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1.
Coronavirus Resistance Database (CoV-RDB): SARS-CoV-2 susceptibility to monoclonal antibodies, convalescent plasma, and plasma from vaccinated persons.
Tzou, PL, Tao, K, Pond, SLK, Shafer, RW
PloS one. 2022;(3):e0261045
Abstract
As novel SARS-CoV-2 variants with different patterns of spike protein mutations have emerged, the susceptibility of these variants to neutralization by antibodies has been rapidly assessed. However, neutralization data are generated using different approaches and are scattered across different publications making it difficult for these data to be located and synthesized. The Stanford Coronavirus Resistance Database (CoV-RDB; https://covdb.stanford.edu) is designed to house comprehensively curated published data on the neutralizing susceptibility of SARS-CoV-2 variants and spike mutations to monoclonal antibodies (mAbs), convalescent plasma (CP), and vaccinee plasma (VP). As of December 31, 2021, CoV-RDB encompassed 257 publications including 91 (35%) containing 9,070 neutralizing mAb susceptibility results, 131 (51%) containing 16,773 neutralizing CP susceptibility results, and 178 (69%) containing 33,540 neutralizing VP results. The database also records which spike mutations are selected during in vitro passage of SARS-CoV-2 in the presence of mAbs and which emerge in persons receiving mAbs as treatment. The CoV-RDB interface interactively displays neutralizing susceptibility data at different levels of granularity by filtering and/or aggregating query results according to one or more experimental conditions. The CoV-RDB website provides a companion sequence analysis program that outputs information about mutations present in a submitted sequence and that also assists users in determining the appropriate mutation-detection thresholds for identifying non-consensus amino acids. The most recent data underlying the CoV-RDB can be downloaded in its entirety from a GitHub repository in a documented machine-readable format.
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2.
Insights on the mutational landscape of the SARS-CoV-2 Omicron variant receptor-binding domain.
Miller, NL, Clark, T, Raman, R, Sasisekharan, R
Cell reports. Medicine. 2022;(2):100527
Abstract
The Omicron variant features enhanced transmissibility and antibody escape. Here, we describe the Omicron receptor-binding domain (RBD) mutational landscape using amino acid interaction (AAI) networks, which are well suited for interrogating constellations of mutations that function in an epistatic manner. Using AAI, we map Omicron mutations directly and indirectly driving increased escape breadth and depth in class 1-4 antibody epitopes. Further, we present epitope networks for authorized therapeutic antibodies and assess perturbations to each antibody's epitope. Since our initial modeling following the identification of Omicron, these predictions have been realized by experimental findings of Omicron neutralization escape from therapeutic antibodies ADG20, AZD8895, and AZD1061. Importantly, the AAI predicted escape resulting from indirect epitope perturbations was not captured by previous sequence or point mutation analyses. Finally, for several Omicron RBD mutations, we find evidence for a plausible role in enhanced transmissibility via disruption of RBD-down conformational stability at the RBDdown-RBDdown interface.
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3.
Newer Biologic and Small-Molecule Therapies for Inflammatory Bowel Disease.
Baumgart, DC, Le Berre, C
The New England journal of medicine. 2021;(14):1302-1315
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4.
Begelomab for severe refractory dermatomyositis: A case report.
De Lorenzo, R, Sciorati, C, Monno, A, Cavalli, S, Bonomi, F, Tronci, S, Previtali, S, Rovere-Querini, P
Medicine. 2021;(9):e24372
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Abstract
RATIONALE Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody. PATIENT CONCERNS A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia. DIAGNOSIS Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed. INTERVENTIONS The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26. OUTCOMES Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life. CONCLUSION Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
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Anti-interleukin-21 antibody and liraglutide for the preservation of β-cell function in adults with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled, phase 2 trial.
von Herrath, M, Bain, SC, Bode, B, Clausen, JO, Coppieters, K, Gaysina, L, Gumprecht, J, Hansen, TK, Mathieu, C, Morales, C, et al
The lancet. Diabetes & endocrinology. 2021;(4):212-224
Abstract
BACKGROUND Type 1 diabetes is characterised by progressive loss of functional β-cell mass, necessitating insulin treatment. We aimed to investigate the hypothesis that combining anti-interleukin (IL)-21 antibody (for low-grade and transient immunomodulation) with liraglutide (to improve β-cell function) could enable β-cell survival with a reduced risk of complications compared with traditional immunomodulation. METHODS This randomised, parallel-group, placebo-controlled, double-dummy, double-blind, phase 2 trial was done at 94 sites (university hospitals and medical centres) in 17 countries. Eligible participants were adults aged 18-45 years with recently diagnosed type 1 diabetes and residual β-cell function. Individuals with unstable type 1 diabetes (defined by an episode of severe diabetic ketoacidosis within 2 weeks of enrolment) or active or latent chronic infections were excluded. Participants were randomly assigned (1:1:1:1), with stratification by baseline stimulated peak C-peptide concentration (mixed-meal tolerance test [MMTT]), to the combination of anti-IL-21 and liraglutide, anti-IL-21 alone, liraglutide alone, or placebo, all as an adjunct to insulin. Investigators, participants, and funder personnel were masked throughout the treatment period. The primary outcome was the change in MMTT-stimulated C-peptide concentration at week 54 (end of treatment) relative to baseline, measured via the area under the concentration-time curve (AUC) over a 4 h period for the full analysis set (intention-to-treat population consisting of all participants who were randomly assigned). After treatment cessation, participants were followed up for an additional 26-week off-treatment observation period. This trial is registered with ClinicalTrials.gov, NCT02443155. FINDINGS Between Nov 10, 2015, and Feb 27, 2019, 553 adults were assessed for eligibility, of whom 308 were randomly assigned to receive either anti-IL-21 plus liraglutide, anti-IL-21, liraglutide, or placebo (77 assigned to each group). Compared with placebo (ratio to baseline 0·61, 39% decrease), the decrease in MMTT-stimulated C-peptide concentration from baseline to week 54 was significantly smaller with combination treatment (0·90, 10% decrease; estimated treatment ratio 1·48, 95% CI 1·16-1·89; p=0·0017), but not with anti-IL-21 alone (1·23, 0·97-1·57; p=0·093) or liraglutide alone (1·12, 0·87-1·42; p=0·38). Despite greater insulin use in the placebo group, the decrease in HbA1c (a key secondary outcome) at week 54 was greater with all active treatments (-0·50 percentage points) than with placebo (-0·10 percentage points), although the differences versus placebo were not significant. The effects diminished upon treatment cessation. Changes in immune cell subsets across groups were transient and mild (<10% change over time). The most frequently reported adverse events included gastrointestinal disorders, in keeping with the known side-effect profile of liraglutide. The rate of hypoglycaemic events did not differ significantly between active treatment groups and placebo, with an exception of a lower rate in the liraglutide group than in the placebo group during the treatment period. No events of diabetic ketoacidosis were observed. One participant died while on liraglutide (considered unlikely to be related to trial treatment) in connection with three reported adverse events (hypoglycaemic coma, pneumonia, and brain oedema). INTERPRETATION The combination of anti-IL-21 and liraglutide could preserve β-cell function in recently diagnosed type 1 diabetes. The efficacy of this combination appears to be similar to that seen in trials of other disease-modifying interventions in type 1 diabetes, but with a seemingly better safety profile. Efficacy and safety should be further evaluated in a phase 3 trial programme. FUNDING Novo Nordisk.
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Cell Surface GRP94 as a Novel Emerging Therapeutic Target for Monoclonal Antibody Cancer Therapy.
Kim, JW, Cho, YB, Lee, S
Cells. 2021;(3)
Abstract
Glucose-regulated protein 94 (GRP94) is an endoplasmic reticulum (ER)-resident member of the heat shock protein 90 (HSP90) family. In physiological conditions, it plays a vital role in regulating biological functions, including chaperoning cellular proteins in the ER lumen, maintaining calcium homeostasis, and modulating immune system function. Recently, several reports have shown the functional role and clinical relevance of GRP94 overexpression in the progression and metastasis of several cancers. Therefore, the current review highlights GRP94's physiological and pathophysiological roles in normal and cancer cells. Additionally, the unmet medical needs of small chemical inhibitors and the current development status of monoclonal antibodies specifically targeting GRP94 will be discussed to emphasize the importance of cell surface GRP94 as an emerging therapeutic target in monoclonal antibody therapy for cancer.
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Development of Vasoinhibin-Specific Monoclonal Antibodies.
Müller, N, Robles, JP, Zamora, M, Ebnet, J, Markl-Hahn, H, Martínez de la Escalera, G, Clapp, C, Bertsch, T, Triebel, J
Frontiers in endocrinology. 2021;:645085
Abstract
Vasoinhibin is a protein hormone with antiangiogenic, antivasodilatatory, and antivasopermeability effects generated by the proteolytic cleavage of prolactin. The discovery of its role in diabetic retinopathy and peripartum cardiomyopathy led to the evaluation of new pharmacological treatments in clinical interventional trials. However, the quantitative evaluation of vasoinhibin in biological samples from patients has not been possible due to the lack of vasoinhibin-specific antibodies. Recently, loop 1 of vasoinhibin was identified to have a different three-dimensional structure compared to PRL, and thus to contain vasoinhibin-specific epitopes. Here, we report the development of two sets of vasoinhibin-specific monoclonal antibodies against two neighboring regions of the vasoinhibin loop 1. An experimental sandwich ELISA with two monoclonal anti-vasoinhibin antibodies was developed, which had no cross-reactivity to recombinant human full-length prolactin. The ELISA had a quantitation limit of 100 ng/ml, and intra-assay- and inter-assay coefficients of variation of 12.5% and 14%, respectively. The evaluation of 15 human serum samples demonstrated concentrations of below limit of detection (n=3), below limit of quantitation (n=1) and between 0.23 µg/ml (230 ng/ml) to 605 µg/ml (n=12) in the quantifiable range. Despite the high specificity of the monoclonal-monoclonal antibody sandwiches which discriminate vasoinhibin from PRL, there might be cross-reactivities by serum proteins other than vasoinhibin. A fully established vasoinhibin ELISA may support diagnostic and therapeutic measures in vascular diseases.
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Immunoinformatic epitope prediction to select monoclonal antibodies for Phl p 1 quantification.
González-Ruiz, A, López-Matas, MÁ, Moya, R, Carnés, J
Molecular immunology. 2021;:1-7
Abstract
BACKGROUND Allergen quantification has become a relevant parameter for allergen extract characterization and to guarantee the consistency of the manufacturing process at allergen immunotherapy. The aim of this study was to develop and validate a method to quantify the major allergen Phl p 1 based on a prediction of the antigenic regions by immunoinformatic strategies. METHODS Phl p 1 was purified from a Phleum pratense native extract by chromatographic methods. Immunoinformatic tools were used to predict B-cell epitopes. In silico predictions were verified by mapping linear epitopes with a peptide library and used to select the appropriate regions for producing the mAbs to develop an ELISA method, which was validated. Phl p 1 was quantified in 24 batches of P. pratense extracts. RESULTS Phl p 1 was purified with 95 % purity and completely functional. Eight B-cell epitopes in each of the two Phl p 1 isoforms were predicted. Two of the predicted B-cell epitopes overlapped with the experimentally determined peptides recognized by two mAbs selected for development of the kit. The quantification method demonstrated to be specific to Phl p 1, linear, accurate and precise in the range from 7.7 to 123.3 μg/mg. Mean Phl p 1 content was 28.95 μg of allergen/mg of lyophilized native extract and 44.23 μg of allergen/mg of lyophilized depigmented extract. CONCLUSIONS An ELISA method for measuring Phl p 1 in P. pratense extracts was developed and validated by producing the appropriate mAbs against epitopes selected by immunoinformatic tools.
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Mapping antibody binding using multiplexed epitope substitution analysis.
Paull, ML, Bozekowski, JD, Daugherty, PS
Journal of immunological methods. 2021;:113178
Abstract
A more complete understanding of antibody epitopes would aid the development of diagnostics, therapeutic antibodies, and vaccines. However, current methods for mapping antibody binding to epitopes require a targeted experimental approach, which limits throughput. To address these limitations, we developed Multiplexed Epitope Substitution Analysis (MESA) which can rapidly characterize various distinct epitopes using millions of antibody-binding peptides. We screened peptides from a random 12-mer library that bound to human serum antibody repertoires and determined their sequences using next-generation sequencing (NGS). Computationally, we divided target epitope sequences into overlapping k-mer subsequences and substituted the positions in each k-mer with all 20 amino acids, mimicking a saturation mutagenesis. We then determined enrichments of the substituted k-mers in the screened peptide dataset and used these enrichments to identify substitutions favored for binding at each position in the target epitope, ultimately revealing the precise binding motif. To validate MESA, we determined binding motifs for monoclonal antibodies spiked into serum, recovering the expected binding positions and amino acid preferences. To characterize epitopes bound by a population, we analyzed 50 serum specimens to determine the binding motifs within various target epitopes from common pathogens. Additionally, by analyzing various HSV-1 glycoprotein epitopes, MESA revealed unique binding signatures for HSV-1 seropositive specimens and demonstrated the variability of binding signatures within a population. These results demonstrate that MESA can rapidly identify and characterize binding motifs for an unlimited number of epitopes from a single experiment, accelerating discoveries and enhancing our understanding of antibody-epitope interactions.
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Safety and Clinical Activity of a New Anti-PD-L1 Antibody as Monotherapy or Combined with Targeted Therapy in Advanced Solid Tumors: The PACT Phase Ia/Ib Trial.
Patnaik, A, Yap, TA, Chung, HC, de Miguel, MJ, Bang, YJ, Lin, CC, Su, WC, Italiano, A, Chow, KH, Szpurka, AM, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021;(5):1267-1277
Abstract
PURPOSE This phase Ia/Ib PACT study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of a new programmed cell death ligand 1 (PD-L1) inhibitor, LY3300054, as monotherapy or in combination with ramucirumab, abemaciclib, or merestinib (a type II MET kinase inhibitor) in patients with advanced, refractory solid tumors (NCT02791334). PATIENTS AND METHODS Patients were enrolled into cohorts of escalating LY3300054 dose (phase Ia) as monotherapy (N = 15) or combined with ramucirumab (N = 10), abemaciclib (N = 24), or merestinib (N = 12). The phase Ib dose expansion enrolled 8 patients with melanoma in the monotherapy arm and 12 patients with pancreatic cancer in the merestinib combination arm. Combination treatments were administered concurrently from day 1 of each cycle. A 14-day lead-in abemaciclib arm was also explored. Primary endpoints were dose-limiting toxicity (DLT) and safety. RESULTS Treatment-related adverse events included fatigue and nausea in the monotherapy arm (13% for each), hypothyroidism (30%) in the ramucirumab arm, diarrhea (54%) in the abemaciclib arm, and nausea (25%) in the merestinib arm. DLTs associated with hepatoxicity were observed in 3 of 4 patients in the abemaciclib lead-in cohorts. No DLTs or grade 3 or 4 hepatoxicity were reported in the concurrent abemaciclib arm. Pharmacokinetic characteristics were comparable with other PD-L1 inhibitors. One patient in each arm experienced a partial response per RECIST v1.1 lasting ≥7 months. CONCLUSIONS LY3300054 was well tolerated without unexpected safety concerns when administered alone or concurrently with ramucirumab, abemaciclib, or merestinib. Lead-in abemaciclib before combining with LY3300054 was not feasible due to hepatotoxicity. Durable clinical benefits were seen in all regimens.