AstraZeneca said today it has begun human clinical testing of a two-antibody combination therapy against COVID-19 that it is licensing from Vanderbilt University Medical Center (VUMC).
The Phase I trial (NCT04507256) is a first-in-humans dose escalation study of AZD7442. The antibody combination will be tested in up to 48 healthy participants in the U.K., ages 18–55 for safety, tolerability, pharmacokinetics, and generation of anti-drug antibodies (ADAs), with the goal of enabling future studies of AZD7442’s efficacy in preventing and treating COVID-19.
Should AZD7442 show positive results, AstraZeneca said, it will advance the antibody combination into Phase II and Phase III trials to evaluate its efficacy in preventing and treating COVID-19.
“This combination of antibodies, coupled to our proprietary half-life extension technology, has the potential to improve both the effectiveness and durability of use in addition to reducing the likelihood of viral resistance,” Menelas (Mene) Pangalos, PhD, executive vice president, biopharmaceuticals R&D, said in a statement.
AZD7442 consists of two monoclonal antibodies derived from convalescent patients with SARS-CoV-2 infection, AZD8895 and AZD1061. Both were discovered at VUMC’s Vanderbilt Vaccine Center.
After licensing the combination from VUMC in June, AstraZeneca optimized the antibodies with half-life extension and reduced Fc receptor binding. The half-life extended monoclonal antibodies should afford at least six months of protection from COVID-19, according to AstraZeneca.
Positive animal studies
The company cited, “Potently neutralizing and protective human antibodies against SARS-CoV-2,” a study published July 15 in Nature in which researchers from VUMC, AstraZeneca, and their clinical partners reported positive results for the two monoclonal antibodies in studies conducted in mice and rhesus macaques.
Of 389 SARS-CoV-2 protein reactive monoclonal antibodies from the B cells of two convalescing individuals who were infected with SARS-CoV-2 in Wuhan, China, researchers tested 40 antibodies pre-selected by rapid neutralization screening assay. Two of the antibodies bound simultaneously to the S protein and neutralized wild-type SARS-CoV-2 virus synergistically, after recognizing non-overlapping sites of the receptor-binding domain of the S protein (SRBD).
In total, AstraZeneca said, it has evaluated the ability of more than 1,500 monoclonal antibodies to bind to the SARS-CoV-2 virus and inhibit its capacity to infect healthy cells in a laboratory setting.
AstraZeneca and VUMC began partnering in COVID-19 in April. Based on preclinical results, AstraZeneca then inked an exclusive license to six candidate antibodies in VUMC’s portfolio that target the SARS-CoV-2 virus—with the goal of advancing the two top performers into clinical studies.
The Phase I trial is funded with a $23.65 million “base award” announced in June by the Biomedical Advanced Research and Development Authority (BARDA), part of the Office of the Assistant Secretary for Preparedness and Response at the U.S. Department of Health and Human Services (HHS); and the Defense Advanced Research Projects Agency (DARPA), part of the US Department of Defense (DoD).
In May, BARDA awarded AstraZeneca up to $1.2 billion toward development, production, and delivery of AZD1222, the COVID-19 vaccine the company is developing with the University of Oxford and its spinout company. AZD1222—one of 18 “Front Runner” candidates on GEN’s COVID-19 Tracker—is in Phase II/III trials ongoing in the U.K. and Brazil, a Phase I/II trial in South Africa, and trials planned in the United States, Japan, and Russia. Results from the late-stage trials are anticipated later this year.
AstraZeneca is also investigating whether COVID-19 can be treated with Calquence® (acalabrutinib), the company’s marketed Bruton’s tyrosine kinase (BTK) inhibitor indicated for Mantle cell lymphoma patients who have received at least one prior therapy, and chronic lymphocytic leukemia or small lymphocytic leukemia. In a study published June 5 in Science Immunology, investigators observed that off-label use of Calquence was associated with reduced respiratory distress and a reduction in the overactive immune response in most of the treated patients.