DUBLIN – The Genentech arm of Basel, Switzerland-based Roche Holding AG plans to move its interleukin-6 (IL-6) inhibitor, Actemra (tocilizumab), into a global phase III trial in patients with severe pneumonia associated with COVID-19 infection. The same drug is already undergoing – or soon will be – a number of investigator-initiated trials in China and in Italy and was included in treatment guidelines issued by China’s National Health Commission on March 3. (See Clinical trials of therapeutic antibodies in COVID-19, below.)

Clinical data have yet to emerge, but the rationale for all of those studies is clear. Originally approved a decade ago for treating rheumatoid arthritis, the anti-inflammatory therapy received a new lease of life in 2017, when it gained FDA approval for treating severe or life-threatening cytokine release syndrome (CRS) in leukemia or lymphoma patients undergoing CAR T therapy.

It gained that approval, under priority review, on the basis of retrospective data on 45 pediatric and adult patients. Thirty-one attained resolution of their CRS within 14 days after receiving one or two doses of the antibody plus corticosteroids. The effect was confirmed in a further 15 patients from a separate cohort.

For COVID-19, Genentech will build a more robust evidence base. The prospective study will be placebo-controlled and will include U.S. sites, where there is most experience in treating CRS associated with CAR T. That precious knowledge – pioneered by Stephan Grupp at the Children’s Hospital of Philadelphia – should be transferable to critically ill ICU COVID-19 patients suffering life-threatening immune reactions. The study, which is due to kick off in April, is being conducted in cooperation with the U.S. Biomedical Advanced Research and Development Authority. Primary and secondary endpoints will include clinical status, mortality, mechanical ventilation and ICU variables, Genentech said.

Genentech’s move follows that of Paris-based Sanofi SA and Tarrytown, NY-based Regeneron Pharmaceuticals Inc., which unveiled plans Wednesday, March 18, to move their IL-6 inhibitor, Kevzara (sarilumab), into a phase II/III trial in patients with severe COVID-19 infection. Kevzara is approved for treating rheumatoid arthritis infection only – it gained FDA approval in May 2017 – but the present study has been informed by a trial in COVID-19 of another IL-6 inhibitor in China. IL-26, like IL-2, is implicated in CRS.

Several other antibodies have also been tested in investigator-initiated studies in China, including another Genentech product, Avastin (bevacizumab), a VEGF inhibitor long used in cancer but with no history of use in severe pneumonia. The theoretical rationale for the current studies is VEGF is a potent driver of vascular permeability – indeed, its original name was vascular permeability factor – and a major contributor to the pulmonary edema that is one of the main causes of acute respiratory distress. Elevated levels of the signaling protein have been detected in the circulation of COVID-19 patients. An open-label pilot trial is underway at present, but a larger placebo-controlled study is also planned, which should help to establish what contribution, if any, Avastin makes to patient outcomes.

Another group, led by scientists at the Fourth Military Medical University in Xi’an, China, published in BioRxiv data on meplazumab, an antibody-based CD147 inhibitor, which, they claimed, offers the SARS-CoV-2 virus an alternative entry route to cells. The virus uses angiotensin converting enzyme 2 (ACE2) as its main route into the host, but their claim that the viral spike protein – which binds ACE2 – can also interact with CD147 is controversial. The preprint, published March 14, reported in vitro data indicating that the antibody prevents viral entry to Vero E6 cells and that the SARS-CoV-2 spike protein and the CD147 receptor (also called basigin) interacted in a surface plasmon resonance assay.

Several centers in China are also trialing passive immunotherapy, using plasma-derived immunoglobulin preparations from recovered patients, a classic move in any rapidly moving outbreak.

Several newly discovered monoclonal antibodies directed against the virus itself or its receptor have been reported of late and could form the basis of drugs that could protect at-risk individuals and health care workers or that could help struggling patients to lower their viral load.

On March 12, scientists at the University of Utrecht, in the Netherlands, and other centers in the Netherlands and Germany, reported in BioRxiv that they had developed a monoclonal antibody, 47D11, which could block cellular entry of both SARS-CoV-2 and SARS-CoV, its relative that caused the first SARS outbreak in 2002-2003. The antibody, which was obtained by immunizing transgenic mice that express a chimeric antibody repertoire comprising human variable heavy and light chains and rat constant regions, binds a shared epitope on the binding domain of the spike protein on each virus. It could form the basis of both serological tests and a therapeutic antibody. Earlier this week, scientists at the Flanders Institute of Biotechnology and the University of Ghent in Belgium, and collaborators at the University of Texas, Austin, and the German Primate Center, Leibniz Institute for Primate Research in Göttingen, Germany, reported on an antibody that can neutralize a lab variant of the SARS-CoV-2 virus. Both reports represent the starting point of what would be a long campaign to realize an actual antibody drug.

Clinical trials of therapeutic antibodies in COVID-19 infection

Drug Developer Mechanism Trial sponsor Number of patients

Actemra (tocilizumab)

Genentech Inc., South San Francisco

Interleukin-6 (IL-6) receptor inhibitor



Avigan (favipiravir) + tocilizumab

Fujifilm Holdings Corp., Tokyo; Genentech Inc.

Viral RNA polymerase inhibitor + IL-6 inhibitor

Peking University First Hospital, Beijing, China


Tocilizumab vs. Continuous replacement renal therapy

Genentech Inc. (tocilizumab only)

IL-6 receptor inhibitor vs. extracorporeal blood purification

Tongji Hospital, China



Genentech Inc.

IL-6 receptor inhibitor

Università Politecnica delle Marche, Ancona, Italy


Kevzara (sarilumab)

Sanofi SA, Paris; Regeneron Pharmaceuticals Inc., Tarrytown, N.Y.

IL-2 inhibitor

Sanofi, Regeneron


Avastin (bevacizumab)

Genentech Inc.

Vascular endothelial growth factor (VEGF) inhibitor

Qilu Hospital of Shandong University, Shandong, China


Avastin (bevacizumab)

Genentech Inc.

Vascular endothelial growth factor (VEGF) inhibitor

Qilu Hospital of Shandong University

20 (pilot study)

Intravenous immunoglobulin therapy

Not applicable (NA)

Antibodies isolated from plasma of patients who have recovered from COVID-19 infection

Peking Union Medical College Hospital


Intravenous immunoglobulin therapy


Antibodies isolated from plasma of patients who have recovered from COVID-19 infection

Wuhan Union Hospital, Wuhan, China


Intravenous immunoglobulin therapy

Not applicable (NA)

Antibodies isolated from plasma of patients who have recovered from COVID-19 infection

Shanghai Public Health Clinical Center, Shanghai, China


Soliris (eculizumab)

Alexion Pharmaceuticals Inc., New Haven, Conn.

Complement inhibitor

Hudson Medical, New York

Individual patients under IND

Humanized meplazumab

Jiangsu Pacific Meinuoke Biopharmaceutical Co., Changzhou, China

CD147 inhibitor

Tang Du Hospital, Xi’an, China


Sources: Company websites; ClinicalTrials.gov