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  1. Article ; Online: Tyrosine O-sulfation proteoforms affect HIV-1 monoclonal antibody potency

    Cindy X. Cai / Nicole A. Doria-Rose / Nicole A. Schneck / Vera B. Ivleva / Brad Tippett / William R. Shadrick / Sarah O’Connell / Jonathan W. Cooper / Zachary Schneiderman / Baoshan Zhang / Daniel B. Gowetski / Daniel Blackstock / Jacob Demirji / Bob C. Lin / Jason Gorman / Tracy Liu / Yile Li / Adrian B. McDermott / Peter D. Kwong /
    Kevin Carlton / Jason G. Gall / Q. Paula Lei

    Scientific Reports, Vol 12, Iss 1, Pp 1-

    2022  Volume 11

    Abstract: Abstract CAP256V2LS, a broadly neutralizing monoclonal antibody (bNAb), is being pursued as a promising drug for HIV-1 prevention. The total level of tyrosine-O-sulfation, a post-translational modification, was known to play a key role for antibody ... ...

    Abstract Abstract CAP256V2LS, a broadly neutralizing monoclonal antibody (bNAb), is being pursued as a promising drug for HIV-1 prevention. The total level of tyrosine-O-sulfation, a post-translational modification, was known to play a key role for antibody biological activity. More importantly, here wedescribe for the first time the significance of the tyrosine-O-sulfation proteoforms. We developed a hydrophobic interaction chromatography (HIC) method to separate and quantify different sulfation proteoforms, which led to the direct functionality assessment of tyrosine-sulfated species. The fully sulfated (4-SO3) proteoform demonstrated the highest in vitro relative antigen binding potency and neutralization efficiency against a panel of HIV-1 viruses. Interestingly, highly variable levels of 4-SO3 were produced by different clonal CHO cell lines, which helped the bNAb process development towards production of a highly potent CAP256V2LS clinical product with high 4-SO3 proteoform. This study presents powerful insight for any biotherapeutic protein development where sulfation may play an important role in product efficacy.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2022-05-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Soluble prefusion-closed HIV-envelope trimers with glycan-covered bases

    Adam S. Olia / Cheng Cheng / Tongqing Zhou / Andrea Biju / Darcy R. Harris / Anita Changela / Hongying Duan / Vera B. Ivleva / Wing-Pui Kong / Li Ou / Reda Rawi / Yaroslav Tsybovsky / David J. Van Wazer / Angela R. Corrigan / Christopher A. Gonelli / Myungjin Lee / Krisha McKee / Sandeep Narpala / Sijy O’Dell /
    Danealle K. Parchment / Erik-Stephane D. Stancofski / Tyler Stephens / Ivy Tan / I-Ting Teng / Shuishu Wang / Qing Wei / Yongping Yang / Zhengrong Yang / Baoshan Zhang / Jan Novak / Matthew B. Renfrow / Nicole A. Doria-Rose / Richard A. Koup / Adrian B. McDermott / Jason G. Gall / Q. Paula Lei / John R. Mascola / Peter D. Kwong

    iScience, Vol 26, Iss 8, Pp 107403- (2023)

    2023  

    Abstract: Summary: Soluble HIV-1-envelope (Env) trimers elicit immune responses that target their solvent-exposed protein bases, the result of removing these trimers from their native membrane-bound context. To assess whether glycosylation could limit these base ... ...

    Abstract Summary: Soluble HIV-1-envelope (Env) trimers elicit immune responses that target their solvent-exposed protein bases, the result of removing these trimers from their native membrane-bound context. To assess whether glycosylation could limit these base responses, we introduced sequons encoding potential N-linked glycosylation sites (PNGSs) into base-proximal regions. Expression and antigenic analyses indicated trimers bearing six-introduced PNGSs to have reduced base recognition. Cryo-EM analysis revealed trimers with introduced PNGSs to be prone to disassembly and introduced PNGS to be disordered. Protein-base and glycan-base trimers induced reciprocally symmetric ELISA responses, in which only a small fraction of the antibody response to glycan-base trimers recognized protein-base trimers and vice versa. EM polyclonal epitope mapping revealed glycan-base trimers –even those that were stable biochemically– to elicit antibodies that recognized disassembled trimers. Introduced glycans can thus mask the protein base but their introduction may yield neo-epitopes that dominate the immune response.
    Keywords Molecular structure ; Virology ; Science ; Q
    Subject code 500
    Language English
    Publishing date 2023-08-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Safety and immunogenicity of an HIV-1 prefusion-stabilized envelope trimer (Trimer 4571) vaccine in healthy adults

    Katherine V. Houser / Martin R. Gaudinski / Myra Happe / Sandeep Narpala / Raffaello Verardi / Edward K. Sarfo / Angela R. Corrigan / Richard Wu / Ro Shauna Rothwell / Laura Novik / Cynthia S. Hendel / Ingelise J. Gordon / Nina M. Berkowitz / Cora Trelles Cartagena / Alicia T. Widge / Emily E. Coates / Larisa Strom / Somia Hickman / Michelle Conan-Cibotti /
    Sandra Vazquez / Olga Trofymenko / Sarah Plummer / Judy Stein / Christopher L. Case / Martha Nason / Andrea Biju / Danealle K. Parchment / Anita Changela / Cheng Cheng / Hongying Duan / Hui Geng / I-Ting Teng / Tongqing Zhou / Sarah O'Connell / Chris Barry / Kevin Carlton / Jason G. Gall / Britta Flach / Nicole A. Doria-Rose / Barney S. Graham / Richard A. Koup / Adrian B. McDermott / John R. Mascola / Peter D. Kwong / Julie E. Ledgerwood

    EClinicalMedicine, Vol 48, Iss , Pp 101477- (2022)

    A first-in-human open-label, randomized, dose-escalation, phase 1 clinical trial

    2022  

    Abstract: Background: Advances in therapeutic drugs have increased life-expectancies for HIV-infected individuals, but the need for an effective vaccine remains. We assessed safety and immunogenicity of HIV-1 vaccine, Trimer 4571 (BG505 DS-SOSIP.664) adjuvanted ... ...

    Abstract Background: Advances in therapeutic drugs have increased life-expectancies for HIV-infected individuals, but the need for an effective vaccine remains. We assessed safety and immunogenicity of HIV-1 vaccine, Trimer 4571 (BG505 DS-SOSIP.664) adjuvanted with aluminum hydroxide (alum), in HIV-negative adults. Methods: We conducted a phase I, randomized, open-label, dose-escalation trial at the National Institutes of Health Clinical Center in Bethesda, MD, USA. Eligible participants were HIV-negative, healthy adults between 18-50 years. Participants were randomized 1:1 to receive Trimer 4571 adjuvanted with 500 mcg alum by either the subcutaneous (SC) or intramuscular (IM) route at weeks 0, 8, and 20 in escalating doses of 100 mcg or 500 mcg. The primary objectives were to evaluate the safety and tolerability of Trimer 4571 with a secondary objective of evaluating vaccine-induced antibody responses. The primary and safety endpoints were evaluated in all participants who received at least one dose of Trimer 4571. Trial results were summarized using descriptive statistics. This trial is registered at ClinicalTrials.gov, NCT03783130. Findings: Between March 7 and September 11, 2019, 16 HIV-negative participants were enrolled, including six (38%) males and ten (62%) females. All participants received three doses of Trimer 4571. Solicited reactogenicity was mild to moderate in severity, with one isolated instance of severe injection site redness (6%) following a third 500 mcg SC administration. The most commonly reported solicited symptoms included mild injection site tenderness in 14 (88%) and mild myalgia in six (38%) participants. The most frequent unsolicited adverse event attributed to vaccination was mild injection site pruritus in six (38%) participants. Vaccine-induced seropositivity occurred in seven (44%) participants and resolved in all but one (6%). No serious adverse events occurred. Trimer 4571-specific binding antibodies were detected in all groups two weeks after regimen completion, primarily focused on ...
    Keywords HIV-1 ; Vaccine ; Trimer 4571 ; BG505 DS-SOSIP.664 ; Phase 1 clinical trial ; NIH ; Medicine (General) ; R5-920
    Subject code 630
    Language English
    Publishing date 2022-06-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

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