‘Reduced Cell Surface Levels of C-C Chemokine Receptor 5 and Immunosuppression in Long Coronavirus Disease 2019 Syndrome’

alexandrossfakianakis shared this article with you from Inoreader Response to 'Reduced Cell Surface Levels of C-C Chemokine Receptor 5 and Immunosuppression in Long Coronavirus Disease 2019 Syndrome' via Clinical Infectious Diseases Advance Access to the editor—Gaylis et al offer "an unexpected mechanism of abnormal immune downmodulation in some persons that is normalized by leronlimab" [1]. The disclosure of a public statement [2] and a Warning Letter [3] on leronlimab (PubChem SID 384585377) by the Food and Drug Administration (FDA) is appropriate. Gaylis et al offer no biostatistical methods but cite the clinical trial record. Using the Supplementary Data provided by Gaylis et al [1] with nonparametric Wilcoxon signed ranked test for change (Weeks 8–0), the 2-sided P-values for Figure 1A are .003 (leronlimab) and .0139 (placebo) and for Figure 1B are .0002 (leronlimab, Improving), .7344 (leronlimab, not improving), .0640 (placebo, not improving), and .1272 (placebo, not improving). Paired t-test results were not meaningfully different. Reporting nonsignificance (NS) for the latter 2 P-values with the given sample sizes is not advised, but the NS for placebo (Figure 1A) is significant and affects the conclusion. They do not define "responder" or state if the definition was made a priori. Some of the symptoms may not be independent (eg, cough/sore throat, headache/sleep disturbance) so using them all to generate a "responder" score should be explained. They fail to provide a mechanism of action or gene expression results to explain how a monoclonal antibody to CCR5, a G-protein-coupled receptor (GPCR), might increase the proportion of CD45+/CCR5+ T cells relative to total cell counts or increase expression of CCR5 in T cells. The authors should report the time between positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) test and enrollment, duration of COVID-19 infection, re-exposure to SARS-CoV-2, especially to variants different from the original infecting viruses, other factors that affect immune responses, distribution of severity of COVID-19 among the treatment groups, the results by age and sex, the receptor occupancy, and the potential effects of the half-life of leronlimab. Galanti and Shaman [4] report multiple (re-)infections per year in the same subjects with other coronaviruses. Lee et al [5] reported that "granulocyte macrophage colony-stimulating factor caused a marked decrease of CXCR4 (from ∼5000 ABS to <500) while up-regulating CCR5 expression (from ∼5000 to ∼20 000 ABS)." Jacobson et al [6] reported 'mean terminal half-lives (PRO 140 Serum Concentration) were 3.4 and 3.7 days, but Yang et al [7] suggested an "estimated half-life of about 10 days." With T-cell proliferation and the potential increase in CCR5 expression, the half-life and receptor occupancy need to be appropri ately addressed in different patient populations. Roche and Futura state that "plasma membrane of eukaryotic cells is constantly being internalized" [8]; how long a 146.7 kDa [9] antibody bound to the 62 kDa [10] transmembrane CCR5 (NP_001381712.1) remains at the surface or, when it is internalized, whether it is trafficked back to surface or to the lysosomes is of interest. T-cell exhaustion [11] could help explain the results; with small sample sizes, imbalances can occur so duration, sev erity, and time from PCR test for each patient is important. Finally, genotypes of CCR5, which may affect binding of leronlimab, and of the ligands of CCR5, such as CCL3L1 with copy number variants [12], and any antidrug antibodies (ADA) against leronlimab would help elucidate this finding. View on Web

Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.