CELL AND GENE THERAPY
Genscript Biotech Corporation | September 23, 2022
GenScript USA Inc., the world's leading life-science research tools and services provider, is collaborating with researchers at the Gladstone-UCSF Institute of Genomic Immunology to advance the development of new, non-viral cell therapies that modify genomic sequences in the pursuit of more effective cell therapy products while limiting the cellular toxicity that is typically associated with previously available methods.
A new study, published in Nature Biotechnology, details methods for achieving highly efficient non-viral knock-in using GenScript's GenExact™ single-strand DNA modified with Cas9-target sequences. This method achieved up to ˜40% knock-in efficiency in primary immune cell types.
One powerful application of CRISPR/Cas genome editing technology involves the precise insertion of DNA sequences via the HDR pathway. Traditionally, researchers have relied on viral vectors to deliver DNA insertion templates used for gene therapy into cells. However, difficulties manufacturing large amounts of clinical-grade viral vectors have delayed getting cell therapies to patients. Additionally, viral vectors can insert genes at any location within the genome, leading to safety concerns.
Previous research by the group at Gladstone and UCSF has shown that synthetic DNA templates can be delivered without the use of viral vectors, but high levels of double-stranded DNA can be toxic to cells, resulting in low efficiency. Efficiency can be improved using a modified version of the DNA templates that can bind to the Cas9 enzyme. However, additional work was required to improve the yield of successfully engineered cells and to make the process compatible with the manufacturing of future cell therapies. Those goals motivated the team's current study.
In this study, the team tested modified GenExact ssDNA designed with Cas9-targeted sequences to determine if the gene-editing efficiency could be improved with lower toxicity. First, synthetic sgRNA was complexed with Cas9 protein to form a RNP complex. Then the RNP and ssDNA template were delivered into the cell via electroporation, enabling efficient gene editing.
The team discovered that this combination of GenExact ssDNA with Cas9-targeted sequence offers up to 40% knock-in editing efficiency with minimal cellular toxicity. This approach can accelerate the development and manufacture of novel, high-yield non-viral gene therapies — and at lower cost.
"We are very proud to have collaborated on this groundbreaking scale-up work by the talented team at Gladstone and UCSF. GenScript is excited for the opportunities that this high-yield cell-line engineering process will provide to our customers," said Ray Chen, Ph.D, president of GenScript Life Science Group.
"We were very happy to partner with Genscript on critical experiments demonstrating high efficiency and yield of CAR knock-in cells at clinical scale. The long ssDNA produced by Genscript exceeded our expectations and helped us clearly demonstrate the potential for future therapeutic applications using these methods.",
Brian Shy, MD, PhD, a former clinical fellow in the lab of Alex Marson, MD, PhD, director of the Gladstone-UCSF Institute of Genomic Immunology
About GenScript Biotech Corporation
GenScript Biotech Corporation is a global biotechnology group. Based on its leading gene synthesis technology, GenScript has developed four major platforms including the global cell therapy platform, the biologics contract development and manufacturing organization platform, the contract research organization platform, and the industrial synthesis product platform.
GenScript was founded in New Jersey, USA in 2002 and listed on the Hong Kong Stock Exchange in 2015. GenScript's business operation spans over 100 countries and regions worldwide, with legal entities located in the USA, mainland China, Hong Kong, Japan, Singapore, the Netherlands, and Ireland. GenScript has provided premium, convenient, and reliable products and services for over 100,000 customers.
Enveric Biosciences, Inc | July 14, 2022
Enveric Biosciences, Inc. a neuroscience-focused biotechnology company developing next-generation, psychedelic-inspired mental health medicines, today revealed drug discovery and development progress targeting mental health indications and intellectual property advances achieved during the first half of 2022.
“The first half of 2022 was foundationally successful for Enveric. We validated and executed on the corporate premise that we can deploy PsyAITM, our proprietary artificial intelligence tool, and PsybraryTM, our expanding proprietary portfolio of new chemical entities and drug candidates, to design and improve upon new drug molecules inspired by legacy psychedelic drugs,”
Dr. Joseph Tucker, PhD, Enveric’s Chief Executive Officer
“Enveric is pleased to advise that our predictions have materialized, and our platforms have successfully generated a large number of promising new molecules that have successfully passed primary screening and moved on to lead optimization, providing us with a strong slate of drug candidates. Our leading program, EVM-201, includes a number of new molecules currently in lead optimization that are geared towards providing improved characteristics and drug-like properties compared with psilocybin. The successful outcomes from our testing efforts completed in the first half of 2022 have positioned the company very well to advance our drug candidates towards the clinic,” continued Dr. Tucker.
Based on extensive direct clinical understanding of the current unmet needs in anxiety, depression, PTSD, and other mental health indications, coupled with in-depth knowledge of the current treatment landscape, Enveric’s Clinical Team is well positioned to tackle the challenges ahead, while aiming to shepherd novel new treatments for a host of mental health indications.
Enveric’s Clinical Team is led by a past Board-certified psychiatrist and clinical trialist Chief Medical Officer, Dr. Bob Dagher, MD. Dr. Dagher joined Enveric in December 2021, bringing a wealth of clinical trial management and new CNS-drug development experience from his past roles, including at WCG, Cadent, Covance, Sanofi and GSK, in addition to his first-hand experience in treating patients from his previous clinical practice in psychiatric medicine.
Next-Generation Drug Discovery
Enveric’s Discovery Team, spearheaded by Chief Innovation Officer Dr. Peter Facchini, PhD, an international leader in natural product biochemistry and biotechnology, completed the rational design of more than 300 Generation-2 (“Gen-2”) psilocin prodrug candidates using well-established design strategies, but adapted to the unique structure of psilocin.
The 300 Gen-2 original concept designs, now housed within the PsybraryTM, were screened using PsyAITM. The assessment helped predict chemical structures with appropriate receptor binding, toxicology, and pharmacokinetic profiles that would trigger the desired mechanisms of action while reducing undesirable side effects, and the initial candidate evaluation included, among other metrics, prodrug-likeness, toxicity, ease of chemical synthesis and degree of IP-white space surrounding the molecule.
Ranked scoring of these and other AI assessments, as well as commercial considerations (e.g., ease of procuring synthetic starting materials), prioritized 31 novel Gen-2 molecules that have been synthesized in sufficient quantities (~10 mg, 95% purity) for preliminary pharmacological screening. Enveric’s Chemistry Group, led by Dr. Kaveh Matinkhoo, PhD, completed these syntheses, 29 of which were deemed stable enough to advance.
Deep-dive chemical structure searches, patentability, and freedom-to-operate reviews were performed on all 29 candidates, under the leadership of Lead Internal Counsel C. Michael Gegenheimer. All the patentability analyses indicated potential patentability results, and 25 of the 29 molecules presented minimal concern with freedom to operate.
To strengthen the IP protection for the overall Gen-2 prodrug program, three provisional patent applications, covering 7 structurally diverse clinical classes and thousands of additional potential new drug candidates, have been filed so far in 2022, and additional provisional and PCT filings are expected to continue throughout the year.
In other IP developments, an additional three of Enveric’s international patent applications protecting tryptamine derivatives have been published by the World Intellectual Property Organization, bringing the total published so far to seven.
EVM-201 Drug Candidate Testing
Following the initial Gen-2 ideation, patent filing, synthesis, and screening efforts, more extensive assays were performed on the advancing drug candidates. Numerous internal assays were performed under the leadership of Dr. Jill Hagel, PhD, Vice-President of Innovation and Dr. Sheetal Raithatha, PhD, Director of Research and Development. The internal results were then confirmed and validated using leading independent, third-party Contract Research Organizations (CROs), covering 122 Toxicology tests, 72 receptor-binding and potency tests, 31 pharmacokinetic tests and 24 animal-model tests to provide ample information to support candidate nomination.
The synthesis and analysis of these comprehensive pharmacology and toxicology datasets, both internal and external, was led by Dr. Kevin Leach, PhD DABT, Vice President of Preclinical and Translational Research. Enveric is now moving towards lead-candidate nomination and, in preparation for IND filing, has initiated numerous IND-enabling studies on several of the leading candidates at third-party CROs.
Recognizing the need for stable drugs with robust, reproducible, and cost-effective manufacturing, several Contract Development & Manufacturing Organizations (CDMOs) are currently engaged with Enveric’s Chemistry Team to determine how best to manufacture our molecules. Enveric has plans in place to produce material at commercial facilities and the CDMO personnel have worked with our chemists to validate that our processes will work at their facilities. This is another necessary step prior to filing the IND. Finally, preliminary formulation work is underway, with a particular focus on enabling improved routes of administration.
“The first half of the year has indeed been busy and productive for the dedicated team here at Enveric. We are all very excited at how those efforts have begun to bear fruit. We look forward to advising our shareholders of further key developments, which we anticipate will continue to unfold during the remainder of 2022,” concluded Dr. Tucker.
About Enveric Biosciences
Enveric Biosciences, Inc. is a neuroscience-focused pharmaceutical company developing next-generation, psychedelic-inspired mental health medicines. Enveric's robust pipeline supports drug development from the clinic to commercialization aimed to help millions of patients in need around the world suffering from conditions that include cancer-related distress, PTSD and more.
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.”
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.
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.