NCI takes lead on serological test validation as cancer center joins COVID-19 fight
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Deploying its HPV serology testing lab to validate COVID-19 assays is one of three ways NIH’s National Cancer Institute is retooling cancer research activities to take on the pandemic.
In a virtual advisory committee meeting Thursday, Deputy Director Douglas Lowy shared how NCI’s Frederick National Laboratory for Cancer Research will help validate COVID-19 serology tests, discover genetic determinants of susceptibility to severe disease, and screen for covalent inhibitors of SARS-CoV-2 proteinases.
The test validation initiative, which will be coordinated with FDA, CDC, NIAID and several academic centers, was disclosed in a press conference Monday by Brett Giroir, U.S. assistant secretary for health and head of the public health service. The announcement came as European researchers reported that none of the marketed COVID-19 serological assays they reviewed met acceptable performance standards (see “Serology Assays Don’t Meet Criteria”).
Serological tests -- which detect patient antibodies against SARS-CoV-2 as a signal of past or present viral exposure, and of possible immunity going forward -- can’t be used to diagnose infections, but are viewed as a key to determining who can go back to work. The tests began to enter U.S. markets after FDA’s March 16 guidance said they could be sold without agency review under certain conditions, and were available in Asia and Europe even earlier.
NCI’s serology testing expertise comes from its Vaccine, Immunity and Cancer Program, which supports studies of HPV vaccines used to prevent cervical cancer and other malignancies by generating antibodies and other forms of immunity against the oncogenic virus.
In the short term, NCI and its partners will characterize the performance of various serological assays, including tests submitted to FDA; correlate their results with those of neutralization assays; and investigate whether tests cross-react with other coronaviruses found in sera collected before the pandemic, suggesting they could be prone to false positives that could put unprotected people at risk.
Longer-term goals include understanding the relationship between testing positive for COVID-19 antibodies and resistance to infection, investigating how long seropositivity lasts, and longitudinal monitoring of COVID-19 serology in cancer patients.
Separately, NCI’s Cancer Genomics Research Laboratory is collaborating with other NIH institutes to conduct genome-wide association studies (GWAS) for COVID-19 susceptibility using single nucleotide polymorphism (SNP) or genomic sequencing data from patient blood samples.
The goals are to identify therapeutic targets, gain insights into the biology of COVID-19 pathogenesis, and find biomarkers for population screening. The study cohort will contain patients from the NIH Clinical Center, including cancer patients, and up to 2,500 patients from the Italian COVID-19 epidemic, which is skewed toward patients with poor outcomes.
NCI’s push to find covalent inhibitors of the SARS-CoV-2 protienases 3CLpro and PLPro will use fragment-based drug discovery technology developed by the institute’s RAS initiative.
Both viral targets have at least 10 exposed cysteine residues, which can form covalent disulfide bonds with small molecules, potently blocking protein function. A similar strategy is the basis for K-Ras inhibitors from Amgen Inc. (NASDAQ:AMGN), Mirati Therapeutics Inc. (NASDAQ:MRTX) and others.
Frederick National Lab will contribute its library of “disulfide tethering” compounds; Argonne National Laboratory will conduct structural and computational studies of the candidates; and University of Chicago researchers will do medicinal chemistry and biochemical experiments to refine leads.
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3CLpro - Coronavirus 3C-like proteinase (Coronavirus NSP5; Mpro)
PLPro - Papain-like protease