An antibody targeting the N-terminal domain of SARS-CoV-2 disrupts the spike trimer

The protective human antibody response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus focuses on the spike (S) protein which decorates the virion surface and mediates cell binding and entry. Most SARS-CoV-2 protective antibodies target the receptor-binding domain or a single dominant epitope (supersite) on the N terminal domain (NTD). Here, using the single B cell technology LIBRA-seq, we isolated a large panel of NTD-reactive and SARS-CoV-2 neutralizing antibodies from an individual who had recovered from COVID-19. We found that neutralizing antibodies to the NTD supersite commonly are encoded by the IGHV1-24 gene, forming a genetic cluster that represents a public B cell clonotype. However, we also discovered a rare human antibody, COV2-3434, that recognizes a site of vulnerability on the SARS-CoV-2 S protein in the trimer interface and possesses a distinct class of functional activity. COV2-3434 disrupted the integrity of S protein trimers, inhibited cell-to-cell spread of virus in culture, and conferred protection in human ACE2 transgenic mice against SARS-CoV-2 challenge. This study provides insight about antibody targeting of the S protein trimer interface region, suggesting this region may be a site of virus vulnerability.

A Comparative Pharmacokinetic Study to Evaluate the Bioequivalence and Safety of A Humanized Recombinant Monoclonal Antibody Targeting Human Epidermal Growth Factor Receptor 2 (HER2) with the Reference Herceptin in Healthy Chinese Subjects

Purpose:This study aimed to evaluate the safety, tolerability, pharmacokinetics and bioequivalence of a test humanized recombinant monoclonal antibody targeting Human Epidermal Growth Factor receptor 2 (HER-2) with the reference Herceptin®.Materials and methods:The trial consists of two parts (part I and part II). Part I was an open-label, sequential-cohort dose-escalation study, QLHER2 (test) was intravenous infusion at single doses escalating from 0.2 to 6 mg/kg (0.2, 1, 2, 4 and 6mg/kg) and Herceptin(reference) 4 mg/kg in 16 healthy subjects, to evaluated the safety, tolerability and pharmacokinetics of QLHER2. Part II was a randomized, double-blind, parallel-group study to evaluate the bioequivalence of QLHER2 and Herceptin in 60 subjects.Results:Following a 1.5-h intravenous infusion of single ascending doses of QLHER2 (1, 2, 4, or 6 mg/kg) In part I, Cmax and Tmax were 19.43-120.01 μg/mL and 68.91-157.87 h, respectively. AUC0-t and CL were 1.91-34.21 h*μg/mL and 0.54-0.12 ml/h/kg, indicating decreased clearance at higher doses, with a greater than proportional increase in the AUC0-t , and the t1/2 was 68.91-157.87 h. In part II, Plasma concentrations appeared to be comparable between QLHER2 and Herceptin over the 70-day sampling period and the QLHER2/Herceptin ratio of the Cmax and AUC0-t was 105.90% (90% CI: 95.69-117.26) and 95.79% (90% CI: 87.74-106.40%), respectively.Conclusion:The 90% CIs of the Cmax and AUC0-t for QLHER2/Herceptin ratio were within the range of 80.0-125.00% indicated that QLHER2 was bioequivalent to Herceptin. The results supported for further evaluation of QLHER2.Trial registration number: ChiCTR2000041577 and ChiCTR2100041802Date of registration: December 30,2020 and January 5, 2021

Viral surface geometry shapes influenza and coronavirus spike evolution through antibody pressure

The evolution of circulating viruses is shaped by their need to evade antibody response, which mainly targets the viral spike. Because of the high density of spikes on the viral surface, not all antigenic sites are targeted equally by antibodies. We offer here a geometry-based approach to predict and rank the probability of surface residues of SARS spike (S protein) and influenza H1N1 spike (hemagglutinin) to acquire antibody-escaping mutations utilizing in-silico models of viral structure. We used coarse-grained MD simulations to estimate the on-rate (targeting) of an antibody model to surface residues of the spike protein. Analyzing publicly available sequences, we found that spike surface sequence diversity of the pre-pandemic seasonal influenza H1N1 and the sarbecovirus subgenus highly correlates with our model prediction of antibody targeting. In particular, we identified an antibody-targeting gradient, which matches a mutability gradient along the main axis of the spike. This identifies the role of viral surface geometry in shaping the evolution of circulating viruses. For the 2009 H1N1 and SARS-CoV-2 pandemics, a mutability gradient along the main axis of the spike was not observed. Our model further allowed us to identify key residues of the SARS-CoV-2 spike at which antibody escape mutations have now occurred. Therefore, it can inform of the likely functional role of observed mutations and predict at which residues antibody-escaping mutation might arise.