Therapeutic effect of CT-P59 against SARS-CoV-2 South African variant

Abstract

The global circulation of newly emerging variants of SARS-CoV-2 is a new threat to public health due to their increased transmissibility and immune evasion. Moreover, currently available vaccines and therapeutic antibodies were shown to be less effective against new variants, in particular, the South African (SA) variant, termed 501Y.V2 or B.1.351. To assess the efficacy of the CT-P59 monoclonal antibody against the SA variant, we sought to perform as in vitro binding and neutralization assays, and in vivo animal studies. CT-P59 neutralized B.1.1.7 variant to a similar extent as to wild type virus. CT-P59 showed reduced binding affinity against a RBD (receptor binding domain) triple mutant containing mutations defining B.1.351 (K417N/E484K/N501Y) also showed reduced potency against the SA variant in live virus and pseudovirus neutralization assay systems. However, in vivo ferret challenge studies demonstrated that a therapeutic dosage of CT-P59 was able to decrease B.1.351 viral load in the upper and lower respiratory tracts, comparable to that observed for the wild type virus. Overall, although CT-P59 showed reduced in vitro neutralizing activity against the SA 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 SA variant.

Keywords: B.1.351; CT-P59; Regdanvimab; SARS-CoV-2 virus; Therapeutic antibody; Variant.

Fig. 1

In vitro binding and neutralization of CT-P59 against B.1.351. Wild type RBD (circle) or SA triple RBD mutant protein (rectangle) was coated and incubated with CT-P59, followed by optical density (OD) measurement. Binding affinity of CT-P59 was measured by ELISA (A). In addition, serially diluted CT-P59 mixed with D614G (black circle) or 501Y.V2 (red rectangle) variant pseudovirus. %Neutralization was calculated by measuring luciferase activities (B). CT-P59 was premixed with SARS-CoV-2 variant and wild type viruses (B.1.1.7, B.1.351, and BavPat1/2020). The inocula were added into VeroE6 cells, incubated and detected by anti-nucleocapsid antibody and staining (C). VC and CC represent as virus control and cell control, respectively. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

In vivo efficacy of CT-P59 against B.1.351 and wild type virus in animal model. Female ferrets (n = 6/group) were challenged with 10^5.5 TCID₅₀/ml of B.1.351 or wild type virus, and CT-P59 was administered intravenously after 24 h of virus inoculation. Both viral RNA (A, B, E, F) and viral titer (C, D, G, H) were measured from nasal wash and lung by using qPCR and TCID₅₀, respectively. The graphs are shown as means ± SD from six or three animals at each interval, and dashed lines indicate below the limit of quantification (BLQ) as following; 0.3 log₁₀ copies Log₁₀/mL (Nasal wash) and 0.3 log copies/mL (Lung) for qPCR, 0.8 log₁₀ TCID₅₀/mL (Nasal wash) and 0.8 log₁₀ TCID₅₀/g (Lung) for TCID₅₀ assay. Asterisks indicate statistical significance between the control and each group as determined by one-way ANOVA and post-hoc Dunnett's test. (∗ indicates P < 0.05, ∗∗ indicates P < 0.01, ∗∗∗ indicates P < 0.001, and ∗∗∗∗ indicates P < 0.0001).