Study Shows How Bacteria Become Antibiotic Resistant

genengnews | April 24, 2019

Scientists from Denmark and Switzerland say they have shown that bacteria produce a stress molecule, divide more slowly, and thus save energy when they are exposed to antibiotics. The new knowledge is expected to form the basis for the development of a new type of antibiotic, according to the researchers. In a paper—“(p)ppGpp Regulates a Bacterial Nucleosidase by an Allosteric Two-Domain Switch”—published in Molecular Cell, a team from Aarhus University, the University of Copenhagen, and the technical university ETH Zürich in Switzerland demonstrated that bacteria quickly reduce their rate of cell division when exposed to antibiotics in order to maintain the highest possible tolerance, but rapidly start growing again when the substances are removed. “The stringent response alarmones pppGpp and ppGpp are essential for rapid adaption of bacterial physiology to changes in the environment. In Escherichia coli, the nucleosidase PpnN (YgdH) regulates purine homeostasis by cleaving nucleoside monophosphates and specifically binds (p)ppGpp. Here, we show that (p)ppGpp stimulates the catalytic activity of PpnN both in vitro and in vivo causing accumulation of several types of nucleobases during stress. The structure of PpnN reveals a tetramer with allosteric (p)ppGpp binding sites located between subunits. pppGpp binding triggers a large conformational change that shifts the two terminal domains to expose the active site, providing a structural rationale for the stimulatory effect. We find that PpnN increases fitness and adjusts cellular tolerance to antibiotics and propose a model in which nucleotide levels can rapidly be adjusted during stress by simultaneous inhibition of biosynthesis and stimulation of degradation, thus achieving a balanced physiological response to constantly changing environments,” the investigators wrote.

Spotlight

A full description of the lifecycle of Karenia brevis could lead to improved monitoring, prediction, and mitigation of the harmful algal blooms it regularly causes.

Spotlight

A full description of the lifecycle of Karenia brevis could lead to improved monitoring, prediction, and mitigation of the harmful algal blooms it regularly causes.

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CELL AND GENE THERAPY

Spotlight Therapeutics Closes its Series A Financing Bringing the Total Raised to $30 Million

Spotlight Therapeutics | December 01, 2020

Spotlight Therapeutics, Inc., a biotechnology organization creating non-viral quality altering therapeutics for direct in vivo altering of target genes, closed its Series A financing bringing the complete raised to $30 million. The financing was driven by GV, in the past Google Ventures, with interest from extra undisclosed investors. Realizing the full revolutionary potential of CRISPR genome editing requires the ability to edit target genes directly in the right cells of the human body. Spotlight's proprietary technology platform develops programmable CRISPR ribonucleoproteins (RNPs) optimized for in vivo cell-targeted delivery. The modular biologics approach is designed to avoid the complexity and toxicities associated with current cell, viral and nanoparticle delivery methods. Spotlight’s technology integrates the game-changing power of CRISPR with well-established biologics precepts. The company is advancing lead programs in hemoglobinopathies and immuno-oncology.

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RESEARCH

Synthace Unveils First Life Sciences R&D Cloud Addressing Complexity, Speed & Reproducibility for Scientists

Synthace | August 03, 2021

Synthace, a leading life sciences software company, today announced the first life sciences R&D cloud that includes a no-code software platform addressing the largest barriers to innovation that R&D life scientists currently face. With the release of this new platform, Synthace is also the first vendor to enable scientists to automate experimentation and insight sharing in a unified, global R&D environment. Scientists can now focus on asking the most impactful questions and unlock the true potential of biology. To solve humanity’s hardest problems, such as delivering breakthrough therapies or alternative food sources, the life sciences industry is under tremendous pressure to simultaneously overcome biology’s complexity, accelerate speed to scientific insight, and ensure the reproducibility of experiments. Synthace alleviates these challenges by empowering scientists to improve and accelerate decision-making with more statistically powerful, automated experiments that can minimize human error. Furthermore, Synthace’s cloud platform leverages intelligent, dynamic automation to produce the highest quality data sets that are primed for machine learning (ML) and other advanced analyses to lead to better insights. With Synthace, the life sciences can now benefit from a quantum leap in experimentation capabilities, accelerating development timelines that would have previously been impossible. Customers Accelerate R&D with Synthace Ipsen has been using Synthace to automate the design and construction of therapeutic candidates. With Synthace, Ipsen produced approximately 90 constructs five times faster than previous methods, substantially increasing the number of molecules entering the screening cascade. The platform also achieved a 10-fold reduction in costs associated with DNA synthesis. Karen Bunting, Director of Protein Sciences at Ipsen commented, “Synthace sits very well at the beginning of our drug discovery process. It allows us to explore larger drug design space by simplifying planning and production of multiple molecule variants with combinatorial construct assembly. These throughput improvements help us deliver well-tolerated and effective therapeutic solutions more rapidly to our patients.” Microsoft Research also uses Synthace to automatically generate biological data at a volume that allows its ML algorithms to rapidly improve. As part of reporting on advancements in programming biological systems, a member of its Biocomputation Group noted: “Synthace really comes into its own when we’re performing experiments with complex layouts like combinatorial construct assembly and design of experiments. When we’re building 12 constructs at a time, Synthace automates all the planning that would go into setting up such an experiment and allows it to become routine.” Synthace Life Sciences R&D Cloud The platform provides end-to-end management of the experimental lifecycle, from design through execution to data visualization and knowledge transfer. Synthace adheres to FAIR principles to support interoperability with other major lab informatics platforms to ensure streamlined data management for all of its customers. Only the Synthace Life Sciences R&D Cloud delivers: Complete experimental design, planning and automation, requiring no coding expertise. Scientists can define more informative and impactful experiments that would otherwise be impossible to run and easily implement Quality by Design (QbD) and Design of Experiments (DOE). Seamless, cloud-based data capture, processing, and visualization. R&D teams can deliver deeper and faster insights from fully contextualized, machine learning-ready data sets that are automatically generated from the laboratory. Minimal deployment and onboarding. Customers experience rapid time-to-insight through Synthace’s out-of-the-box platform features and pre-validated protocols for common applications such as ELISA and high-throughput purification, helping them shorten R&D cycles and study more candidates per program. About Synthace Synthace is a life sciences software company enabling life science the way it should be done. Delivering a life sciences R&D cloud to scientists who want to innovate faster, the Synthace platform seamlessly automates experimentation and insight sharing so that scientists can focus on asking the most impactful questions to unlock the true potential of biology. Top global pharmaceuticals, high-growth biotech companies, leading CDMOs, and innovators in artificial intelligence all turn to Synthace to discover solutions to humanity’s hardest problems.

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MEDTECH

Patritumab Deruxtecan Granted U.S. FDA Breakthrough Therapy Designation in Patients with Metastatic EGFR-Mutated Non-Small Cell Lung Cancer

Daiichi Sankyo | December 24, 2021

Daiichi Sankyo Company, Limited announced that the U.S. Food and Drug Administration has granted Breakthrough Therapy Designation to patritumab deruxtecan, a potential first-in-class HER3 directed antibody drug conjugate, for the treatment of patients with metastatic or locally advanced EGFR-mutated non-small cell lung cancer with disease progression on or after treatment with a third-generation tyrosine kinase inhibitor and platinum-based therapies. Lung cancer is the second most common cancer and the leading cause of cancer-related mortality worldwide, with 80% to 85% classified as NSCLC.1,2,3 While the efficacy of targeted therapy with EGFR TKIs is well-established in the treatment of advanced EGFR-mutated NSCLC, which comprises approximately 30% of patients, the development of a broad range of resistance mechanisms commonly leads to disease progression.4,5,6 After failure of an EGFR TKI, platinum-based chemotherapy has limited efficacy with progression-free survival (PFS) of approximately 4.4 to 6.4 months.7 Subsequent salvage therapies after EGFR TKI and platinum-based chemotherapy have PFS of 2.8 to 3.2 months.8 The U.S. FDA’s BTD is designed to accelerate the development and regulatory review of potential new medicines that are intended to treat a serious condition and address a significant unmet medical need. The new medicine needs to have shown encouraging preliminary clinical results that demonstrate substantial improvement on a clinically significant endpoint over available medicines. The FDA granted the BTD based on data from the dose escalation portion and two expansion cohorts of a three-cohort phase 1 study of patritumab deruxtecan. Extended follow-up data from the dose escalation portion and dose expansion cohort 1 of the study were recently presented at the 2021 American Society of Clinical Oncology annual meeting and published in Cancer Discovery. This is the first BTD for patritumab deruxtecan and the seventh BTD across Daiichi Sankyo’s oncology portfolio. “The Breakthrough Therapy Designation for patritumab deruxtecan acknowledges the need for new treatment approaches to overcome resistance and improve survival in patients with metastatic TKI-resistant, EGFR-mutated non-small cell lung cancer. We are proud that the FDA has once again recognized our innovative science and technology and we look forward to bringing this potential first-in-class HER3 directed antibody drug conjugate to patients with this specific type of lung cancer as quickly as possible.” Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo About Non-Small Cell Lung Cancer Lung cancer is the second most common cancer and the leading cause of cancer-related mortality worldwide, with 80% to 85% classified as NSCLC.1,2,3 There were an estimated 2.2 million new cases of lung cancer and 1.8 million deaths in 2020.9 NSCLC is diagnosed at an advanced stage in more than 50% of patients and often has a poor prognosis with worsening outcomes after each line of subsequent therapy.10,11,12 The introduction of targeted therapies and checkpoint inhibitors in the past decade has improved the treatment landscape for patients with advanced or metastatic NSCLC. For patients with advanced EGFR-mutated NSCLC, targeted therapy with EGFR TKIs offer higher response rates and PFS compared to chemotherapy.13 However, most patients eventually develop resistance to these therapies and subsequent therapy after EGFR TKI with platinum-based chemotherapy have limited efficacy with PFS of approximately 4.4 to 6.4 months.7,14 Subsequent salvage therapies after EGFR TKI and platinum-based chemotherapy have PFS of 2.8 to 3.2 months.8 New treatment approaches are needed to overcome resistance and improve survival in this subtype of NSCLC. About HER3 HER3 is a member of the EGFR family of receptor tyrosine kinases, which are associated with aberrant cell proliferation and survival.15 Approximately 25% to 30% of lung cancers have an EGFR-activating mutation, and it is estimated that about 83% of all NSCLC tumors express the HER3 protein, which can be associated with an increased incidence of metastases, reduced survival and resistance to standard of care treatment.16,17,18 Currently, no HER3 directed medicines are approved for the treatment of cancer. About the Phase 1 Non-Small Cell Lung Cancer Study The global, multicenter, open label, two-part phase 1 study is evaluating patritumab deruxtecan in previously treated patients with metastatic or unresectable NSCLC. The dose escalation part of the study evaluated patients with EGFR-mutated disease either with progression on osimertinib or T790M-negative after progression on erlotinib, gefitinib or afatinib. The primary objective of this part of the study was to assess the safety and tolerability of patritumab deruxtecan and determine the recommended dose for expansion. The dose expansion part of the study is evaluating patritumab deruxtecan at the RD in three cohorts. Cohort 1 includes patients with locally advanced or metastatic EGFR-mutated NSCLC who experienced disease progression after taking one or more EGFR TKIs and one or more platinum-based chemotherapy regimens. Cohort 2 includes patients with squamous or non-squamous NSCLC without EGFR-activating mutations following platinum-based chemotherapy and following an anti-PD-1 or anti-PD-L1 antibody regimen. Cohort 3 includes patients with NSCLC with EGFR-activating mutations including any histology other than combined small cell and non-small cell lung cancer; patients in Cohort 3 are randomized 1:1 to receive the 5.6 mg/kg RDE regimen or an escalating up-titration regimen of patritumab deruxtecan. The primary objective of the dose expansion part of the study is to assess efficacy of patritumab deruxtecan as measured by confirmed objective response rate assessed by blinded independent central review. Secondary study endpoints include investigator-assessed ORR, safety and pharmacokinetics. The study enrolled patients at multiple sites in Asia, Europe and North America. For more information, visit ClinicalTrials.gov. About Patritumab Deruxtecan Patritumab deruxtecan is one of three lead DXd ADCs in the oncology pipeline of Daiichi Sankyo. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, patritumab deruxtecan is comprised of a fully human anti-HER3 IgG1 monoclonal antibody attached to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. Patritumab deruxtecan is currently being evaluated in a comprehensive development program across multiple cancers as both a monotherapy and in combination with other anticancer treatments. The development program includes HERTHENA-Lung01, a pivotal phase 2 study in patients with locally advanced or metastatic EGFR-mutated NSCLC previously treated with a TKI and platinum-based chemotherapy; a phase 1/2 study in HER3 expressing metastatic breast cancer; a phase 1 study in combination with osimertinib in locally advanced/metastatic EGFR-mutated NSCLC; and, a phase 1 study in previously treated patients with metastatic or unresectable NSCLC. Patritumab deruxtecan is an investigational medicine that has not been approved for any indication in any country. Safety and efficacy have not been established. About Daiichi Sankyo in Oncology The oncology portfolio of Daiichi Sankyo is powered by our team of world-class scientists that push beyond traditional thinking to create transformative medicines for people with cancer. Anchored by our DXd antibody drug conjugate technology, our research engines include biologics, medicinal chemistry, modality and other research laboratories in Japan, and Plexxikon, our small molecule structure-guided R&D center in the U.S. We also work alongside leading academic and business collaborators to further advance the understanding of cancer as Daiichi Sankyo builds towards our ambitious goal of becoming a global leader in oncology by 2025. About Daiichi Sankyo Daiichi Sankyo is dedicated to creating new modalities and innovative medicines by leveraging our world-class science and technology for our purpose “to contribute to the enrichment of quality of life around the world.” In addition to our current portfolio of medicines for cancer and cardiovascular disease, Daiichi Sankyo is primarily focused on developing novel therapies for people with cancer as well as other diseases with high unmet medical needs. With more than 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 16,000 employees around the world draw upon a rich legacy of innovation to realize our 2030 Vision to become an “Innovative Global Healthcare Company Contributing to the Sustainable Development of Society.”

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