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1. Analysis of SARS-CoV-2 Emergent Variants Following AZD7442 (Tixagevimab/Cilgavimab) for Early Outpatient Treatment of COVID-19 (TACKLE Trial)

Author

Gustavo H. Kijak, Bahar Ahani, Douglas Arbetter, Fernando Chuecos, Vancheswaran Gopalakrishnan, Jagadish Beloor, Tyler Brady, Amy Nguyen, Tiffany L. Roe, Nicolette Schuko, Tianhui Zhang, F. D. Richard Hobbs, Francisco Padilla, Elizabeth J. Kelly, Hugh Montgomery, and Katie Streicher

Subjects
AZD7442, Cilgavimab, COVID-19, Tixagevimab, Treatment-emergent viral variants, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Introduction AZD7442 (tixagevimab/cilgavimab) comprises neutralising monoclonal antibodies (mAbs) that bind to distinct non-overlapping epitopes on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. Viral evolution during mAb therapy can select for variants with reduced neutralisation susceptibility. We examined treatment-emergent SARS-CoV-2 variants during TACKLE (NCT04723394), a phase 3 study of AZD7442 for early outpatient treatment of coronavirus disease 2019 (COVID-19). Methods Non-hospitalised adults with mild-to-moderate COVID-19 were randomised and dosed ≤ 7 days from symptom onset with AZD7442 (n = 452) or placebo (n = 451). Next-generation sequencing of the spike gene was performed on SARS-CoV-2 reverse-transcription polymerase chain reaction-positive nasopharyngeal swabs at baseline and study days 3, 6, and 15 post dosing. SARS-CoV-2 lineages were assigned using spike nucleotide sequences. Amino acid substitutions were analysed at allele fractions (AF; % of sequence reads represented by substitution) ≥ 25% and 3% to 25%. In vitro susceptibility to tixagevimab, cilgavimab, and AZD7442 was evaluated for all identified treatment-emergent variants using a pseudotyped microneutralisation assay. Results Longitudinal spike sequences were available for 461 participants (AZD7442, n = 235; placebo, n = 226) and showed that treatment-emergent variants at any time were rare, with 5 (2.1%) AZD7442 participants presenting ≥ 1 substitution in tixagevimab/cilgavimab binding sites at AF ≥ 25%. At AF 3% to 25%, treatment-emergent variants were observed in 15 (6.4%) AZD7442 and 12 (5.3%) placebo participants. All treatment-emergent variants showed in vitro susceptibility to AZD7442. Conclusion These data indicate that AZD7442 creates a high genetic barrier for resistance and is a feasible option for COVID-19 treatment.

Published
2023
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2. Fc-mediated functions of nirsevimab complement direct respiratory syncytial virus neutralization but are not required for optimal prophylactic protection

Author

Tyler Brady, Corinne Cayatte, Tiffany L. Roe, Scott D. Speer, Hong Ji, LeeAnn Machiesky, Tianhui Zhang, Deidre Wilkins, Kevin M. Tuffy, and Elizabeth J. Kelly

Subjects
nirsevimab, respiratory syncytial virus, Fc-mediated effector function, anti-RSV F protein monoclonal antibodies, RSV immunoprophylaxis, Immunologic diseases. Allergy, RC581-607
Abstract

IntroductionNirsevimab is an extended half-life (M252Y/S254T/T256E [YTE]-modified) monoclonal antibody to the pre-fusion conformation of the respiratory syncytial virus (RSV) Fusion protein, with established efficacy in preventing RSV-associated lower respiratory tract infection in infants for the duration of a typical RSV season. Previous studies suggest that nirsevimab confers protection via direct virus neutralization. Here we use preclinical models to explore whether fragment crystallizable (Fc)-mediated effector functions contribute to nirsevimab-mediated protection.MethodsNirsevimab, MEDI8897* (i.e., nirsevimab without the YTE modification), and MEDI8897*-TM (i.e., MEDI8897* without Fc effector functions) binding to Fc γ receptors (FcγRs) was evaluated using surface plasmon resonance. Antibody-dependent neutrophil phagocytosis (ADNP), antibody-dependent cellular phagocytosis (ADCP), antibody-dependent complement deposition (ADCD), and antibody-dependent cellular cytotoxicity (ADCC) were assessed through in vitro and ex vivo serological analyses. A cotton rat challenge study was performed with MEDI8897* and MEDI8897*-TM to explore whether Fc effector functions contribute to protection from RSV.ResultsNirsevimab and MEDI8897* exhibited binding to a range of FcγRs, with expected reductions in FcγR binding affinities observed for MEDI8897*-TM. Nirsevimab exhibited in vitro ADNP, ADCP, ADCD, and ADCC activity above background levels, and similar ADNP, ADCP, and ADCD activity to palivizumab. Nirsevimab administration increased ex vivo ADNP, ADCP, and ADCD activity in participant serum from the MELODY study (NCT03979313). However, ADCC levels remained similar between nirsevimab and placebo. MEDI8897* and MEDI8897*-TM exhibited similar dose-dependent reduction in lung and nasal turbinate RSV titers in the cotton rat model.ConclusionNirsevimab possesses Fc effector activity comparable with the current standard of care, palivizumab. However, despite possessing the capacity for Fc effector activity, data from RSV challenge experiments illustrate that nirsevimab-mediated protection is primarily dependent on direct virus neutralization.

Published
2023
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3. Qualification of a Biolayer Interferometry Assay to Support AZD7442 Resistance Monitoring

Author

Tyler Brady, Tianhui Zhang, Kevin M. Tuffy, Nantaporn Haskins, Qun Du, Jia Lin, Gilad Kaplan, Steven Novick, Tiffany L. Roe, Kuishu Ren, Kim Rosenthal, Patrick M. McTamney, Michael E. Abram, Katie Streicher, and Elizabeth J. Kelly

Subjects
severe acute respiratory syndrome coronavirus 2, coronavirus disease 2019, monoclonal antibody, spike protein, receptor binding domain, Microbiology, QR1-502
Abstract

ABSTRACT AZD7442, a combination of two long-acting monoclonal antibodies (tixagevimab [AZD8895] and cilgavimab [AZD1061]), has been authorized for the prevention and treatment of coronavirus disease 2019 (COVID-19). The rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants requires methods capable of quickly characterizing resistance to AZD7442. To support AZD7442 resistance monitoring, a biolayer interferometry (BLI) assay was developed to screen the binding of tixagevimab and cilgavimab to SARS-CoV-2 spike proteins to reduce the number of viral variants for neutralization susceptibility verification. Six spike variants were chosen to assess the assay’s performance: four with decreased affinity for tixagevimab (F486S:D614G and F486W:D614G proteins) or cilgavimab (S494L:D614G and K444R:D614G proteins) and two reference proteins (wild-type HexaPro and D614G protein). Equilibrium dissociation constant (KD) values from each spike protein were used to determine shifts in binding affinity. The assay’s precision, range, linearity, and limits of quantitation were established. Qualification acceptance criteria determined whether the assay was fit for purpose. By bypassing protein purification, the BLI assay provided increased screening throughput. Although limited correlation between pseudotype neutralization and BLI data (50% inhibitory concentration versus KD) was observed for full immunoglobulins (IgGs), the correlations for antibody fragments (Fabs) were stronger and reflected a better comparison of antibody binding kinetics with neutralization potency. Therefore, despite strong assay performance characteristics, the use of full IgGs limited the screening utility of the assay; however, the Fab approach warrants further exploration as a rapid, high-throughput variant-screening method for future resistance-monitoring programs. IMPORTANCE SARS-CoV-2 variants harbor multiple substitutions in their spike trimers, potentially leading to breakthrough infections and clinical resistance to immune therapies. For this reason, a BLI assay was developed and qualified to evaluate the reliability of screening SARS-CoV-2 spike trimer variants against anti-SARS-CoV-2 monoclonal antibodies (MAbs) tixagevimab and cilgavimab, the components of AZD7442, prior to in vitro pseudovirus neutralization susceptibility verification testing. The assay bypasses protein purification with rapid assessment of the binding affinity of each MAb for each recombinant protein, potentially providing an efficient preliminary selection step, thus allowing a reduced testing burden in the more technically complex viral neutralization assays. Despite precise and specific measures, an avidity effect associated with MAb binding to the trimer confounded correlation with neutralization potency, negating the assay’s utility as a surrogate for neutralizing antibody potency. Improved correlation with Fabs suggests that assay optimization could overcome any avidity limitation, warranting further exploration to support future resistance-monitoring programs.

Published
2022
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4. Molecular Characterization of AZD7442 (Tixagevimab-Cilgavimab) Neutralization of SARS-CoV-2 Omicron Subvariants

Author

Tiffany L. Roe, Tyler Brady, Nicolette Schuko, Amy Nguyen, Jagadish Beloor, Johnathan D. Guest, Anastasia A. Aksyuk, Kevin M. Tuffy, Tianhui Zhang, Katie Streicher, Elizabeth J. Kelly, and Gustavo H. Kijak

Subjects
Microbiology (medical), Infectious Diseases, General Immunology and Microbiology, Ecology, Physiology, Genetics, Cell Biology
Abstract

MAbs are key therapeutic options for COVID-19 prophylaxis and treatment in immunosuppressed and vulnerable populations. Due to the emergence of SARS-CoV-2 variants, including Omicron, it is vital to ensure that neutralization is maintained for MAb-based interventions.

Published
2023

5. 1110. AZD7442 (Tixagevimab/Cilgavimab) Demonstrates Potent In Vitro Activity Against SARS-CoV-2 Spike Variants Identified in Circulation and in Prophylaxis Clinical Studies

Author

Kevin M Tuffy, Michael E Abram, Tiffany L Roe, Bahar Ahani, Tyler Brady, Nicolette Schuko, Lori Clarke, Carolina Caceres, Tara Kenny, Virginia Takahashi, Tianhui Zhang, David E Tabor, Gustavo H Kijak, Elizabeth J Kelly, and Katie Streicher

Subjects
Infectious Diseases, Oncology
Abstract

Background AZD7442 is a combination of extended–half-life SARS-CoV-2–neutralizing monoclonal antibodies (tixagevimab/cilgavimab) that bind to distinct epitopes on the SARS-CoV-2 spike protein. In the PROVENT study, a single 300 mg intramuscular dose of AZD7442 demonstrated 77% efficacy for prevention of COVID-19 vs placebo at primary analysis, with 83% efficacy through 6-months follow-up, and was well-tolerated. We report conservation of AZD7442 binding sites and neutralizing activity against pseudotyped virus-like particles (VLPs) harboring spike substitutions identified in surveillance, and clinical SARS-CoV-2 isolates from the PROVENT study. Methods Consensus SARS-CoV-2 whole genome sequences were analyzed from open source databases to identify prevalent spike substitutions within the AZD7442 binding site. Phenotypic analyses determined neutralization susceptibility of pseudotyped VLPs with identified spike substitutions. Genotypic analyses were also performed on SARS-CoV-2 spike sequences from PROVENT study (NCT04625725) participants with RT-PCR-positive symptomatic illness. Results Most residues in tixagevimab (13/17) and cilgavimab (13/19) binding sites were >99% conserved among global SARS-CoV-2 isolates (N=8,373,740 through Apr 19, 2022). In 2021, AZD7442 binding site polymorphisms emerged among circulating strains (prevalence: R346K, 11%; N440K, 22%; G446S, 15%; S477N, 28%; L452R, 43%; T478K, 70%; E484A, 27%; E484K, 3%; Q493R, 27%), but these did not affect AZD7442 in vitro neutralization potency. AZD7442 retained neutralization activity against variants of concern or interest tested, including Omicron BA.2, with moderate reduction observed for Omicron BA.1. By median 6-months follow-up (Aug 29, 2021, data cut-off) in the PROVENT study, there were no AZD7442-resistant substitutions observed in breakthrough SARS-CoV-2 illness visits. Conclusion AZD7442 retained neutralization activity against all SARS-CoV-2 variants of concern or interest evaluated. Binding site substitutions identified in circulation, and in breakthrough SARS-CoV-2 infections following a single 300 mg dose of AZD7442 in the PROVENT study, were not associated with AZD7442 escape. Disclosures Kevin M. Tuffy, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Michael E. Abram, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Tiffany L. Roe, B.S., AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Bahar Ahani, BSC, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Tyler Brady, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Nicolette Schuko, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Lori Clarke, B.S., AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Carolina Caceres, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Tara Kenny, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Virginia Takahashi, B.S., AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Tianhui Zhang, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds David E. Tabor, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Gustavo H. Kijak, PharmD PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Elizabeth J. Kelly, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Katie Streicher, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds.

Published
2022

6. 1160. Treatment-Emergent Viral Variants in the Phase 3 TACKLE Trial Investigating Efficacy and Safety of AZD7442 (Tixagevimab/Cilgavimab) for the Treatment of Mild to Moderate COVID-19 in Adults

Author

Gustavo H Kijak, Bahar Ahani, Douglas Arbetter, Tyler Brady, Fernando Chuecos, Vancheswaran Gopalakrishnan, Tiffany L Roe, Nicolette Schuko, F D Richard Hobbs, Francisco Padilla, Elizabeth J Kelly, Hugh Montgomery, and Katie Streicher

Subjects
Infectious Diseases, Oncology
Abstract

Background AZD7442 (tixagevimab/cilgavimab) is a combination of neutralizing monoclonal antibodies (mAbs) that bind to distinct epitopes on the SARS-CoV-2 spike protein, with neutralization activity against variants including Omicron. In the Phase 3 TACKLE study, AZD7442 significantly reduced severe disease progression or death and was well-tolerated through Day 29. Viral evolution during treatment has the potential for resistance selection, such as variants exhibiting reduced mAb binding. We report genotypic analysis and phenotypic characterization of variants identified over 15 days after AZD7442 treatment in TACKLE. Methods In TACKLE (NCT04723394), non-hospitalized adults with mild to moderate COVID19 were randomized and dosed ≤7 days from symptom onset with a single 600-mg AZD7442 dose (2 consecutive intramuscular injections, 300 mg of each antibody; n=452) or placebo (n=451). Next-generation sequencing of the spike gene was performed on SARS-CoV-2 reverse-transcription polymerase chain reaction–positive nasal swabs (at baseline and Days 3, 6, and 15). SARS-CoV-2 lineages were assigned using spike nucleotide sequences. Amino acid substitutions, insertions, and deletions were analyzed at allele fractions (AF, % of sequence reads represented by mutation) ≥25% and 3–25%. Results Baseline spike sequences were available from 744 participants (82.4%) (AZD7442, n=380; placebo, n=364); 87% of sequences corresponded to variants of concern/interest; these were balanced between AZD7442 and placebo groups (Table 1). Treatment-emergent (post-dosing) viral variants were rare, with 11 (4.5%) AZD7442 and 3 (1.3%) placebo participants showing the emergence of ≥1 mutation at tixagevimab/cilgavimab binding sites, with an AF ≥25% (Table 2). At AF 3–25%, treatment-emergent viral variants in the AZD7442 binding site were observed in 16 (6.6%) AZD7442 and 15 (6.5%) placebo participants. Conclusion Following AZD7442 treatment, low levels of SARS-CoV-2 variants bearing mutations at tixagevimab/cilgavimab binding sites were identified. These data indicate that combination of two antibodies creates a high genetic barrier for resistance, supporting the use of mAb combinations that bind to distinct epitopes for the treatment of COVID-19. Disclosures Gustavo H. Kijak, PharmD PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Bahar Ahani, BSC, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Douglas Arbetter, MPH, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Tyler Brady, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Fernando Chuecos, BS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Vancheswaran Gopalakrishnan, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Tiffany L. Roe, B.S., AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Nicolette Schuko, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds F.D. Richard Hobbs, FMedSci, AstraZeneca: Grant/Research Support|AstraZeneca: Principal investigator|NIHR Applied Research Collaboration, Oxford Thames Valley: Director|Oxford BRC and NIHR MedTech: Investigator|UKRI and NIHR: Grant/Research Support Francisco Padilla, MD, Amgen: Grant/Research Support|Amgen: Personal fees|AstraZeneca: Grant/Research Support|AstraZeneca: Personal fees|Boehringer Ingelheim: Grant/Research Support|Boehringer Ingelheim: Personal fees|Ferrer: Grant/Research Support|Ferrer: Personal fees|Kowa: Grant/Research Support|Kowa: Personal fees|Medix: Grant/Research Support|Medix: Personal fees|Merck Sharp and Dohme: Grant/Research Support|Merck Sharp and Dohme: Personal fees|Novartis: Grant/Research Support|Novartis: Personal fees|Pfizer: Grant/Research Support|Pfizer: Personal fees|Sanofi: Grant/Research Support|Sanofi: Personal fees|Servier: Grant/Research Support|Servier: Personal fees|Silanes: Grant/Research Support|Silanes: Personal fees Elizabeth J. Kelly, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Hugh Montgomery, MD, AstraZeneca: Advisor/Consultant|Millfield Medical Ltd: Advisor/Consultant|UK National Institute for Health Research's Comprehensive Biomedical Research Centre at University College London Hospitals: Grant/Research Support Katie Streicher, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds.

Published
2022

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