Transcriptome Analysis Reveals the Biocontrol Mechanism of Endophytic Bacterium AM201, Rhodococcus sp., against Root Rot Disease of Atractylodes macrocephala

Article

作者: Qin, Luping ; Yuan, Xiaofeng ; Hong, Yueqing ; Ming, Qianliang ; Yu, Le ; Wu, Yutong ; Gao, Xiaoqi ; Shen, Zhanyun ; Wu, Wei ; Zhu, Bo

Atractylodes macrocephala Koidz (AMK) is a perennial herb from the plant family Asteraceae (formerly Compositae). This herb is mainly distributed in mountainous wetlands in Zhejiang, Sichuan, Yunnan, and Hunan provinces of China. Its medicinal production and quality, however, are severely impacted by root rot disease. In our previous study, endophytic bacterium designated AM201 exerted a high biocontrol effect on the root rot disease of AMK. However, the molecular mechanisms underlying this effect remain unclear. In this study, the identity of strain AM201 as Rhodococcus sp. was determined through analysis of its morphology, physiological and biochemical characteristics, as well as 16S rDNA sequencing. Subsequently, we performed transcriptome sequencing and bioinformatics analysis to compare and analyze the transcriptome profiles of root tissues from two groups: AM201 (AMK seedlings inoculated with Fusarium solani [FS] and AM201) and FS (AMK seedlings inoculated with FS alone). We also conducted morphological, physiological, biochemical, and molecular identification analyses for the AM201 strain. We obtained 1,560 differentially expressed genes, including 187 upregulated genes and 1,373 downregulated genes. We screened six key genes (GOLS2, CIPK25, ABI2, egID, PG1, and pgxB) involved in the resistance of AM201 against AMK root rot disease. These genes play a critical role in reactive oxygen species (ROS) clearance, Ca²⁺ signal transduction, abscisic acid signal inhibition, plant root growth, and plant cell wall defense. The strain AM201 was identified as Rhodococcus sp. based on its morphological characteristics, physiological and biochemical properties, and 16S rDNA sequencing results. The findings of this study could enable to prevent and control root rot disease in AMK and could offer theoretical guidance for the agricultural production of other medicinal herbs.

2021-06-01·Drugs in R&D4区 · 医学

Bispecific Antibody Molecule Inhibits Tumor Cell Proliferation More Efficiently Than the Two-Molecule Combination

4区 · 医学

ArticleOA

作者: Rockberg, Johan ; Ko, Bong-Kook ; Lee, Jong-Seo ; Mebrahtu, Aman ; Karlander, Maximilian ; Volk, Anna-Luisa ; Kim, Kyu-Tae ; Lee, Hyun-Jong ; Frejd, Fredrik Y ; Lundqvist, Magnus

BACKGROUND:

Monoclonal antibodies (mAbs) have proved to be a valuable tool for the treatment of different cancer types. However, clinical use of an increasing number of mAbs, have also highlighted limitations with monotherapy for cancers, in particular for such with more complex mechanisms, requiring action on additional molecules or pathways, or for cancers quickly acquiring resistance following monotherapy. An example for the latter is the mAb trastuzumab, FDA approved for treatment of metastatic gastric carcinoma. To circumvent this, researchers have reported synergistic, anti-proliferative effects by combination targeting of HER2 and EGFR by trastuzumab and the EGFR-targeting mAb Cetuximab overcoming trastuzumab resistance.

METHODS:

Maintaining the proven functionality of trastuzumab, we have designed bi-specific antibody molecules, called AffiMabs, by fusing an EGFR-targeting Affibody molecule to trastuzumab's heavy or light chains. Having confirmed binding to EGFR and Her2 and cytotoxicity of our AffiMabs, we analyzed apoptosis rate, receptor surface levels, phosphorylation levels of receptors and associated signaling pathways as well as differentially expressed genes on transcriptome level with the aim to elucidate the mode of action of our AffiMabs.

RESULTS:

The AffiMabs are able to simultaneously bind HER2 and EGFR and show increased cytotoxic effect compared to the original trastuzumab therapeutic molecule and, more importantly, even to the combination of trastuzumab and EGFR-targeting Affibody molecule. Analyzing the mode of action, we could show that bi-specific AffiMabs lead to reduced surface receptor levels and a downregulation of cell cycle associated genes on transcriptome level.

CONCLUSION:

Our study shows that transcriptome analysis can be used to validate the choice of receptor targets and guide the design of novel multi-specific molecules. The inherent modularity of the AffiMab format renders it readily applicable to other receptor targets.

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2023-04-17

·BioSpace

Promising Efficacy of AT101 CAR-T for Blood Cancer

SEOUL, South Korea, April 17, 2023 /PRNewswire/ -- AbClon, a South Korean biotech firm, presented non-clinical and phase 1 interim results of its AT101 novel CAR-T therapy at the annual 2023 AACR conference. AT101 targets the CD19 protein for treatment of blood cancer. AT101 demonstrated superior anti-cancer efficacy compared to FMC63-based CAR-T therapies in non-clinical data. AT101 utilizes the h1218 antibody, developed through AbClon's Novel Epitope Screening Technology (NEST), and binds in a unique manner to CD19. AT101 demonstrated efficacy even in CD19 mutant cancer cell models that did not respond to FMC63-based CAR-T therapies. Overall, AT101 has the potential to provide new treatment opportunities for patients including those who do not respond to currently available CAR-T therapies. An open-label, non-randomized, multicenter phase 1 study was conducted at three different dose levels in patients with relapsed / refractory B-NHL. The results of the first two dose levels in Phase 1, low and medium, have been determined. For medium dose, although the dosage administered to patients is lower than that of currently available CAR-T therapies, all three patients achieved complete response (CR) four weeks after administration. Even at 5-fold lower dosage to medium dose, CR was observed in 3 out of 6 patients and partial response (PR) was observed in 2 patients. Cytokine release syndrome (CRS) and neurotoxicity (ICANS), which appear as side effects of CAR-T therapy, were also observed at low levels of 11.1% and 22.2%. In particular, the rate of 3 or higher grade on side effects was 11.1%, showing encouraging signs with regard to safety. Clinical trial of high dosage level is currently in progress. AT101 was administered to patients with diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Effective responses to AT101 potentiate the application of AT101 for different types of hematologic malignancies. Research teams led by Professor Marco Ruella of Perelman School of Medicine at University of Pennsylvania, Professor Junho Chung of Seoul National University College of Medicine, and Professor Dok hyun Yoon of Asan Medical Center are participating in this study. AbClon owns independent intellectual property rights for the technologies applied to AT101 and is currently building channels for global expansion with local partners. AT101 patent registration has been completed in U.S., Canada, Japan, and South Korea. Further registrations are underway in Europe and China. Jong-Seo Lee, CEO of AbClon, said, "AT101 showed promising results in r/r B-NHL patients, including multiple CRs in the dose escalation stage and excellent safety. We are hopeful for ongoing trials of AT101 to provide more affordable and effective treatment opportunities to patients fighting blood cancer." For more information on the ongoing trial, refer to the ClinicalTrials.gov Identifier: NCT05338931 Details of the presentation are as follows: Presentation Title: An open label, dose escalation, phase 1 study of AT101, a novel CD19-directed CAR-T cell therapy targeting a membrane-proximal epitope of CD19, in patients with relapsed or refractory B cell non-Hodgkin lymphoma Session Title: Phase I Clinical Trials in Progress About AT101 AT101 is a CAR-T therapy that targets CD19 protein for blood cancer. AbClon has initiated a Phase 1/2 clinical study of AT101 in adults with relapsed or refractory B-cell non-Hodgkin lymphoma (NCT05338931) Phase 1/2 study is being conducted in Asan Medical Center and Ulsan University Hospital under the support of the Korea Drug Development Fund (KDDF) in Korea. About AbClon AbClon is a biopharmaceutical company with a robust, wholly owned R&D pipeline in oncology. It is headquartered in Seoul, South Korea. Further information about the company and its drug development programs and capabilities may be found online at Company Codes: Korea:174900

临床1期细胞疗法临床结果AACR会议免疫疗法

2018-11-20

·GlobeNewswire

Auris Medical Announces Results of Pre-IND Meeting With FDA For AM-201 Program in Olanzapine-Induced Weight Gain

Zug, Switzerland, November 20, 2018 - Auris Medical Holding AG (NASDAQ: EARS), a clinical-stage company dedicated to developing therapeutics that address important unmet medical needs in neurotology and mental health supportive care, today announced the results of its pre-Investigational New Drug (pre-IND) meeting with the United States Food & Drug Administration (FDA), where the FDA addressed the Company's questions and provided guidance on its AM-201 program with intranasal betahistine for the prevention of olanzapine-induced weight gain. In its written response, the FDA supported the planned conduct of a multiple dose Phase 1 trial with AM-201 administered to healthy subjects in combination with olanzapine to evaluate the pharmacokinetics, pharmacodynamics, and safety, and to establish proof-of-concept. Further, the FDA endorsed weight gain normalized to baseline body weight versus placebo as reasonable primary efficacy endpoint for a subsequent Phase 2 trial. The Agency deemed the 505(b)(2) pathway appropriate for the AM-201 program as the Company intends to rely on part of its future submission dossier on existing data from other parties and sources. "We are very pleased with the outcomes of the pre-IND meeting with the FDA as it provided important confirmation and guidance for our AM-201 development plans," commented Thomas Meyer, Auris Medical's founder, Chairman and CEO. "Following this milestone, we look forward to moving ahead with our development program and to continuing our work towards the development of an effective and safe treatment for the prevention of antipsychotic-induced weight gain." The Company plans to initiate a Phase 1 pharmacokinetic/pharmacodynamic study in the first quarter of 2019 to evaluate AM-201 in the prevention of olanzapine-induced weight gain. The randomized double blind placebo controlled proof-of-concept trial will be conducted in a European country and enroll 50 healthy volunteers who will receive either AM-201 or placebo concomitantly with olanzapine over four weeks. Doses will be escalated in five steps. Following the read-out from the study, the Company expects to file the IND application for AM-201 later in 2019. About Auris Medical Auris Medical is a Swiss biopharmaceutical company dedicated to developing therapeutics that address important unmet medical needs in neurotology and mental health supportive care. The company is focused on the development of intranasal betahistine for the treatment of vertigo (AM-125) and for the treatment of antipsychotic-induced weight gain and somnolence (AM-201). This program is currently in Phase 1. In addition Auris Medical has two Phase 3 programs under development: Sonsuvi® (AM-111) for acute inner ear hearing loss and Keyzilen® (AM-101) for acute inner ear tinnitus. The Company was founded in 2003 and is headquartered in Zug, Switzerland. The shares of Auris Medical Holding AG trade on the NASDAQ Capital Market under the symbol "EARS." Forward-looking Statements This press release may contain statements that constitute "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Forward-looking statements are statements other than historical facts and may include statements that address future operating, financial or business performance or Auris Medical's strategies or expectations. In some cases, you can identify these statements by forward-looking words such as "may", "might", "will", "should", "expects", "plans", "anticipates", "believes", "estimates", "predicts", "projects", "potential", "outlook" or "continue", or the negative of these terms or other comparable terminology. Forward-looking statements are based on management's current expectations and beliefs and involve significant risks and uncertainties that could cause actual results, developments and business decisions to differ materially from those contemplated by these statements. These risks and uncertainties include, but are not limited to, Auris Medical's need for and ability to raise substantial additional funding to continue the development of its product candidates, the ability to pursue strategic partnering and non-dilutive funding for its Phase 3 programs, the results of Auris Medical's review of strategic options and the outcome of any action taken as a result of such review, the timing and conduct of clinical trials of Auris Medical's product candidates, the clinical utility of Auris Medical's product candidates, the timing or likelihood of regulatory filings and approvals, Auris Medical's intellectual property position and Auris Medical's financial position, including the impact of any future acquisitions, dispositions, partnerships, license transactions or changes to Auris Medical's capital structure, including future securities offerings. These risks and uncertainties also include, but are not limited to, those described under the caption "Risk Factors" in Auris Medical's Annual Report on Form 20-F for the year ended December 31, 2017, and in Auris Medical's other filings with the SEC, which are available free of charge on the Securities Exchange Commission's website at: www.sec.gov. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those indicated. All forward-looking statements and all subsequent written and oral forward-looking statements attributable to Auris Medical or to persons acting on behalf of Auris Medical are expressly qualified in their entirety by reference to these risks and uncertainties. You should not place undue reliance on forward-looking statements. Forward-looking statements speak only as of the date they are made, and Auris Medical does not undertake any obligation to update them in light of new information, future developments or otherwise, except as may be required under applicable law. Investor contact: Joseph Green / Andrew GibsonEdison Advisors for Auris Medical646-653-7030 / 7719jgreen@edisongroup.com / agibson@edisongroup.com Or investors@aurismedical.com

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