BONN, Germany—DiosCURE Therapeutics recently published an article in Science, describing its core technology of multivalent single-chain antibodies with a unique molecular mode-of-action to inactivate SARS-CoV-2 virions. The study, entitled “Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape,” details the identification of DiosCURE’s lead candidates out of millions of potential structures, as well as the rational design of multivalent constructs.
“The emergence of SARS-CoV-2 escape mutants will remain an ongoing challenge in this pandemic, and novel therapies are urgently needed to address this problem,” explained Eicke Latz, director of the Institute of Innate Immunity at the University of Bonn, as well as co-founder and board member of DiosCURE. “Our understanding of the short- and long-term consequences of SARS-CoV-2 is rapidly evolving, and rational therapeutics targeting the virus are needed to curb the potentially devastating consequences of COVID-19.”
An international team led by scientists at the University of Bonn developed and characterized the lead candidates, DIOS-202 and DIOS-203, which have been exclusively licensed by DiosCURE. DIOS-202 and DIOS-203 are synergistic combinations of single-domain antibodies derived from camelid heavy chain-only antibodies. These next-generation immunotherapies against SARS-CoV-2 were designed based on detailed structural information of the antibodies’ interaction with its viral target protein, and result from functional and evolutionary experiments.
“The company’s candidates, DIOS-202 and DIOS-203, are synergistic combinations of single-domain antibodies derived from camelid heavy chain-only antibodies,” notes Klaus Wilgenbus, CEO of DiosCURE. “Based on their structures, the engineered multivalent nanobodies have a more than 100-fold improved neutralizing activity than monovalent nanobodies. DIOS-202 and DIOS-203 selectively target two distinct epitopes at the receptor binding domain of the SARS-CoV-2 spike protein at once, preventing the emergence of escape mutants.”
“We found that both nanobodies act synergistically. The binding interface E overlaps with the ACE2 binding site, while the use of interface UVW sterically interferes with ACE2 binding. The nanobodies therefore compete with the ACE2 receptor for binding to the spike protein, but additionally induce the activation of the spike by stabilizing the 3-up confirmation of the RBD [receptor-binding domain],” say Wilgenbus and Dr. Florian Schmidt, scientific co-founder of DiosCURE and last author of the Science article. “This premature activation likely induces the conversion to the thermodynamically favorable post-fusion conformation without catalyzing a fusion event, a process that is irreversible and renders the virus noninfectious.”
These discoveries were accomplished through a collaborative effort of research groups at the University Hospital of the University of Bonn, led by the Institute of Innate Immunity and the Core Facility Nanobodies, Scripps Research, and the Karolinska Institutet.
“We believe that the ongoing pandemic requires a continued development of both prophylactics and treatments for non-infected [people], but especially exposed as well as already infected patients. A current global challenge is the emergence of escape mutants, and our lead candidates are optimally designed to protect from the rapid emergence of these viral mutants,” Wilgenbus adds. “As a next-generation, highly specific approach, we are confident that DIOS-202 and DIOS-203 can contribute to the combat with their broad potential for clinical applications, increased neutralizing activity, ease of manufacturing process, favorable biophysical properties, and protection from escape mutants.”
DiosCURE expects that their lead candidates will be highly efficacious, well-tolerated, cost-efficient in production, and amenable to a wide range of clinical applications. As immunotherapies, DIOS-202 and DIOS-203 are said to be suitable both as prophylactic treatment and for treating infected patients in order to avoid severe COVID-19 symptoms.
“Nanobodies represent a versatile alternative to conventional antibodies for passive immunization against SARS-CoV-2. They are efficiently produced in prokaryotic expression systems at low cost, exhibit favorable biophysical properties including high thermostability, and are amenable to engineering of multimeric nanobody constructs with additional benefits,” Wilgenbus reports. “We have already entered preclinical development, with the goal to enter clinical evaluation by the end of this year.”
“Our versatile platform approach allows for the development of novel immunotherapies against SARS-CoV-2, including already known [variants] as well as future genetic variants thereof. Our antibodies are amenable to a broad range of clinical applications, and can be produced by a cost-efficient manufacturing process,” he concludes. “These unique properties will provide us with a strong position to find novel therapies battling COVID-19 and potentially also other future pandemics.”