Tocilizumab Does Not Inhibit Antibody Response to SARS-CoV-2

Treatment with tocilizumab does not appear to inhibit the induction of anti-SARS-CoV-2 antibodies in patients with severe coronavirus disease 2019 (COVID-19), according to findings from a study presented at the AACR Virtual Meeting on COVID-19 and Cancer.¹

Rather, tocilizumab-treated patients generated similar levels of antibodies against the Spike and receptor binding domain (RBD) proteins of SARS-CoV-2 as patients in the control arm.

The maximum antibody titer at least 10 days after symptom onset was comparable between the tocilizumab-treated group (Mean log₁₀, 4.911; n = 15) and the control group (Mean log₁₀, 5.000; n = 30) for the Spike (P = .7262) and RBD proteins, respectively (Mean log₁₀, 4.365; n = 15; 4.748; n = 30; P = .1487).

“Our study shows that treatment with tocilizumab does not impair antibody generation in response to SARS-CoV-2,” lead study author, Alexandra Cabanov, graduate student researcher at the University of Chicago, said during the session.

Interleukin-6 (IL-6) is a proinflammatory cytokine that has been implicated in the cytokine storm observed in a subset of COVID-19–infected patients, said Cabanov. In SARS-CoV-2, it is hypothesized that IL-6 binding to the soluble IL-6 receptor leads to the activation of downstream signaling driving the inflammatory storm seen in some patients.

Tocilizumab is a humanized anti–IL-6 receptor antibody which inhibits the interaction between IL-6 and its cognate receptor. Tocilizumab works by binding to the IL-6 receptor, thereby blocking the glycoprotein 130 homodimerization, the subsequent IL-6 interaction, and resulting downstream signal transduction.

Because IL-6 has been implicated in COVID-19 immunopathology, tocilizumab has been repurposed to treat patients with severe SARS-CoV-2 infection, said Cabanov.

IL-6 has also been shown to be involved in the development, maturation, proliferation, and survival of plasma cells, which are critical in clearing viral infection, such as SARS-CoV-2.

Animals deficient in IL-6 have been shown to have decreased germinal centers as well as decreased antigen-specific antibody titers.²

“Because of these previous reports, we and others were concerned that interrupting IL-6 signaling could represent a potentially detrimental effect. Namely, that treating with anti–IL-6 antibodies could blunt the antibody response to SARS-CoV-2 infection,” said Cabanov.

To that end, investigators tested the antibody response to COVID-19 infection in patients treated with tocilizumab compared with a controlled cohort.

Investigators performed ELISA assays on longitudinally drawn plasma and serum samples from patients over the course of their disease. Total immunoglobulin was evaluated to determine whether patients generated antibodies against the Spike and RBD proteins.

Investigators enrolled patients from the COVID-19 Biobank study who were polymerase chain reaction positive for SARS-CoV-2 (n = 148).

Of these patients, 30 were treated with tocilizumab. Eleven patients were treated off study with high-dose tocilizumab, and 19 were treated with low-dose tocilizumab on the COVIDOSE study. The 11 patients treated off study were further assessed for inclusion criteria, which consisted of high fever, a temperature equal to or higher than 100.4 Fahrenheit, and 1 C-reactive protein (CRP) equal to or higher than 40 mg/L, all within 24 hours prior to tocilizumab treatment (n = 6). Two additional patients were excluded (n = 4) due to bacteremia and organ transplant, resulting in a total of 23 tocilizumab-treated patients.

Patients who did not receive tocilizumab (n = 118) and satisfied the COVIDOSE fever, CRP, and oxygen requirement inclusion criteria were eligible for enrollment in the control cohort (n = 45). A few patients were excluded due to bacteremia, mechanical ventilation, superimposed bacterial infection.

Among the 37 evaluable patients in the control group, 26 received the anti-viral drug remdesivir. Notably, treatment with remdesivir did not affect antibody generation against the Spike and RBD proteins.

Rather, results showed comparable maximum antibody titers for the Spike protein against SARS-CoV-2 in the remdesivir (Mean log₁₀, 5.068; n = 22) and non-remdesivir control groups (Mean log₁₀, 4.811; n = 8; P = .6300). Comparable maximum antibody titers were also seen for the RBD protein in the tocilizumab on-study (Mean log₁₀, 4.867; n = 22) and non-remdesevir control group (Mean log₁₀, 4.422; n = 8; P = .3695).

“Ongoing studies are assessing the effect of tocilizumab on other immune parameters, such as antibody subclasses, circulating immune cell phenotypes, as well as T-cell responses, and serum cytokine levels,” concluded Cabanov.

References:

1. Cabanov A, Flood B, Bloodworth J, et al. Treatment with tocilizumab does not inhibit induction of anti-COVID antibodies in patients with severe SARS-CoV-2 infection. Presented at: AACR Virtual Meeting: COVID-19 and Cancer; July 20-22, 2020; Virtual. Accessed July 20, 2020.
2. Kopf M, Herren S, Wiles MV, et al. Interleukin 6 influences germinal center development and antibody production via a contribution of C3 complement component. J Exp Med. 1998;188(10):1895-1906. doi:10.1084/jem.188.10.1895