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  • 1
    Online Resource
    Online Resource
    A Coreceptor-Mimetic Peptide Enhances the Potency of V3-Glycan Antibodies
    American Society for Microbiology ; 2019
    In:  Journal of Virology Vol. 93, No. 5 ( 2019-03)
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 93, No. 5 ( 2019-03)
    Abstract: Broadly neutralizing antibodies (bNAbs) target five major epitopes on the HIV-1 envelope glycoprotein (Env). The most potent bNAbs have median half-maximal inhibitory concentration (IC 50 ) values in the nanomolar range, and the broadest bNAbs neutralize up to 98% of HIV-1 strains. The engineered HIV-1 entry inhibitor eCD4-Ig has greater breadth than bNAbs and similar potency. eCD4-Ig is markedly more potent than CD4-Ig due to its C-terminal coreceptor-mimetic peptide. Here we investigated whether the coreceptor-mimetic peptide mim6 improved the potency of bNAbs with different epitopes. We observed that when mim6 was appended to the C terminus of the heavy chains of bNAbs, this sulfopeptide improved the potency of all classes of bNAbs against HIV-1 isolates that are sensitive to neutralization by the sulfopeptide alone. However, mim6 did not significantly enhance neutralization of other isolates when appended to most classes of bNAbs, with one exception. Specifically, mim6 improved the potency of bNAbs of the V3-glycan class, including PGT121, PGT122, PGT128, and 10-1074, by an average of 2-fold for all HIV-1 isolates assayed. Despite this difference, 10-1074 does not induce exposure of the coreceptor-binding site, and addition of mim6 to 10-1074 did not promote shedding of the gp120 subunit of Env. Mixtures of 10-1074 and an Fc domain fused to mim6 neutralized less efficiently than a 10-1074/mim6 fusion, indicating that mim6 enhances the avidity of this fusion. Our data show that mim6 can consistently improve the potency of V3-glycan antibodies and suggest that these antibodies bind in an orientation that facilitates mim6 association with Env. IMPORTANCE HIV-1 requires both the cellular receptor CD4 and a tyrosine-sulfated coreceptor to infect its target cells. CD4-Ig is a fusion of the HIV-1-binding domains of CD4 with an antibody Fc domain. Previous studies have demonstrated that the potency of CD4-Ig is markedly increased by appending a coreceptor-mimetic sulfopeptide to its C terminus. We investigated whether this coreceptor-mimetic peptide improves the potency of broadly neutralizing antibodies (bNAbs) targeting five major epitopes on the HIV-1 envelope glycoprotein (Env). We observed that inclusion of the sulfopeptide dramatically improved the potency of all bNAb classes against isolates with more-open Env structures, typically those that utilize the coreceptor CXCR4. In contrast, the sulfopeptide improved only V3-glycan antibodies when neutralizing primary isolates, on average by 2-fold. These studies improve the potency of one class of bNAbs, show that coreceptor-mimetic sulfopeptides enhance neutralization through distinct mechanisms, and provide insight for the design of novel multispecific entry inhibitors.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.01653-18
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2019
    detail.hit.zdb_id: 1495529-5
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  • 2
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    Online Resource
    T-Cells Expressing a Highly Potent PRAME-Specific T-Cell Receptor in Combination with a Chimeric PD1-41BB Co-Stimulatory Receptor Show a Favorable Preclinical Safety Profile and Strong Anti-Tumor Reactivity
    MDPI AG ; 2022
    In:  Cancers Vol. 14, No. 8 ( 2022-04-14), p. 1998-
    Details
    In: Cancers, MDPI AG, Vol. 14, No. 8 ( 2022-04-14), p. 1998-
    Abstract: The hostile tumor microenvironment (TME) is a major challenge for the treatment of solid tumors with T-cell receptor (TCR)-modified T-cells (TCR-Ts), as it negatively influences T-cell efficacy, fitness, and persistence. These negative influences are caused, among others, by the inhibitory checkpoint PD-1/PD-L1 axis. The Preferentially Expressed Antigen in Melanoma (PRAME) is a highly relevant cancer/testis antigen for TCR-T immunotherapy due to broad expression in multiple solid cancer indications. A TCR with high specificity and sensitivity for PRAME was isolated from non-tolerized T-cell repertoires and introduced into T-cells alongside a chimeric PD1-41BB receptor, consisting of the natural extracellular domain of PD-1 and the intracellular signaling domain of 4-1BB, turning an inhibitory pathway into a T-cell co-stimulatory pathway. The addition of PD1-41BB to CD8+ T-cells expressing the transgenic PRAME-TCR enhanced IFN-γ secretion, improved cytotoxic capacity, and prevented exhaustion upon repetitive re-challenge with tumor cells in vitro without altering the in vitro safety profile. Furthermore, a single dose of TCR-Ts co-expressing PD1-41BB was sufficient to clear a hard-to-treat melanoma xenograft in a mouse model, whereas TCR-Ts without PD1-41BB could not eradicate the PD-L1-positive tumors. This cutting-edge strategy supports development efforts to provide more effective TCR-T immunotherapies for the treatment of solid tumors.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers14081998
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527080-1
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  • 3
    Online Resource
    Online Resource
    Anti-drug Antibody Responses Impair Prophylaxis Mediated by AAV-Delivered HIV-1 Broadly Neutralizing Antibodies
    Elsevier BV ; 2019
    In:  Molecular Therapy Vol. 27, No. 3 ( 2019-03), p. 650-660
    Details
    In: Molecular Therapy, Elsevier BV, Vol. 27, No. 3 ( 2019-03), p. 650-660
    Type of Medium: Online Resource
    ISSN: 1525-0016
    URL: Article
    DOI: 10.1016/j.ymthe.2019.01.004
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
    detail.hit.zdb_id: 2001818-6
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  • 4
    Online Resource
    Online Resource
    eCD4-Ig Variants That More Potently Neutralize HIV-1
    American Society for Microbiology ; 2018
    In:  Journal of Virology Vol. 92, No. 12 ( 2018-06-15)
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 92, No. 12 ( 2018-06-15)
    Abstract: The human immunodeficiency virus type 1 (HIV-1) entry inhibitor eCD4-Ig is a fusion of CD4-Ig and a coreceptor-mimetic peptide. eCD4-Ig is markedly more potent than CD4-Ig, with neutralization efficiencies approaching those of HIV-1 broadly neutralizing antibodies (bNAbs). However, unlike bNAbs, eCD4-Ig neutralized all HIV-1, HIV-2, and simian immunodeficiency virus (SIV) isolates that it has been tested against, suggesting that it may be useful in clinical settings, where antibody escape is a concern. Here, we characterize three new eCD4-Ig variants, each with a different architecture and each utilizing D1.22, a stabilized form of CD4 domain 1. These variants were 10- to 20-fold more potent than our original eCD4-Ig variant, with a construct bearing four D1.22 domains (eD1.22-HL-Ig) exhibiting the greatest potency. However, this variant mediated less efficient antibody-dependent cell-mediated cytotoxicity (ADCC) activity than eCD4-Ig itself or several other eCD4-Ig variants, including the smallest variant (eD1.22-Ig). A variant with the same architecture as the original eCD4-Ig (eD1.22-D2-Ig) showed modestly higher thermal stability and best prevented the promotion of infection of CCR5-positive, CD4-negative cells. All three variants, and eCD4-Ig itself, mediated more efficient shedding of the HIV-1 envelope glycoprotein gp120 than did CD4-Ig. Finally, we show that only three D1.22 mutations contributed to the potency of eD1.22-D2-Ig and that introduction of these changes into eCD4-Ig resulted in a variant 9-fold more potent than eCD4-Ig and 2-fold more potent than eD1.22-D2-Ig. These studies will assist in developing eCD4-Ig variants with properties optimized for prophylaxis, therapy, and cure applications. IMPORTANCE HIV-1 bNAbs have properties different from those of antiretroviral compounds. Specifically, antibodies can enlist immune effector cells to eliminate infected cells, whereas antiretroviral compounds simply interfere with various steps in the viral life cycle. Unfortunately, HIV-1 is adept at evading antibody recognition, limiting the utility of antibodies as a treatment for HIV-1 infection or as part of an effort to eradicate latently infected cells. eCD4-Ig is an antibody-like entry inhibitor that closely mimics HIV-1's obligate receptors. eCD4-Ig appears to be qualitatively different from antibodies, since it neutralizes all HIV-1, HIV-2, and SIV isolates. Here, we characterize three new structurally distinct eCD4-Ig variants and show that each excels in a key property useful to prevent, treat, or cure an HIV-1 infection. For example, one variant neutralized HIV-1 most efficiently, while others best enlisted natural killer cells to eliminate infected cells. These observations will help generate eCD4-Ig variants optimized for different clinical applications.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.02011-17
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2018
    detail.hit.zdb_id: 1495529-5
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  • 5
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    Online Resource
    Abstract 1521: Combining a PRAME-specific TCR showing potent in vitro and in vivo anti-tumor reactivity and a favorable preclinical safety profile with a PD1-41BB switch receptor results in highly efficient T cells
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1521-1521
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1521-1521
    Abstract: The development of effective adoptive T cell therapies to treat cancer patients has two main challenges. The first is identifying an antigen that is highly expressed in tumors with limited or no expression in normal tissues. The second is to develop a receptor that specifically binds to this antigen inducing potent anti-tumor activity without cross-reactivity to healthy cells. An additional challenge in the treatment of solid tumors is the hostile tumor microenvironment (TME) including the T cell inhibitory PD-1/PD-L1 axis. The cancer/testis antigen PRAME is an attractive target for immunotherapies of solid tumors using TCR-modified T cells as it is highly expressed in several solid tumor indications while its expression in normal tissues is mainly restricted to the testis. TCR candidates with high specificity for a PRAME-derived peptide presented on HLA-A2 were isolated from a non-tolerized T cell repertoire using our well-established high-throughput TCR generation process. Based on multi-parameter screening a lead TCR candidate was selected from more than 30 analyzed specific TCRs. T cells genetically modified to express the lead TCR (MDG1014) were characterized using a dedicated set of multi-parameter in vitro assays to evaluate specificity and activity. Favorable preclinical specificity was confirmed by analysis of the potential cross-recognition of partially homologous peptides presented on HLA-A2 and the allo-cross-recognition of common HLAs. In addition, no off-target toxicity was observed when testing a set of normal cells. Specific effector functions were confirmed by cytotoxicity and cytokine release assays using a panel of PRAME-positive tumor cell lines from various solid tumor types. Furthermore, the efficacy of MDG1014 was corroborated in a xenograft melanoma mouse model. To prevent the inhibition of T cells via the PD1-PD-L1 axis in the TME, we developed a switch receptor fusing the extracellular domain of PD1 with the intracellular signaling domain of 4-1BB. Co-expressing the switch receptor on MDG1014 in vitro led to enhanced proliferation and increased effector function against PRAME/PD-L1-positive tumor cell lines, including after repeated exposure, suggesting increased T cell fitness under chronic antigen stimulation. To confirm this effect in vivo, we have established a xenograft mouse model with tumor cells expressing PRAME and high PD-L1 levels, mimicking the TME of hard to treat solid tumors. In summary, we developed a TCR specific for an HLA-A2-restricted PRAME-epitope with high natural anti-tumor reactivity and specificity. Its favorable preclinical profile qualifies the TCR for evaluation in clinical trials. Combining this potent TCR with our PD1-41BB switch receptor results in a very promising T cell product, especially for the treatment of solid tumors. Citation Format: Ina Fetzer, Nadja Sailer, Melanie Salvermoser, Manon Weis, Christian Krendl, Maja Bürdek, Doris Brechtefeld, Isabella Rampp, Julian Rydzek-Wiesner, Monika Braun, Christian Ellinger, Christiane Geiger, Daniel Sommermeyer, Susanne Wilde. Combining a PRAME-specific TCR showing potent in vitro and in vivo anti-tumor reactivity and a favorable preclinical safety profile with a PD1-41BB switch receptor results in highly efficient T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1521.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-1521
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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