PurposeTo test the hypothesis that the C-X-C chemokines CXCL1, CXCL2, and CXCL10 contribute to inflammation during Staphylococcus aureus endophthalmitis.MethodsS. aureus endophthalmitis was induced by intravitreal injection of 5000 colony forming units of S. aureus into the eyes of C57BL/6J, CXCL1-/-, CXCL2-/-, or CXCL10-/- mice. At 12, 24, and 36 hours postinfection, bacterial counts, intraocular inflammation, and retinal function were assessed. Based on these results, the effectiveness of intravitreal administration of anti-CXCL1 in reducing inflammation and improving retinal function was evaluated in S. aureus-infected C57BL/6J mice.ResultsWe observed significant attenuation of inflammation and improvement in retinal function in CXCL1-/- mice relative to C57BL/6J at 12 hours but not at 24 or 36 hours postinfection with S. aureus. Co-administration of anti-CXCL1 antibodies with S. aureus, however, did not improve retinal function or reduce inflammation at 12 hours postinfection. In CXCL2-/- and CXCL10-/- mice, retinal function and intraocular inflammation were not significantly different from those of C57BL/6J mice at 12 and 24 hours postinfection. At 12, 24, or 36 hours, an absence of CXCL1, CXCL2, or CXCL10 did not alter intraocular S. aureus concentrations.ConclusionsCXCL1 appears to contribute to the early host innate response to S. aureus endophthalmitis, but treatment with anti-CXCL1 did not effectively limit inflammation in this infection. CXCL2 and CXCL10 did not seem to play an integral role in inflammation during the early stages of S. aureus endophthalmitis.

2022-10-01·Experimental Dermatology

The landscape of genetic alterations of UVB‐induced skin tumors in DNA repair‐deficient mice

Article

作者: Yoshioka, Ai ; Fukumoto, Takeshi ; Inoue, Ituro ; Kunisada, Makoto ; Nishigori, Chikako ; Nakaoka, Hirofumi

AbstractNon‐melanoma skin cancer (NMSC) is mainly caused by ultraviolet (UV)‐induced somatic mutations and is characterized by UV signature modifications. Xeroderma pigmentosum group A (Xpa) knockout mice exhibit extreme UV‐induced photo‐skin carcinogenesis, along with a photosensitive phenotype. We performed whole‐exome sequencing (WES) of squamous cell carcinoma (SCC) samples after repetitive ultraviolet B (UVB) exposure to investigate the differences in the landscape of somatic mutations between Xpa knockout and wild‐type mice. Although the tumors that developed in mice harboured UV signature mutations in a similar set of cancer‐related genes, the pattern of transcriptional strand asymmetry was largely different; UV signature mutations in Xpa knockout and wild‐type mice preferentially occurred in transcribed and non‐transcribed strands, respectively, reflecting a deficiency in transcription‐coupled nucleotide excision repair in Xpa knockout mice. Serial time point analyses of WES for a tumor induced by only a single UVB exposure showed pathogenic mutations in Kras, Fat1, and Kmt2c, which may be driver genes for the initiation and promotion of SCC in Xpa knockout mice. Furthermore, the inhibitory effects on tumor production in Xpa knockout mice by the anti‐inflammatory CXCL1 monoclonal antibody affected the pattern of somatic mutations, wherein the transcriptional strand asymmetry was attenuated and the activated signal transduction was shifted from the RAS/RAF/MAPK to the PIK3CA pathway.

2021-12-01·Veterinary Research2区 · 农林科学

GSDMD contributes to host defence against Staphylococcus aureus skin infection by suppressing the Cxcl1–Cxcr2 axis

2区 · 农林科学

ArticleOA

作者: Yang, Yong-Jun ; Zhou, Feng-Hua ; Liu, Zhen-Zhen ; Lin, Xiao-Qi ; Ma, Ke ; Gao, Yu ; Yan, Shi-Qing ; Chen, Wei

AbstractGasdermin D (GSDMD), a member of the gasdermin protein family, is a caspase substrate, and its cleavage is required for pyroptosis and IL-1β secretion. To date, the role and regulatory mechanism of GSDMD during cutaneous microbial infection remain unclear. Here, we showed that GSDMD protected against Staphylococcus aureus skin infection by suppressing Cxcl1–Cxcr2 signalling. GSDMD deficiency resulted in larger abscesses, more bacterial colonization, exacerbated skin damage, and increased inflammatory cell infiltration. Although GSDMD deficiency resulted in defective IL-1β production, the critical role of IL-1β was counteracted by the fact that Caspase-1/11 deficiency also resulted in less IL-1β production but did not aggravate disease severity during S. aureus skin infection. Interestingly, GSDMD-deficient mice had increased Cxcl1 secretion accompanied by increased recruitment of neutrophils, whereas Caspase-1/11-deficient mice presented similar levels of Cxcl1 and neutrophils as wild-type mice. Moreover, the absence of GSDMD promoted Cxcl1 secretion in bone marrow-derived macrophages induced by live, dead, or different strains of S. aureus. Corresponding to higher transcription and secretion of Cxcl1, enhanced NF-κB activation was shown in vitro and in vivo in the absence of GSDMD. Importantly, inhibiting the Cxcl1–Cxcr2 axis with a Cxcr2 inhibitor or anti-Cxcl1 blocking antibody rescued host defence defects in the GSDMD-deficient mice. Hence, these results revealed an important role of GSDMD in suppressing the Cxcl1–Cxcr2 axis to facilitate pathogen control and prevent tissue damage during cutaneous S. aureus infection.

项与 NTC-001 相关的新闻（医药）

2023-10-16

·GlobeNewswire-Health Care

BioNTech to Present Multiple Program Updates Across Modalities at ESMO Congress 2023

Program updates include new data for investigational CAR-T and ex-vivo T cell therapies, a novel ADC, a FixVac off-the-shelf mRNA cancer vaccine, and a bi-specific antibody New data from BioNTech’s investigational autologous CAR-T therapy BNT211 demonstrate the potential of the Company’s innovative approach of combining an autologous CAR-T cell therapy targeting Claudin-6 (“CLDN6”) with a CLDN6-encoding CAR-T cell amplifying mRNA vaccine (“CARVac”)First-in-human data from Phase 1/2 study with next-generation Trop-2 targeting ADC candidate BNT325 (DB-1305) in advanced/metastatic solid tumors show encouraging initial efficacy signals and a manageable safety profileBioNTech advances key clinical programs into late-stage development while strengthening its clinical-stage oncology pipeline with synergistic potential MAINZ, Germany, October 16, 2023 – BioNTech SE (Nasdaq: BNTX, “BioNTech” or “the Company”) will present data across its oncology pipeline, covering multiple solid tumor types and novel mechanisms of action, at the European Society for Molecular Oncology (“ESMO”) Congress 2023 in Madrid, Spain from October 20-24, 2023. The updates will feature oral and poster presentations for five candidates of BioNTech’s clinical pipeline across the Company’s drug classes, which comprise mRNA-based immunotherapies, cell therapies, protein-based therapeutics, and small molecules. “This year’s ESMO presentations underline the potential of BioNTech’s precision medicine toolkit for the treatment of solid tumor indications with high unmet medical need, where many patients still remain underserved,” said Prof. Özlem Türeci, M.D., Co-Founder and Chief Medical Officer at BioNTech. “We aim to develop and combine innovative immunotherapies for patients at different disease stages, which we believe could increase the likelihood of therapeutic success, reduce the risk of emergence of secondary resistance mechanisms, and unlock a larger potential patient population.” Highlights of BioNTech’s clinical stage programs to be presented at ESMO Congress 2023: Cell Therapies BioNTech will present new data of its investigational autologous Claudin-6 (CLDN6)-directed CAR-T cell therapy BNT211 (NCT04503278), including data showing the potential of combining these CAR-T cells with a CLDN6-encoding CAR-T cell amplifying mRNA vaccine (“CARVac”).Initial data from BioNTech's first-in-human Phase 1 study with BNT221 (NCT04625205), a personalized, autologous neoantigen-specific T cell therapy, will be presented. The initial results show a manageable safety profile and tumor regression in several patients with anti-PD-1 and anti-CTLA4 pretreated advanced or metastatic melanoma. Protein-based Therapeutics The Company will present first-in-human data of BNT325 (DB-1305) (NCT05438329), a next-generation Trop-2-targeting antibody-drug conjugate (“ADC”), which is being jointly developed with Duality Biologics. Initial data with this candidate show encouraging preliminary efficacy and a manageable safety profile in patients with advanced/metastatic non-small cell lung cancer (NSCLC). mRNA-based immunotherapies A trial in progress poster will inform on the ongoing EMPOWERVAX Lung 1 Phase 2 trial (NCT05557591), which is being conducted together with Regeneron, evaluating the efficacy and safety of BioNTech’s fully-owned off-the-shelf mRNA cancer vaccine candidate BNT116 in combination with cemiplimab versus cemiplimab alone in the first-line treatment of patients with advanced NSCLC and PD-L1 expression ≥50%. In addition, BioNTech will also present pre-clinical data from its BNT314 (GEN1059) program, which is being jointly developed with Genmab. BNT314 (GEN1059) is a novel bispecific antibody candidate aimed at boosting antitumor immune responses through EpCAM-dependent 4-1BB agonistic activity. In pre-clinical studies, BNT314 (GEN1059) enhanced T-cell activation, proliferation, and effector functions in vitro and ex vivo and promoted antitumor activity in vivo. A Phase 1/2 trial is planned to start by early 2024 and will assess the safety and preliminary antitumor activity of BNT314 (GEN1059) in patients with advanced or metastatic solid tumors. BioNTech has established a diversified clinical oncology pipeline of more than 25 programs in high unmet medical need solid tumor indications in more than 30 clinical studies, including seven programs in advanced Phase 2 studies and one candidate in a pivotal Phase 3 study. BioNTech is advancing the Company’s key programs into late-stage development while strengthening its clinical-stage oncology pipeline with synergistic potential, with the aim to deliver the next generation of oncology breakthroughs. The full abstracts are available on the ESMO Congress website. Click here for further information on BioNTech’s pipeline candidates. Full Presentation Details: Late-breaking presentationCandidate: BNT211Session Title: Developmental TherapeuticsAbstract Title: “BNT211-01: Interim results from a repeat dose escalation study of CLDN6 CAR-T cells manufactured with an automated process ± a CLDN6-encoding CAR-T cell-Amplifying RNA Vaccine (CARVac)”Abstract Number: LBA35Date: Monday, October 23, 2023Time: 4:30-6:00 PM CET Proffered paper sessionCandidate: BNT221Session title: Investigational ImmunotherapyAbstract Title: “NTC-001: A phase I study to test safety and efficacy of BNT221, a non-engineered neoantigen-specific T cell product, in patients with advanced or metastatic melanoma”Abstract Number: 1017ODate: Monday, October 23, 2023Time: 10:15-11:40 AM CET PosterCandidate: BNT325 (DB-1305)Session Title: Developmental TherapeuticsAbstract Title: “DB-1305 (a Trop-2 targeted antibody-drug-conjugate [ADC]) in patients with advanced solid tumors: Preliminary clinical results from the Phase 1/2a study”Poster Number: 689PDate: Monday, October 23, 2023 Candidate: BNT116Session Title: NSCLC. metastaticAbstract Title: "A phase 2 study of cemiplimab plus BNT116 versus cemiplimab alone in first-line treatment of patients with advanced non-small cell lung cancer with PD-L1 expression ≥50%"Poster Number: 1503TiPDate: Monday, October 23, 2023 Candidate: BNT314 (GEN1059)Session Title: Investigational ImmunotherapyAbstract Title: “DuoBody-EpCAMx4-1BB mediates conditional T cell co-stimulation and promotes antitumor activity in preclinical models”Poster Number: 1072PDate: Monday, October 23, 2023 About BioNTechBiopharmaceutical New Technologies (BioNTech) is a next generation immunotherapy company pioneering novel therapies for cancer and other serious diseases. The Company exploits a wide array of computational discovery and therapeutic drug platforms for the rapid development of novel biopharmaceuticals. Its broad portfolio of oncology product candidates includes individualized and off-the-shelf mRNA-based therapies, innovative chimeric antigen receptor (CAR) T cells, several protein-based therapeutics, including bispecific immune checkpoint modulators, targeted cancer antibodies and antibody-drug conjugate (ADC) therapeutics, as well as small molecules. Based on its deep expertise in mRNA vaccine development and in-house manufacturing capabilities, BioNTech and its collaborators are developing multiple mRNA vaccine candidates for a range of infectious diseases alongside its diverse oncology pipeline. BioNTech has established a broad set of relationships with multiple global pharmaceutical collaborators, including Duality Biologics, Fosun Pharma, Genentech, a member of the Roche Group, Genevant, Genmab, OncoC4, Regeneron, Sanofi and Pfizer. For more information, please visit www.BioNTech.com. BioNTech Forward-Looking StatementsThis press release may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, but not be limited to, statements concerning: the initiation, timing, progress and results of BioNTech’s research and development programs in oncology; BioNTech’s current and future preclinical studies and clinical trials in oncology, including CAR-T cell therapy candidate BNT211, neoantigen-specific T cell therapy candidate BNT221, Trop-2-targeting ADC candidate BNT325 (DB-1305), bispecific antibody candidate BNT314 (GEN1059) and mRNA cancer vaccine candidate BNT116, including statements regarding the timing of initiation and completion of studies or trials and related preparatory work and the availability of results; timing for any data readouts; the registrational potential of any trial we may initiate for our product candidates; the potential safety and efficacy of our product candidates; and BioNTech’s anticipated market opportunity and size for its product candidates. In some cases, forward-looking statements can be identified by terminology such as “will,” “may,” “should,” “expects,” “intends,” “plans,” “aims,” “anticipates,” “believes,” “estimates,” “predicts,” “potential,” “continue,” or the negative of these terms or other comparable terminology, although not all forward-looking statements contain these words. The forward-looking statements in this press release are neither promises nor guarantees, and you should not place undue reliance on these forward-looking statements because they involve known and unknown risks, uncertainties, and other factors, many of which are beyond BioNTech’s control, and which could cause actual results to differ materially from those expressed or implied by these forward-looking statements. These risks and uncertainties include, but are not limited to: the uncertainties inherent in research and development, including the ability to meet anticipated clinical endpoints, commencement and/or completion dates for clinical trials, regulatory submission dates, regulatory approval dates and/or launch dates, as well as risks associated with preclinical and clinical data; the nature of the clinical data, which is subject to ongoing peer review, regulatory review and market interpretation; future commercial demand and medical need; the availability of raw materials; competition from other product candidates, including those with different mechanisms of action and different manufacturing and distribution constraints, on the basis of, among other things, efficacy, cost, convenience of storage and distribution, breadth of approved use, side-effect profile and durability of immune response; BioNTech's ability to identify research opportunities and discover and develop investigational medicines; the ability and willingness of BioNTech's third-party collaborators to continue research and development activities relating to BioNTech's product candidates; the timing of and BioNTech's ability to obtain and maintain regulatory approval for its product candidates; and other factors not known to BioNTech at this time. You should review the risks and uncertainties described under the heading “Risk Factors” in BioNTech’s Report on Form 6-K for the period ended June 30, 2023, and in subsequent filings made by BioNTech with the U.S. Securities and Exchange Commission (“SEC”), which are available on the SEC’s website at www.sec.gov. Except as required by law, BioNTech disclaims any intention or responsibility for updating or revising any forward-looking statements contained in this press release in the event of new information, future developments or otherwise. These forward-looking statements are based on BioNTech’s current expectations and speak only as of the date hereof. CONTACTS Media Relations Jasmina Alatovic +49 (0)6131 9084 1513 Media@biontech.de Investor RelationsVictoria Meissner, M.D.+1 617 528 8293Investors@biontech.de

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