Computationally restoring the potency of a clinical antibody against SARS-CoV-2 Omicron subvariants

The COVID-19 pandemic has highlighted how viral variants that escape monoclonal antibodies can limit options to control an outbreak. With the emergence of the SARS-CoV-2 Omicron variant, many clinically used antibody drug products lost in vitro and in vivo potency, including AZD7442 and its constituent, AZD1061 [VanBlargan2022, Case2022]. Rapidly modifying such antibodies to restore efficacy to emerging variants is a compelling mitigation strategy. We therefore sought to computationally design an antibody that restores neutralization of BA.1 and BA.1.1 while simultaneously maintaining efficacy against SARS-CoV-2 B.1.617.2 (Delta), beginning from COV2-2130, the progenitor of AZD1061. Here we describe COV2-2130 derivatives that achieve this goal and provide a proof-of-concept for rapid antibody adaptation addressing escape variants. Our best antibody achieves potent and broad neutralization of BA.1, BA.1.1, BA.2, BA.2.12.1, BA.4, BA.5, and BA.5.5 Omicron subvariants, where the parental COV2-2130 suffers significant potency losses. This antibody also maintains potency against Delta and WA1/2020 strains and provides protection in vivo against the strains we tested, WA1/2020, BA.1.1, and BA.5. Because our design approach is computational--driven by high-performance computing-enabled simulation, machine learning, structural bioinformatics and multi-objective optimization algorithms--it can rapidly propose redesigned antibody candidates aiming to broadly target multiple escape variants and virus mutations known or predicted to enable escape.

COVID-19 Outcomes in Patients with Cancer: Findings from the University of California Health System Database

BackgroundPatients with cancer are at risk for poor COVID-19 outcomes. We aimed to identify cancer-related risk factors for poor COVID-19 outcomes. Patients and MethodsWe conducted a retrospective cohort study using the University of California Health COVID Research Data Set. This database includes prospectively-collected, electronic health data of patients who underwent testing for SARS-CoV-2 at seventeen California medical centers. We identified adult patients tested for SARS-CoV-2 between February 1, 2020 and December 31, 2020, and selected a cohort of patients with cancer using diagnostic codes. We obtained demographic, comorbidity, laboratory, cancer type, and antineoplastic therapy data. The primary outcome was hospitalization within 30 days after first positive SARS-CoV-2 test. Secondary outcomes were SARS-CoV-2 positivity and composite endpoint for severe COVID-19 (intensive care, mechanical ventilation, or death within 30 days after first positive test). We used multivariable logistic regression to identify cancer-related factors associated with outcomes. ResultsWe identified 409,462 patients undergoing SARS-CoV-2 testing. Of 49,918 patients with cancer, 1,781 (3.6%) tested positive. Patients with cancer were less likely to test positive (OR 0.69, 95%CI 0.66-0.73, P<0.001). BCR-ABL-negative myeloproliferative neoplasms (polycythemia vera, essential thrombocythemia, and primary myelofibrosis) (OR 2.51, 95%CI 1.29-4.89, P=0.007); venetoclax (OR 3.63, 95%CI 1.02-12.92, P=0.046); methotrexate (OR 3.65, 95%CI 1.17-11.37, P=0.026); Asian race (OR 1.92, 95%CI 1.23-2.98, P=0.004); and Hispanic/Latino ethnicity (OR 1.96, 95%CI 1.41-2.73, P<0.001) were associated with increased hospitalization risk. Among 388 hospitalized patients with cancer and COVID-19, cancer type and therapy type were not associated with severe COVID-19. ConclusionsIn this large, diverse cohort of Californians, cancer was not a risk factor for SARS-CoV-2 positivity. Patients with BCR/ABL-negative myeloproliferative neoplasm and patients receiving methotrexate or venetoclax may be at an increased risk of hospitalization following SARS-CoV-2 infection. Further mechanistic and comparative studies are needed to explain and confirm our findings.

Enhancement of glycosylation by stable co-expression of two sialylation-related enzymes on Chinese hamster ovary cells.

Sialic acid plays important roles in stabilization and modulation of the interaction of molecules and membranes in organisms. Due to its high electronegativity, sialic acid can promote binding effects of molecules and support the transportation of drugs and ions in cells. This also strengthens cells against degradation from glycosidases and proteases. Hence sialic acid helps glycoproteins extend their half-lives and bioactivity. On the other hand, Chinese hamster ovary (CHO) cells have been widely used as a workhorse in biopharmaceutical fields in part due to the similarity between their glycan properties and those in humans. Thus, a high sialylation produced by CHO host cell line is strongly desired. In this study, we simultaneously overexpressed two key sialylated-based enzymes human ß-galactoside α(2,6) sialyltransferase I and UDP-GlcNAc 2-epimerase/ManNAc kinase to achieve greater sialylation pattern produced host cells. The single-cell line thus-generated produced an approximately 41.6% higher level of total free sialic acid, and the glycan profiles showed a significant increase of more than 7-fold in the relative amount of total sialylated N-glycan as compared to the wild-type. These results demonstrated that co-expression of these two sialylated-based key enzymes yielded a cell line that effectively produced glycoproteins with superior sialylation and achievable human-like glycoforms.