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Author Correction: Molecular mechanism of phosphopeptide neoantigen immunogenicity

Patskovsky, Yury; Natarajan, Aswin; Patskovska, Larysa; Nyovanie, Samantha; Joshi, Bishnu; Morin, Benjamin; Brittsan, Christine; Huber, Olivia; Gordon, Samuel; Michelet, Xavier; Schmitzberger, Florian; Stein, Robert B; Findeis, Mark A; Hurwitz, Andy; Van Dijk, Marc; Chantzoura, Eleni; Yague, Alvaro S; Pollack Smith, Daniel; Buell, Jennifer S; Underwood, Dennis; Krogsgaard, Michelle
PMID: 37500629
ISSN: 2041-1723
CID: 5618892

Molecular mechanism of phosphopeptide neoantigen immunogenicity

Patskovsky, Yury; Natarajan, Aswin; Patskovska, Larysa; Nyovanie, Samantha; Joshi, Bishnu; Morin, Benjamin; Brittsan, Christine; Huber, Olivia; Gordon, Samuel; Michelet, Xavier; Schmitzberger, Florian; Stein, Robert B; Findeis, Mark A; Hurwitz, Andy; Van Dijk, Marc; Buell, Jennifer S; Underwood, Dennis; Krogsgaard, Michelle
Altered protein phosphorylation in cancer cells often leads to surface presentation of phosphopeptide neoantigens. However, their role in cancer immunogenicity remains unclear. Here we describe a mechanism by which an HLA-B*0702-specific acute myeloid leukemia phosphoneoantigen, pMLL747-755 (EPR(pS)PSHSM), is recognized by a cognate T cell receptor named TCR27, a candidate for cancer immunotherapy. We show that the replacement of phosphoserine P4 with serine or phosphomimetics does not affect pMHC conformation or peptide-MHC affinity but abrogates TCR27-dependent T cell activation and weakens binding between TCR27 and pMHC. Here we describe the crystal structures for TCR27 and cognate pMHC, map of the interface produced by nuclear magnetic resonance, and a ternary complex generated using information-driven protein docking. Our data show that non-covalent interactions between the epitope phosphate group and TCR27 are crucial for TCR specificity. This study supports development of new treatment options for cancer patients through target expansion and TCR optimization.
PMCID:10290117
PMID: 37353482
ISSN: 2041-1723
CID: 5538512

Cholera toxin B scaffolded, focused SIV V2 epitope elicits antibodies that influence the risk of SIVmac251 acquisition in macaques

Rahman, Mohammad Arif; Becerra-Flores, Manuel; Patskovsky, Yury; Silva de Castro, Isabela; Bissa, Massimiliano; Basu, Shraddha; Shen, Xiaoying; Williams, LaTonya D; Sarkis, Sarkis; N'guessan, Kombo F; LaBranche, Celia; Tomaras, Georgia D; Aye, Pyone Pyone; Veazey, Ronald; Paquin-Proulx, Dominic; Rao, Mangala; Franchini, Genoveffa; Cardozo, Timothy
INTRODUCTION:immune responses in isolation. We therefore designed a single, viral-spike-apical, epitope-focused V2 loop immunogen to reveal individual vaccine-elicited immune factors that contribute to protection against HIV/SIV. METHOD:We generated a novel vaccine by incorporating the V2 loop B-cell epitope in the cholera toxin B (CTB) scaffold and compared two new immunization regimens to a historically protective 'standard' vaccine regimen (SVR) consisting of 2xDNA prime boosted with 2xALVAC-SIV and 1xΔV1gp120. We immunized a cohort of macaques with 5xCTB-V2c vaccine+alum intramuscularly simultaneously with topical intrarectal vaccination of CTB-V2c vaccine without alum (5xCTB-V2/alum). In a second group, we tested a modified version of the SVR consisting of 2xDNA prime and boosted with 1xALVAC-SIV and 2xALVAC-SIV+CTB-V2/alum, (DA/CTB-V2c/alum). RESULTS:T cells compared to the DA/CTB-V2c/alum regimen, whereas the first cell type was associated with reduced risk of viral acquisition. CONCLUSION:Taken together, these data suggest that individual viral spike B-cell epitopes can be highly immunogenic and functional as isolated immunogens, although they might not be sufficient on their own to provide full protection against HIV/SIV infection.
PMCID:10160393
PMID: 37153584
ISSN: 1664-3224
CID: 5503262

Hybrid and vaccine-induced immunity against SAR-CoV-2 in MS patients on different disease-modifying therapies

Kister, Ilya; Curtin, Ryan; Pei, Jinglan; Perdomo, Katherine; Bacon, Tamar E; Voloshyna, Iryna; Kim, Joseph; Tardio, Ethan; Velmurugu, Yogambigai; Nyovanie, Samantha; Valeria Calderon, Andrea; Dibba, Fatoumatta; Stanzin, Igda; Samanovic, Marie I; Raut, Pranil; Raposo, Catarina; Priest, Jessica; Cabatingan, Mark; Winger, Ryan C; Mulligan, Mark J; Patskovsky, Yury; Silverman, Gregg J; Krogsgaard, Michelle
OBJECTIVE:To compare "hybrid immunity" (prior COVID-19 infection plus vaccination) and post-vaccination immunity to SARS CoV-2 in MS patients on different disease-modifying therapies (DMTs) and to assess the impact of vaccine product and race/ethnicity on post-vaccination immune responses. METHODS:Consecutive MS patients from NYU MS Care Center (New York, NY), aged 18-60, who completed primary COVID-19 vaccination series ≥6 weeks previously were evaluated for SARS CoV-2-specific antibody responses with electro-chemiluminescence and multiepitope bead-based immunoassays and, in a subset, live virus immunofluorescence-based microneutralization assay. SARS CoV-2-specific cellular responses were assessed with cellular stimulation TruCulture IFNγ and IL-2 assay and, in a subset, with IFNγ and IL-2 ELISpot assays. Multivariate analyses examined associations between immunologic responses and prior COVID-19 infection while controlling for age, sex, DMT at vaccination, time-to-vaccine, and vaccine product. RESULTS:Between 6/01/2021 and 11/11/2021, 370 MS patients were recruited (mean age 40.6 years; 76% female; 53% non-White; 22% with prior infection; common DMT classes: ocrelizumab 40%; natalizumab 15%, sphingosine-1-phosphate receptor modulators 13%; and no DMT 8%). Vaccine-to-collection time was 18.7 (±7.7) weeks and 95% of patients received mRNA vaccines. In multivariate analyses, patients with laboratory-confirmed prior COVID-19 infection had significantly increased antibody and cellular post-vaccination responses compared to those without prior infection. Vaccine product and DMT class were independent predictors of antibody and cellular responses, while race/ethnicity was not. INTERPRETATION/CONCLUSIONS:Prior COVID-19 infection is associated with enhanced antibody and cellular post-vaccine responses independent of DMT class and vaccine type. There were no differences in immune responses across race/ethnic groups.
PMID: 36165097
ISSN: 2328-9503
CID: 5334142

Cellular and Humoral Immunity to SARS-CoV-2 Infection in Multiple Sclerosis Patients on Ocrelizumab and Other Disease-Modifying Therapies: A Multi-Ethnic Observational Study

Kister, Ilya; Patskovsky, Yury; Curtin, Ryan; Pei, Jinglan; Perdomo, Katherine; Rimler, Zoe; Voloshyna, Iryna; Samanovic, Marie I; Cornelius, Amber R; Velmurugu, Yogambigai; Nyovanie, Samantha; Kim, Joseph J; Tardio, Ethan; Bacon, Tamar E; Zhovtis Ryerson, Lana; Raut, Pranil; Pedotti, Rosetta; Hawker, Kathleen; Raposo, Catarina; Priest, Jessica; Cabatingan, Mark; Winger, Ryan C; Mulligan, Mark J; Krogsgaard, Michelle; Silverman, Gregg J
OBJECTIVE:The objective of this study was to determine the impact of multiple sclerosis (MS) disease-modifying therapies (DMTs) on the development of cellular and humoral immunity to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection. METHODS:Patients with MS aged 18 to 60 years were evaluated for anti-nucleocapsid and anti-Spike receptor-binding domain (RBD) antibody with electro-chemiluminescence immunoassay; antibody responses to Spike protein, RBD, N-terminal domain with multiepitope bead-based immunoassays (MBI); live virus immunofluorescence-based microneutralization assay; T-cell responses to SARS-CoV-2 Spike using TruCulture enzyme-linked immunosorbent assay (ELISA); and IL-2 and IFNγ ELISpot assays. Assay results were compared by DMT class. Spearman correlation and multivariate analyses were performed to examine associations between immunologic responses and infection severity. RESULTS:Between January 6, 2021, and July 21, 2021, 389 patients with MS were recruited (mean age 40.3 years; 74% women; 62% non-White). Most common DMTs were ocrelizumab (OCR)-40%; natalizumab -17%, Sphingosine 1-phosphate receptor (S1P) modulators -12%; and 15% untreated. One hundred seventy-seven patients (46%) had laboratory evidence of SARS-CoV-2 infection; 130 had symptomatic infection, and 47 were asymptomatic. Antibody responses were markedly attenuated in OCR compared with other groups (p ≤0.0001). T-cell responses (IFNγ) were decreased in S1P (p = 0.03), increased in natalizumab (p <0.001), and similar in other DMTs, including OCR. Cellular and humoral responses were moderately correlated in both OCR (r = 0.45, p = 0.0002) and non-OCR (r = 0.64, p <0.0001). Immune responses did not differ by race/ethnicity. Coronavirus disease 2019 (COVID-19) clinical course was mostly non-severe and similar across DMTs; 7% (9/130) were hospitalized. INTERPRETATION/CONCLUSIONS:DMTs had differential effects on humoral and cellular immune responses to SARS-CoV-2 infection. Immune responses did not correlate with COVID-19 clinical severity in this relatively young and nondisabled group of patients with MS. ANN NEUROL 2022.
PMID: 35289960
ISSN: 1531-8249
CID: 5191732

Vaccine against SARS-CoV2-generated Immunity in Ocrelizumab-treated Patients: Longitudinal Assessments (VIOLA): Study design and early results [Meeting Abstract]

Kister, I; Piquet, A; Patskovsky, Y; Voloshyna, I; Ferstler, N; Curtin, R; Yogambigai, V; Nyovanie, S; Rimler, Z; Perdomo, K; Borko, T; Selva, S; Parra, Gonzalez J; Bacon, T; Zhovtis, Ryerson L; Raposo, C; Priest, J; Winger, R; Silverman, G J; Krogsgaard, M
Objective: To examine antibody and T-cell responses to mRNAplatform COVID-19 vaccines in Ocrelizumab-treated MS patients over a 12-month period. Introduction: B-cell depletion with Ocrelizumab attenuates humoral responses to vaccines. The kinetics of humoral and cellular immune responses to COVID-19 vaccines in B-cell depleted MS patients has not been reported.
Method(s): VIOLA (NCT04843774) is an open-label, observational study enrolling 60 MS patients on Ocrelizumab from NYU and Rocky Mountain at the University of Colorado MS Centers. First vaccine dose occurred >=2 weeks after ocrelizumab infusion; second-dose >=8 weeks before the next infusion. Antibody responses to SARS-COV-2 spike proteins were assessed with Elecsys Anti-SARS-CoV-2 (Roche Diagnostics) and multiplex bead-based immunoassays. T-cell responses to SARS-CoV-2 Spike protein were assessed with IFNgamma ELISpot (Invitrogen) and TruCulture (Myriad RBM) and high-dimensional immunophenotyping. Samples are collected pre-vaccination and at 4, 12, 24, and 48-weeks post-vaccination.
Result(s): As of 7/15/2021, 52 subjects have been enrolled (39.7+/-10.0 years; 73% female; 47% non-white), of whom 47 were fully vaccinated (85% Pfizer, 15% Moderna). Anti-spike RBD antibody (Elecsys Anti-SARS-CoV-2) were available for pre- and post-vaccine timepoints for 15 patients. Pre-vaccine, 1/15 (7%) patients had detectable titers, while at 4-weeks postvaccine, 10/15 (66%) patients had detectible titers (mean for positives: 1189 U/ml; 5 patients had positive titers <25 U/ml). T-cell activation based on induced IFNgamma secretion (TruCulture) at baseline and 4-week post-vaccine timepoints were available for 13 patients, of whom 12 (92%) were increased (mean pre-vaccine: 24 pg/ml; mean post-vaccine: 366 pg/ml, two-tailed t-test, p=0.0032).
Conclusion(s): This prospective study of humoral and cellular immune responses to COVID-19 vaccines in Ocrelizumab-treated patients will generate data to help guide management of MS patients on anti-CD20 therapies. Early results suggest that 4-weeks post-vaccination nearly all Ocrelizumab-treated MS patients develop T-cell immunity and two-thirds showed evidence of humoral response. Additional 4-week and 12-week post-vaccination data will be presented
EMBASE:636340378
ISSN: 1477-0970
CID: 5179832

Antibody and T-cell responses to SARS-CoV-2 vaccines in MS patients on Ocrelizumab and other disease-modifying therapies: Preliminary results of an ongoing, prospective study [Meeting Abstract]

Kister, I; Patskovsky, Y; Voloshyna, I; Ferstler, N; Curtin, R; Yogambigai, V; Nyovanie, S; Mulligan, M J; Kim, J; Tardio, E; Rimler, Z; Perdomo, K; Bacon, T; Zhovtis, Ryerson L; Samanovic-Golden, M; Cornelius, A; Raposo, C; Priest, J; Winger, R; Krogsgaard, M; Silverman, G J
Objective: To compare humoral and T-cell responses to COVID- 19 vaccines in 400 MS patients who were on Ocrelizumab ('OCR') v. other disease-modifying therapies ('non-OCR') at the time of vaccination. Introduction: Peripheral B-cell depletion with anti-CD20 therapies attenuates humoral responses to vaccines. Whether immune responses to COVID-19 vaccines differ between B-cell depleted and non-B cell depleted MS patients is not known.
Method(s): Consecutive MS patients from NYU MS Care Center were invited to participate if they completed COVID-19 vaccination >=6 weeks previously. Immune testing included anti-spike RBD antibody (Elecsys Anti-SARS-CoV-2) (Roche Diagnostics); multiplex bead-based immunoassays of antibody-responses to SARS-COV-2 spike proteins; T-cell responses to SARS-CoV-2 Spike protein using IFNgamma enzyme-linked immune-absorbent spot (Invitrogen) and TruCulture (Myriad RBM) assays; high dimensional immunophenotyping; and live virus immunofluorescencebased microneutralization assay.
Result(s): As of 7/15/2021, 105 MS subjects were enrolled (mean age: 40.5 years; 76% female; 41% non-white; 38% on OCR; 12% with prior COVID-19 infection). 95% were fully vaccinated with mRNA vaccines (Pfizer/Moderna); 5% - with adenovirus-based vaccine (Johnson&Johnson). Median time from sample collection to last vaccine was 79 days. Positive Elecsys Anti-SARS-CoV-2 Ab titers post-vaccine were detected in 11/37 (30%) in OCR (mean level: 702 U/mL among seropositives) and 54/54 (100%) patients in non-OCR (mean level: 2310 U/mL; p<0.0001). Positive response by multiplex assay (threshold of 'positive' defined as 2 SD below the mean for the non-OCR) were detected in 10/27 (37%) OCR and 29/31 (94%) non-OCR (p<0.00001). T-cell activation based on induced IFNgamma secretion (TruCulture) was detected in 20/25 (80%) OCR and 16/19 (84%) non-OCR patients (p=0.71).
Conclusion(s): Preliminary results suggest robust T-cell immune response to SARS-CoV2 vaccines in approximately 80% of both OCR and non-OCR MS patients. Antibody responses were markedly attenuated in OCR compared to non-OCR group. Updated results will be presented
EMBASE:636340296
ISSN: 1477-0970
CID: 5179842

Mechanism and Structure of γ-Resorcylate Decarboxylase

Sheng, Xiang; Patskovsky, Yury; Vladimirova, Anna; Bonanno, Jeffrey B; Almo, Steven C; Himo, Fahmi; Raushel, Frank M
γ-Resorcylate decarboxylase (γ-RSD) has evolved to catalyze the reversible decarboxylation of 2,6-dihydroxybenzoate to resorcinol in a nonoxidative fashion. This enzyme is of significant interest because of its potential for the production of γ-resorcylate and other benzoic acid derivatives under environmentally sustainable conditions. Kinetic constants for the decarboxylation of 2,6-dihydroxybenzoate catalyzed by γ-RSD from Polaromonas sp. JS666 are reported, and the enzyme is shown to be active with 2,3-dihydroxybenzoate, 2,4,6-trihydroxybenzoate, and 2,6-dihydroxy-4-methylbenzoate. The three-dimensional structure of γ-RSD with the inhibitor 2-nitroresorcinol (2-NR) bound in the active site is reported. 2-NR is directly ligated to a Mn2+ bound in the active site, and the nitro substituent of the inhibitor is tilted significantly from the plane of the phenyl ring. The inhibitor exhibits a binding mode different from that of the substrate bound in the previously determined structure of γ-RSD from Rhizobium sp. MTP-10005. On the basis of the crystal structure of the enzyme from Polaromonas sp. JS666, complementary density functional calculations were performed to investigate the reaction mechanism. In the proposed reaction mechanism, γ-RSD binds 2,6-dihydroxybenzoate by direct coordination of the active site manganese ion to the carboxylate anion of the substrate and one of the adjacent phenolic oxygens. The enzyme subsequently catalyzes the transfer of a proton to C1 of γ-resorcylate prior to the actual decarboxylation step. The reaction mechanism proposed previously, based on the structure of γ-RSD from Rhizobium sp. MTP-10005, is shown to be associated with high energies and thus less likely to be correct.
PMCID:5988983
PMID: 29283551
ISSN: 1520-4995
CID: 4662562

Mucosal elicitation of anti-V2, A4B7-site-targeted antibodies [Meeting Abstract]

Becerra-Flores, M; Patskovsky, Y; Shmelkov, S; Bissa, M; De, Castro I S; Franchini, G; Cardozo, T
Background: Mucosal immunity may be critical to protection from HIV acquisition. Serum antibodies (Abs) targeted specifically to the region of the V2 loop harboring HIV's a4b7 integrin receptor binding site were associated with protection from HIV acquisition in humans. Mucosal Abs of this type may have been further associated with protection in a matched non-human primate model. Cholera toxin B (CTB) is a powerful mucosal adjuvant. We engineered CTB to display the SIVmac251 region of the V2 loop harboring the a4b7 site for testing in Rhesus macaques.
Method(s): The SIVmac251 a4b7 site was fused to CTB and the integrity of the immunogen was confirmed by X-ray crystallography. Antigenicity of the construct was confirmed with the ITS-12 monoclonal antibody. Serum immunogenicity was tested in rabbits and mucosal immunogenicity in young male Rhesus macaques. The macaque study compares 5 intramuscular (IM) and rectal topical co-administrations of CTB-V2 over 24 weeks to a matched-timeline regimen of two sequential DNA SIV gp120 immunizations followed by three ALVAC-SIV immunizations, the last two of which are coadministered with the IM and mucosal CTB-V2 protein boost.
Result(s): The engineered CTB-V2 protein binds galactose, which approximates mucosal GM1-gangliosides, binds ITS-12 potently and elicits titers >10k against the SIVmac251 a4b7 site in 5 of 5 rabbits. Rhesus macaques were successfully inoculated rectally with 200ug of this protein and tolerated the immunization well. The serum and mucosal responses were profiled.
Conclusion(s): Anti-V2, a4b7-site-targeted antibodies may be elicited by mucosal application of an engineered, validated CTB-V2 immunogen. Comparison to potent ALVAC-based regimens may provide insight into protective immune responses elicited by vaccination
EMBASE:625283457
ISSN: 1931-8405
CID: 3528222

Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin

Metcalf, Brian; Chuang, Chihyuan; Dufu, Kobina; Patel, Mira P; Silva-Garcia, Abel; Johnson, Carl; Lu, Qing; Partridge, James R; Patskovska, Larysa; Patskovsky, Yury; Almo, Steven C; Jacobson, Matthew P; Hua, Lan; Xu, Qing; Gwaltney, Stephen L; Yee, Calvin; Harris, Jason; Morgan, Bradley P; James, Joyce; Xu, Donghong; Hutchaleelaha, Athiwat; Paulvannan, Kumar; Oksenberg, Donna; Li, Zhe
We report the discovery of a new potent allosteric effector of sickle cell hemoglobin, GBT440 (36), that increases the affinity of hemoglobin for oxygen and consequently inhibits its polymerization when subjected to hypoxic conditions. Unlike earlier allosteric activators that bind covalently to hemoglobin in a 2:1 stoichiometry, 36 binds with a 1:1 stoichiometry. Compound 36 is orally bioavailable and partitions highly and favorably into the red blood cell with a RBC/plasma ratio of ∼150. This partitioning onto the target protein is anticipated to allow therapeutic concentrations to be achieved in the red blood cell at low plasma concentrations. GBT440 (36) is in Phase 3 clinical trials for the treatment of sickle cell disease (NCT03036813).
PMCID:5346980
PMID: 28337324
ISSN: 1948-5875
CID: 4662552