Strength in weakness: Fragile DNA regions key to vertebrate evolution

Phys.org | January 04, 2019

DNA regions susceptible to breakage and loss are genetic hotspots for important evolutionary changes, according to a Stanford study. The findings may lead to new understanding of human evolution. Regions of DNA susceptible to deletion during replication may have allowed vertebrates to successfully adapt to rapidly changing environmental conditions during evolution, according to a study by researchers at the Stanford University School of Medicine. The research suggests that some critical evolutionary changes are likely to have occurred in leaps and bounds through the abrupt loss of stretches of DNA, rather than through the slow accumulation and additive effects of many small mutations. The researchers, who studied a tiny fish called the threespine stickleback, found that such "fragile" DNA regions create genetic hot spots that mutate much more rapidly, and dramatically than neighboring sequences. The resulting changes can help an organism vault far ahead of its peers in the evolutionary arms race.
Although similar findings have been described in bacteria, this is one of the first studies to show that the same process has occurred in vertebrates to create dramatic changes in body structure. It also addresses a long-standing mystery in evolutionary biology. "There is a lot of evidence that the same genes across different populations or species are often responsible for similar evolutionary changes," said David Kingsley, Ph.D., professor of developmental biology. "What hasn't been clear is why this is happening. This study describes at a biochemical level, down to the atoms and sequences in DNA, how a particular type of mutation can arise repeatedly, which then contributes to a complex skeletal trait evolving over and over again in wild fish species. It's a great example of how DNA fragility can sometimes contribute to favorable traits rather than diseases in natural populations, and it may give us important insights into the process of human evolution."

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Time-lapse imaging of DU145 prostate cancer spheroids. Cells were first cultured on Cell-able plates. After 4-7 days, media was switched with 100nM anti-cancer drug paclitaxel plus Caspase-3/7 (green stain indicating apoptosis) and ethidium homodimer-1 (red stain indicating necrosis). Cells were imaged on the ImageXpress Micro System every 30 minutes for 72 hours.

Spotlight

Time-lapse imaging of DU145 prostate cancer spheroids. Cells were first cultured on Cell-able plates. After 4-7 days, media was switched with 100nM anti-cancer drug paclitaxel plus Caspase-3/7 (green stain indicating apoptosis) and ethidium homodimer-1 (red stain indicating necrosis). Cells were imaged on the ImageXpress Micro System every 30 minutes for 72 hours.

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INDUSTRIAL IMPACT

Biocytogen and LiberoThera Achieve Milestone Progress in Co-Development of Fully Human GPCR Antibody Drugs

Biocytogen | July 21, 2022

Biocytogen Pharmaceuticals Co., Ltd. entered a strategic collaboration with LiberoThera Co., Ltd to co-develop fully human GPCR antibodies using Biocytogen’s advanced antibody discovery platform based on fully human antibody RenMabTM mice combined with LiberoThera’s outstanding membrane antigen preparation technology. In around a year since the collaboration was established, the two parties have screened out a number of fully human therapeutic antibody clones with excellent anti-tumor activity in vitro and in vivo against the first mutually selected GPCR target, CCR8, which has the potential to become a best-in-class product. These antibody clones exhibit high affinity binding to human CCR8 with species cross-reactivity and good manufacturability. Mechanistically, these clones can deplete Tregs from the tumor micro-environment through enhanced ADCC activity, and can also inhibit the activities of Tregs in the tumor micro-environment by inhibiting CCR8 signaling mediated by its ligand CCL1, thereby enhancing the anti-tumor immune response. In the future, the collaborations between two parties will also be extended to other GPCR targets. GPCRs are seven-transmembrane proteins with short extracellular domains and high homology among them which make it difficult to find antibodies against them with high specificity and desired functions. However, both the success rate and the speed of GPCR antibody discovery have greatly increased by combining Biocytogen’s target knocked-out fully human antibody mice RenMab KO, various immunization and antibody discovery technologies, high-throughput in vitro and in vivo screening platform and LiberoThera’s deep understanding of GPCR target structures plus membrane antigen preparation technologies. “We are very pleased that with the joint efforts of us and LiberoThera, the drug development of CCR8, a potential target for tumor immunotherapy, is progressing smoothly. This undoubtedly validates that LiberoThera's advanced antigen preparation technology synergizes with our RenMice KO platform to generate diverse fully human antibodies. Furthermore, our high-throughput in vivo and in vitro screening capabilities ensured that antibodies against GPCRs can be efficiently obtained. We look forward to advancing our CCR8 antibodies into the clinic soon and we also look forward to continue working with LiberoThera to tackle more GPCR targets.” Dr. Yuelei Shen, Founder, Chairman and CEO of Biocytogen “Many GPCRs are important drug targets for a variety of indications. However, due to the special structure of such targets, the development of antibody drugs against them has always been challenging,” said Dr. Toru Kanke, CEO of LiberoThera. “The structural GPCR antigens prepared with LiberoThera’s proprietary cell-free membrane synthesis technologies together with non-natural amino acid incorporation methods can provide a solution for generating quality antibodies against the challenging targets. Biocytogen’s streamlined fully human antibody development platform greatly accelerates the translation of GPCR research. We are very happy to see the rapid progress and discovery of the best-in-class therapeutic antibodies against CCR8 under the collaboration of both parties. We also look forward to the collaborations in the future with Biocytogen to work on more GPCR targets so that to benefit more patients around the world.” About Biocytogen Biocytogen Pharmaceuticals Co., Ltd. is a global biotechnology company that drives the research and development of novel antibody-based drugs with innovative technologies. Using its proprietary RenMabTM /RenLite® mice platforms for fully human monoclonal and bispecific antibody development, Biocytogen has integrated its in vivo drug efficacy screening platforms and strong clinical development expertise to streamline the entire drug development process. Biocytogen is undertaking a large-scale project to develop antibody drugs for more than 1000 targets, known as Project Integrum, and has entered ongoing collaborations with dozens of partners worldwide to produce a variety of first-in-class and/or best-in-class antibody drugs. At present, many GPCR projects from Project Integrum are under development that are important for treating cancer, metabolic diseases and beyond. In the future, Project Integrum will continue producing more fully human antibodies against GPCRs and other difficult targets. Biocytogen wishes to collaborate with partners around the world to discover, develop and deliver new medicines through innovative technologies that benefit human health. The company's pipeline includes 12 core products, among which two products are in phase II multi-regional clinical trials and two products are in phase I. Headquartered in Beijing, Biocytogen has branches in Haimen Jiangsu, Shanghai, Boston, USA and Heidelberg, Germany. About LiberoThera LiberoThera is a drug discovery company targeting membrane proteins including GPCRs. Founded on the revolutionary research by Prof. Shigeyuki Yokoyama, Emeritus Professor at The University of Tokyo and Distinguished Senior Scientist at RIKEN, LiberoThera utilizes its cutting-edge cell-free protein expression system and non-natural amino acid technology which enable complexed membrane proteins to be prepared in natural forms with structural and functional integrity. LiberoThera is developing novel therapeutic candidates targeting physiologically important membrane proteins, such as GPCRs, in collaboration with multiple partners.

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MEDICAL

Agilent Announces Collaboration with APC on Real-Time Process Monitoring

Agilent Technologies | May 31, 2022

Agilent Technologies Inc. (NYSE: A) today announced a collaboration agreement with APC Ltd., in which the companies commit to working towards combining their technologies to provide unique workflows to customers that support automated process analysis via liquid chromatography (LC). Agilent has selected to partner with APC, a provider of innovative small molecule and large molecule process design and process development solutions. Both APC and Agilent pursue similar goals, which are focused on helping customers in the biopharmaceutical and pharmaceutical industry to improve the human condition and to delivering life-changing drugs to market faster and more efficiently. The collaboration between the companies leverages their complementary strengths to develop specific workflows, which bridge the gap between the analytical and process solutions. We are delighted to be collaborating with APC on a solution for real-time/automated process monitoring, Adapting our analytical capabilities to support online process monitoring requirements reflects the current trend within the pharma and biopharma industry towards continuous manufacturing and helps our mutual customers to develop higher quality drugs faster.” Stefan Schuette, vice president and general manager of Agilent’s Liquid Phase Separations Division. Agilent is a leader in the analytical lab with a comprehensive portfolio of analytical equipment for the biopharma and pharma industry, This collaboration leverages our complementary strengths and ultimately provides even better services and technologies to our customers by giving them greater insights into, and control of, their processes.” Damian Connolly, Analytical Lead at APC. The results obtained during the collaboration will be shared with customers via applications notes and joint webinars, which will also showcase the recently launched InfinityLab Online LC and InfinityLab Bio LC portfolio from Agilent. These new product offerings and the collaboration with APC ensure a leading position in the trend towards continuous manufacturing, process analytical technology (PAT), and real-time release testing (RTRT) in the biopharmaceutical and pharmaceutical industry. About Agilent Technologies Agilent Technologies Inc. (NYSE: A) is a global leader in the life sciences, diagnostics, and applied chemical markets, delivering insight and innovation that advance the quality of life. Agilent’s full range of solutions includes instruments, software, services, and expertise that provide trusted answers to our customers' most challenging questions. The company generated revenue of $6.32 billion in fiscal 2021 and employs 17,000 people worldwide.

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INDUSTRIAL IMPACT

SIGA Announces Oncology Collaboration with KaliVir Immunotherapeutics

SIGA Technologies Inc. | July 16, 2022

SIGA Technologies, Inc. a commercial-stage pharmaceutical company focused on the health security market, today announced a collaboration with KaliVir Immunotherapeutics to make TPOXX® available for use with KaliVir’s proprietary oncolytic vaccinia immunotherapy platform. This novel oncolytic platform includes multiple proprietary genetic modifications that can be combined to generate a unique oncolytic virus that has been optimized for systemic delivery and anti-tumor immune stimulation. Under this partnership, SIGA is providing its TPOXX oral capsules to support future clinical programs. “KaliVir is an innovator in the creation of oncolytic viral immunotherapies, and we are excited to enter into this collaboration with them. TPOXX is a powerful antiviral drug to vaccinia and allows the safe use of higher doses of vaccinia vectors; there is also the potential it could increase immunotherapeutic outcomes. This collaboration helps bring new levels of assurance to physicians, regulators, and especially patients receiving these promising investigational therapies.” Dr. Phil Gomez, CEO of SIGA “We are pleased to announce this collaboration with SIGA Technologies,” said Helena Chaye, Ph.D., J.D., CEO of KaliVir. “Pairing oncolytic immunotherapies with an effective antiviral agent is a critical part of the development of new treatments, and we look forward to enhancing our groundbreaking oncolytic immunotherapy programs with the support of SIGA’s TPOXX.” On July 13, 2018, the U.S. Food and Drug Administration (FDA) approved oral TPOXX for the treatment of smallpox to mitigate the impact of a potential outbreak or bioterror attack. In preclinical studies, TPOXX has been shown to be active against most orthopoxviruses, including vaccinia The unique mechanism of action of TPOXX coupled with published efficacy in animal studies, make it an important addition to development programs focused on vaccinia-based cancer therapies. In 2020, SIGA entered into numerous collaborations, including a partnership with Turnstone Biologics to supply TPOXX to support Turnstone’s clinical oncolytic vaccinia immunotherapy programs. In 2021, SIGA entered into a preclinical research collaboration with Bioarchitech to investigate TPOXX enabling higher doses of vaccinia vectors when used in combination with Bioarchitech’s oncolytic vaccinia-based immunotherapy platform. ABOUT SIGA TECHNOLOGIES, INC. and TPOXX® SIGA Technologies, Inc. is a commercial-stage pharmaceutical company focused on the health security market. Health security comprises countermeasures for biological, chemical, radiological and nuclear attacks (biodefense market), vaccines and therapies for emerging infectious diseases, and health preparedness. Our lead product is TPOXX®, also known as tecovirimat and ST-246®, an orally administered and IV formulation antiviral drug for the treatment of human smallpox disease caused by variola virus. TPOXX is a novel small-molecule drug and the US maintains a supply of TPOXX under Project BioShield. The oral formulation of TPOXX was approved by the FDA for the treatment of smallpox in 2018. The full label is available by clicking here. Oral tecovirimat received approval from the European Medicines Agency (EMA) in 2022. The EMA approval includes labeling for oral tecovirimat indicating its use for the treatment of smallpox, monkeypox, cowpox, and vaccinia complications following vaccination against smallpox. The full label is available by clicking here. In September 2018, SIGA signed a contract with the Biomedical Advanced Research and Development Authority (BARDA), part of the office of the Assistant Secretary for Preparedness and Response within the U.S. Department of Health and Human Services, for additional procurement and development related to both oral and intravenous formulations of TPOXX. ABOUT KALIVIR IMMUNOTHERAPEUTICS. KaliVir Immunotherapeutics is a privately held biotech company developing cutting-edge, next-generation oncolytic viral immunotherapy programs. The company has developed a unique vaccinia virus-based platform that can generate potent novel oncolytic vaccinia viruses with modifications to maximize viral replication and to enhance intravenous delivery and spread (Vaccinia Enhanced Template “VET” Platform). VET™ platform utilizes the large transgene capacity of the vaccinia virus to deliver therapeutics matched to tumor immunophenotypes to stimulate patients’ immune systems and modify the tumor microenvironment. KaliVir’s oncolytic product candidates are designed to be safe, potent and systemically deliverable to treat cancer patients across multiple tumor types. KaliVir is in the process of advancing multiple therapeutic candidates toward the clinic.

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