinity for the RBD triple mutation (K417N/E484K/N501Y) found in B.1.351 was reduced 10-fold.
The monoclonal antibody also showed a 20-fold reduction in neutralization activity against B.1.351 live virus and a 33-fold reduction in the neutralization of B.1.351 pseudotyped viruses.
The team says that, although CT-P59 showed reduced binding and neutralization of B.1.351, the fact that some binding and neutralizing activity was retained prompted them to check whether its efficacy was reduced in a relevant animal model.
What did they find?
Six ferrets challenged with B.1.351 showed significantly reduced levels of viral RNA in nasal and lung samples following a clinically relevant therapeutic dose of 160 mg/kg CT-P59 and a half dose of 80 mg/kg.
In nasal washes, both the 80 mg/kg and 160 mg/kg dose decreased levels of viral RNA by 2.97 log10/mL, compared with control animals, just one day after administration (2 days post-viral challenge).
In the lungs, the level of viral RNA in both treatment groups was also significantly reduced at 2 days post-viral challenge, compared with control animals (1.30 log reduction for the 80 mg/kg dose and 1.57 log for 160 mg/kg).
The infectious viral titer in both nasal washes and the lungs was also significantly decreased in animals treated with CT-P59, compared with controls.
Therapeutic potential for patients with the South African variant
“Here, we have demonstrated the therapeutic potential of neutralizing antibody CT-P59 against the B.1.351 variant of SARS-CoV-2,” says Lee and colleagues.
“Overall, although CT-P59 showed reduced in vitro neutralizing activity against the South African variant, sufficient antiviral effect in B.1.351-infected animals was confirmed with a clinical dosage of CT-P59, suggesting that CT-P59 has therapeutic potential for COVID-19 patients infected with the South African variant,” concludes the team.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.