bebtelovimab (LY-CoV1404) / AbCellera, Eli Lilly - LARVOL DELTA

RECURRENT ORGANIZING PNEUMONIA AFTER CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELL THERAPY (CHEST 2025) - "Medications included posaconazole and acyclovir...The patient was started on 40mg of prednisone daily followed by a taper (January 2022-April 2022), with symptoms rapidly improving. Her course was complicated by a COVID infection resulting in hospitalization and treatment with bebtelovimab and Paxlovid... CAR-T therapy may lead to long term pulmonary complications including organizing pneumonia, and patients remain at risk for relapse of the disease even after appropriate treatment."

Anemia • B Cell Lymphoma • Cough • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Infectious Disease • Leukopenia • Lymphoma • Non-Hodgkin’s Lymphoma • Pneumonia • Respiratory Diseases

Viral escape-inspired framework for structure-guided dual bait protein biosensor design. (PubMed, PLoS Comput Biol) - "CTRL-V's through iterative design cycles was shown to pinpoint 20% (of the 39) reported SARS-CoV-2 point mutations across 30 circulating, infective strains as responsible for immune escape from commercial antibody LY-CoV1404...The publicly availably viral escape data was leveraged as in vivo anchors to streamline a computational workflow that can be generalized for dual bait biosensor design tasks as exemplified by identifying key mutational loci in Raf kinase that enables it to selectively bind Ras and Rap1a GTP. We demonstrate three versions of CTRL-V which use a combination of integer optimization, stochastic sampling by PyRosetta, and deep learning-based ProteinMPNN for structure-guided biosensor design."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • RAP1A • RAS

Mutational Scanning and Binding Free Energy Computations of the SARS-CoV-2 Spike Complexes with Distinct Groups of Neutralizing Antibodies: Energetic Drivers of Convergent Evolution of Binding Affinity and Immune Escape Hotspots. (PubMed, Int J Mol Sci) - "In this study, we conducted a comprehensive structural and energetic analysis of SARS-CoV-2 spike receptor-binding domain (RBD) complexes with neutralizing antibodies from four distinct groups (A-D), including group A LY-CoV016, group B AZD8895 and REGN10933, group C LY-CoV555, and group D antibodies AZD1061, REGN10987, and LY-CoV1404...The results demonstrate excellent qualitative agreement between the predicted binding hotspots and the latest experiments on antibody escape. These findings provide valuable insights into the molecular determinants of antibody binding and viral escape, highlighting the importance of targeting conserved epitopes and leveraging combination therapies to mitigate the risk of immune evasion."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Comparative Effectiveness of Outpatient COVID-19 Therapies in Solid Organ Transplant Recipients. (PubMed, Transpl Infect Dis) - "Outpatient COVID-19 therapies were largely associated with improved outcomes among SOT recipients. These treatment agents showed similar rates of 30-day hospitalization, except for remdesivir. The choice of outpatient COVID-19 therapy in SOT recipients should primarily account for patients' individual circumstances and drug-drug interactions rather than differential therapeutic efficacy."

Clinical • HEOR • Journal • Infectious Disease • Novel Coronavirus Disease • Solid Organ Transplantation • Transplantation

Comparative Effectiveness of Antivirals and Monoclonal Antibodies for Treating COVID-19 Patients Infected With Omicron Variant: A Systematic Review and Network Meta-Analysis. (PubMed, Influenza Other Respir Viruses) - "Molnupiravir and bebtelovimab showed no significant benefits for these outcomes. In conclusion, among individuals infected with COVID-19 during the Omicron wave, mortality risk was lower with nirmatrelvir/ritonavir or sotrovimab use, whereas hospitalization was reduced with nirmatrelvir/ritonavir, remdesivir, or sotrovimab...A key limitation is that findings rely on data from the last search and may be impacted by potential changes in mortality risk due to immune evasion by emerging variants, highlighting the need for ongoing randomized trials across variants and populations. TRIAL REGISTRATION: The study was registered on PROSPERO, CRD42022351508."

Clinical • HEOR • Journal • Retrospective data • Review • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Real-World Effectiveness of Bebtelovimab Versus Nirmatrelvir/Ritonavir in Outpatients with COVID-19. (PubMed, Pulm Ther) - "Treatment with BEB was not inferior to NR with respect to 30-day all-cause hospitalization or death. The risk of secondary outcomes was not different for patients treated with BEB compared to NR."

Journal • Real-world evidence • Infectious Disease • Novel Coronavirus Disease

SARS-CoV-2 variants and bebtelovimab: immune escape mechanisms revealed by computational studies. (PubMed, Phys Chem Chem Phys) - "Our findings revealed that certain residues, including 440(N/K), Lys444, 452(L/R), 484(E/A), 498(Q/R), and THR500, are directly or indirectly responsible for altering the binding position and efficacy of bebtelovimab antibody with the RBD when mutations are introduced. The binding energy studies on three different variants, wild-type, delta, and omicron, revealed that the binding efficacy of bebtelovimab with the RBD diminished over time as additional mutations were introduced."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Therapeutic Potential of Neutralizing Monoclonal Antibodies (nMAbs) against SARS-CoV-2 Omicron Variant. (PubMed, Curr Pharm Des) - "Bebtelovimab has been observed to preserve its efficacy against all subtypes of the Omicron variant. Subsequently, WKS13, mAb-39, 19n01, F61-d2 cocktail, etc., have become effective. This review has highlighted the therapeutic implications of nMAbs in SARS-CoV-2 Omicron treatment and the progress of COVID-19 drug discovery."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Impact of Bebtelovimab Treatment Timing on COVID-19 Outcomes in Ambulatory Solid Organ Transplant Recipients. (PubMed, Transpl Infect Dis) - "Early bebtelovimab treatment in outpatient SOTRs was associated with a lower risk of hospitalization compared to no treatment, while late administration did not show a significant advantage over no treatment. Although bebtelovimab is no longer authorized, these findings suggest that the timing of COVID therapies for SOTRs may be important to optimize outcomes."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • Solid Organ Transplantation • Transplantation

Investigating the Safety Profile of Fast-Track COVID-19 Drugs Using the FDA Adverse Event Reporting System Database: A Comparative Observational Study. (PubMed, Pharmacoepidemiol Drug Saf) - "We identified potential ADRs associated with COVID-19 drugs and provided insights into their real-world safety. This study demonstrated that real-world data and real-time safety reviews could be effective methods for the timely detection of ADR signals of drugs that have received fast-track approval, as exemplified by COVID-19 drugs. These findings underscore the importance of the continued surveillance, efficient data processing, and establishment of automated pipelines for real-time safety reviews."

Adverse events • Clinical • Journal • Observational data • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Adverse events associated with SARS-CoV-2 neutralizing monoclonal antibodies using the FDA adverse event reporting system database. (PubMed, Toxicol Res) - "In this study, data from the FAERS from January 2020 to December 2022 were used to investigate signals associated with five monoclonal antibody products (bamlanivimab, bamlanivimab/etesevimab, bebtelovimab, casirivimab/imdevimab, sotrovimab) in coronavirus disease 2019 (COVID-19) patients and one monoclonal antibody product (tixagevimab/cilgavimab) in patients wherein COVID-19 vaccination was not recommended. Even though the purposes of use were different, the types of signals between drugs were similar. Careful monitoring of these AEs should be considered for certain COVID-19 patients, at risk, when they are treated with monoclonal antibody products."

Adverse events • Journal • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

Identification of Antibody-Resistant SARS-CoV-2 Mutants via N4-Hydroxycytidine Mutagenesis. (PubMed, Antiviral Res) - "By inducing mutations with the active compound of Molnupiravir, N4-hydroxycytidine (NHC), and subsequently passaging the virus in the presence of antibodies, we identified specific Spike mutations linked to resistance...From a Wuhan-like strain of SARS-CoV-2, we identified the following mutations conferring strong resistance towards the corresponding antibodies: Bamlanivimab - E484K, F490S and S494P; Sotrovimab - E340K; Cilgavimab - K444R/E and N450D. From the Omicron B.1.1.529 variant, the strongly selected mutations were: Bebtelovimab - V445A; Sotrovimab - E340K and K356M; Cilgavimab - K444R, V445A and N450D...Notably, many of the identified resistance-conferring mutations are prevalent in real-world SARS-CoV-2 variants, but some of them (G485S, D428G, and K462E) have not yet been observed in circulating strains. Our approach offers a strategy for predicting the therapeutic efficacy of antibodies against emerging virus variants."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Bebtelovimab-bound SARS-CoV-2 RBD mutants: resistance profiling and validation with escape mutations, clinical results, and viral genome sequences. (PubMed, FEBS Lett) - "Through extensive physicochemical analysis, mutational preferences, precision-recall metrics, protein-protein docking, and energetic analyses, combined with all-atom, and coarse-grained molecular dynamics (MD) simulations, we elucidated the structural-dynamics-binding features of the bebtelovimab-RBD complexes. Identification of susceptible RBD residues under positive selection pressure, coupled with validation against bebtelovimab-escape mutations, clinically reported resistance mutations, and viral genomic sequences enhances the translational significance of our findings and contributes to a better understanding of the resistance mechanisms of SARS-CoV-2."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Monoclonal Antibody Therapies Against SARS-CoV-2: Promises and Realities. (PubMed, Curr Top Microbiol Immunol) - "Unfortunately, the Omicron variant of concern has completely reset all achievements so far in mAb therapy for COVID-19. Despite the intrinsic limitations of this strategy, future developments such as respiratory delivery of further engineered mAb cocktails could lead to improved outcomes."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Reprint of: Evaluation of physicians prescribing of COVID-19 guideline-directed outpatient treatments in a primary care walk-in clinic. (PubMed, J Am Pharm Assoc (2003)) - "Nirmatrelvir-ritonavir was the most prescribed medication for the treatment of mild-to-moderate COVID-19, consistent with its position as first-line therapy and widespread accessibility. The study results will inform future educational opportunities, such as in-service presentations and handouts, that may improve the prescribing of outpatient treatment for mild-to-moderate COVID-19 moving forward."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

A bispecific antibody exhibits broad neutralization against SARS-CoV-2 Omicron variants XBB.1.16, BQ.1.1 and sarbecoviruses. (PubMed, Nat Commun) - "Comparative analysis of 7F3 and LY-CoV1404 epitopes highlights a distinct and highly conserved epitope in the RBM region bound by 7F3, facilitating neutralization of the immune-evasive Omicron variant XBB.1.16. G7-Fc holds promise as a potential prophylactic countermeasure against SARS-CoV-2, particularly against circulating and emerging variants."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Assay Interference Causing Persistently Elevated Vancomycin Levels Ultimately Leading to Treatment Failure and Fatal Outcome (ATS 2024) - "Patient received Bebtelovimab (monoclonal antibody) for COVID-19. Transtrachial aspiration (TTA) culture grew Pseudomonas aeruginosa, and the patient was started on intravenous (IV) aztreonam, metronidazole, doxycycline and vancomycin...Patient eventually deteriorated clinically, and due to persistently high vancomycin levels, the antibiotic regimen was switched to inhaled Tobramycin, IV Micafungin and IV Ceftriaxone... The implementation of therapeutic drug monitoring is widely accepted and is a customary approach in the administration of vancomycin, with the primary objective of optimizing patient outcomes while minimizing the potential for toxicity. It is crucial to consider that assay interference can result in inaccurately elevated vancomycin levels. Clinicians should maintain a high level of suspicion if persistently higher vancomycin levels cannot be accounted for by renal function or other causes, especially if the patient continues to clinically deteriorate."

Asthma • Cardiovascular • Congestive Heart Failure • Dermatology • Diabetes • Heart Failure • Hypertension • Immunology • Infectious Disease • Metabolic Disorders • Musculoskeletal Diseases • Novel Coronavirus Disease • Obesity • Orthopedics • Pulmonary Disease • Respiratory Diseases • Septic Shock

Comparative Effectiveness of Outpatient COVID-19 Therapies in Solid Organ Transplant Recipients (ATC 2024) - "However, few data exist comparing their effectiveness in solid organ transplant recipients (SOTR).* We used de-identified administrative claims data from the OptumLabs Data Warehouse (OLDW) to identify adult SOTRs with mild-to-moderate COVID-19 who received anti-spike monoclonal antibody (mAb; i.e., sotrovimab or bebtelovimab), molnupiravir, nirmatrelvir-ritonavir, or remdesivir in the outpatient setting. SOTRs who received outpatient mAb or antiviral treatment for mild-to-moderate COVID-19 had comparable clinical outcomes, as measured by odds of hospitalization. Clinicians may use any of these treatment options according to the individual patient's circumstances and without concern for differential therapeutic efficacy."

Clinical • HEOR • Infectious Disease • Novel Coronavirus Disease • Solid Organ Transplantation • Transplantation

The safety signal detection and analysis of monoclonal antibodies against SARS-CoV-2 based on real-world evidence - the suitable selectivity for different populations. (PubMed, Eur Rev Med Pharmacol Sci) - "In summary, SOT may be unsuitable for allergic patients and may lead to abnormal test results. BEB showed the highest correlations with gastrointestinal and neuropsychiatric events. In addition, its infusion reactions should also be noted. TIX/CIL can lead to a variety of cardiovascular events."

HEOR • Journal • Real-world • Real-world evidence • Cardiovascular • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Novel Coronavirus Disease • Psychiatry • Respiratory Diseases

mRNA delivery of epitope-specific monoclonal antibodies for treatment of viral infection (IMMUNOLOGY 2024) - "We generated mRNAs expressing two different mAbs, LY-CoV1404 (mRNA-1404) and 76E1 (mRNA-76E1), that target different SARS-CoV-2 epitopes and formulated them in LNPs...Following single mRNA-LNP administration (5ug and 15ug dose via intramuscular or subcutaneous route), serum antibodies remained detectable 5 weeks out. Our data indicate that mRNA is a promising platform for the delivery of therapeutic mAbs to treat human disease such as viral infections."

Infectious Disease • Novel Coronavirus Disease • Pulmonary Disease • Respiratory Diseases

Evaluating mAbs binding abilities to Omicron subvariant RBDs: implications for selecting effective mAb therapies. (PubMed, Phys Chem Chem Phys) - "Our results indicated that the antibody LY-COV1404 maintained binding affinities across all studied systems, suggesting the resilience of certain antibodies against variant-induced immune escape, as seen with the mAb 1D1-Fab...These findings enhance our comprehension of the binding interactions between mAbs and RBDs, contributing to the understanding of immune escape mechanisms. They also lay the groundwork for the design and optimization of antiviral drugs and have significant implications for the development of treatments against current and future coronaviruses."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Overcoming antibody-resistant SARS-CoV-2 variants with bispecific antibodies constructed using non-neutralizing antibodies. (PubMed, iScience) - "Furthermore, we created a bispecific antibody by incorporating the scFv of bebtelovimab with our anti-S2 antibody, demonstrating significant restoration of effectiveness against bebtelovimab-resistant BQ.1.1 variants. This study highlights the potential of neutralizing bispecific antibodies, which combine existing less effective anti-RBD antibodies with anti-S2 antibodies, to revive the effectiveness of antibody therapeutics compromised by immune-evading variants."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

In Vitro Combinatorial Activity of Direct Acting Antivirals and Monoclonal Antibodies against the Ancestral B.1 and BQ.1.1 SARS-CoV-2 Viral Variants. (PubMed, Viruses) - "To assess the cooperative effects of dual drug combinations in vitro, we used a VERO E6 cell-based in vitro system with the ancestral B.1 or the highly divergent BQ.1.1 virus to test pairwise combinations of the licensed DAA, including nirmatrelvir (NRM), remdesivir (RDV) and the active metabolite of molnupiravir (EIDD-1931) as well the combination of RDV with four licensed mAbs (sotrovimab, bebtelovimab, cilgavimab, tixagevimab; tested only with the susceptible B.1 virus). This was supported by in vitro confirmation experiments showing a more than a linear shift of a drug-effective concentration (IC50) at increasing concentrations of the companion drug, although the effect was prominent with DAA/DAA combinations and minimal or null with RDV/mAb combinations. These results support the cooperative effects of dual drug combinations in vitro, which should be further investigated in animal models before introduction into the clinic."

Journal • Preclinical • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Coronavirus Disease 2019 (COVID-19) in Heart Transplant Recipients and Anti-SARS-CoV-2 Monoclonal Antibodies: Experience, Lessons Learnt, and Future Challenges. (PubMed, Cardiol Rev) - "We performed a retrospective chart review including adult HT recipients at Westchester Medical Center from January 1, 2020 to December 10, 2022, who received anti-SARS-CoV-2 monoclonal antibodies (mAbs) for treatment of mild-to-moderate COVID-19, and those who received tixagevimab/cilgavimab for preexposure prophylaxis...In this largest single-center study in this population, 42 adult HT recipients received casirivimab/imdevimab (36%), sotrovimab (31%), or bebtelovimab (29%) for treatment of mild-to-moderate COVID-19...Overall, the data suggests that HT recipients receiving mAbs have reduced rates of hospitalization, need for intensive care unit care, or death. Use of anti-SARS-CoV-2 mAbs in SOTRs is resource intensive and requires a programmatic team approach for optimal administration and to minimize any risk of disparities in their use."

Journal • Critical care • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • Solid Organ Transplantation • Transplantation

SARS-CoV-2 evolution during prolonged infection in immunocompromised patients. (PubMed, mBio) - "Two patients were treated with monoclonal antibodies (bebtelovimab and sotrovimab); by the next sampled timepoint, each virus population showed substitutions associated with monoclonal antibody resistance as the dominant forms (spike K444N and spike E340D). All patients received remdesivir, but remdesivir-resistant substitutions were not detected...One model is that long-term viral persistence in infected individuals allows for viral evolution in response to host pressures, resulting in viruses more likely to replicate efficiently in humans. In this study, we characterize replication in several hospitalized and long-term infected individuals, documenting efficient pathways of viral evolution."

Journal • Hematological Malignancies • Infectious Disease • Lymphoma • Novel Coronavirus Disease • Oncology • Respiratory Diseases • Solid Organ Transplantation • Transplantation