ICE Bioscience’s Post

📌 Exploring Protein Structure: A Deep Dive into Antibodies - Post #2 Understanding Glycosylation in Antibodies Continuing our protein structure series, I would like to explore the crucial role of #glycosylation in antibody function. Glycosylation, a vital post-translational modification (#PTM), significantly impacts an antibody's stability, solubility, and interaction with immune cells. This post covers the various types of glycosylation, including N-linked and O-linked, and examines how the presence or absence of #fucose influences antibody efficacy. Advanced cell line, such as Lonza 's #GSEffex, was also discussed for their ability to enhance #ADCC activity by removing fucose, thereby improving therapeutic efficacy. Understanding and controlling glycosylation is essential for optimising therapeutic antibody development. Discover more in my latest article:  https://lnkd.in/eT8Zwuhq #antibodystructure #glycosylation #bioprocessing #therapeutics #Lonza #GS #Effex

💉 𝐁𝐢𝐨𝐬𝐢𝐦𝐢𝐥𝐚𝐫 𝐌𝐨𝐧𝐨𝐜𝐥𝐨𝐧𝐚𝐥 𝐀𝐧𝐭𝐢𝐛𝐨𝐝𝐲 𝐌𝐚𝐫𝐤𝐞𝐭: 𝐄𝐱𝐩𝐚𝐧𝐝𝐢𝐧𝐠 𝐀𝐜𝐜𝐞𝐬𝐬 𝐭𝐨 𝐂𝐨𝐬𝐭-𝐄𝐟𝐟𝐞𝐜𝐭𝐢𝐯𝐞 𝐓𝐡𝐞𝐫𝐚𝐩𝐢𝐞𝐬 🌍 𝐂𝐥𝐢𝐜𝐤 𝐇𝐞𝐫𝐞, 𝐓𝐨 𝐆𝐞𝐭 𝐅𝐫𝐞𝐞 𝐒𝐚𝐦𝐩𝐥𝐞 𝐑𝐞𝐩𝐨𝐫𝐭 https://lnkd.in/gBrJ-eEy The biosimilar monoclonal antibody market is witnessing rapid growth due to the rising demand for cost-effective biologic therapies, increasing prevalence of chronic diseases such as cancer and autoimmune disorders, and the expiration of patents on blockbuster biologics. Monoclonal antibodies (mAbs) are widely used in treating a variety of conditions, including cancer, rheumatoid arthritis, and inflammatory diseases. However, the high cost of these therapies has limited their accessibility. Biosimilar monoclonal antibodies offer a more affordable alternative to originator biologics, providing comparable efficacy and safety while expanding patient access to these critical treatments. This growing demand for biosimilars is driving the expansion of the biosimilar monoclonal antibody market globally. A key factor driving the market is the increasing incidence of chronic diseases that require long-term and costly biologic treatments. Monoclonal antibodies have become an essential component in the treatment of cancer, autoimmune disorders, and infectious diseases. With the global rise in these conditions, the need for affordable therapeutic options is increasing. Biosimilar monoclonal antibodies provide a more cost-effective solution without compromising on treatment quality, offering a significant opportunity for healthcare providers and patients to manage chronic diseases more effectively. #Company Biocon Accord Healthcare AET Biotech Amgen Celltrion Inc Reddy's Laboratories Hospira 3SBio Allergan Alvartis #Type Limited Dilution Method Micromanipulation Soft Agar Plate Method Others #Application Chronic & Autoimmune Diseases Oncology Others #Biosimilars #MonoclonalAntibodies #Biopharmaceuticals #HealthcareInnovation #Oncology #Immunology #AffordableHealthcare #Pharmaceuticals #ChronicDisease #FutureOfHealthcare

Cyrus has redesigned the bacterial enzyme IdeS to be safe in rabbits for redosing! A great step for this future human biologic. [shameless plug: Contact me to subscribe to the computational tools they use: plug over.] IdeS is a protease for IgG. Its useful therapeutically to inhibit a toxic immune response for treatments like gene therapy. IdeS is tested in rabbits because it shares activity for rabbit and human IgG. You can see in the attached article that the WT IdeS is degraded rapidly because of the massive immune response (even as an initial dose and dramatically when redosing). This completely obliterates that activity and is probably highly unpleasant for the bunny. The Cyrus IdeS achieves significant IgG degradation, and doesn't lose significant activity till around day 14 when they redose. And the second dose last longer. [conflict disclosure: I have stock in Cyrus. But they really are amazing and this is an amazing accomplishment. So few groups are focusing so intensely on the many ways to reduce immunogenicity. Cyrus has multiple computational methods, their own internal wet lab experiments, they do the external validation on human immune cells. Their computational approaches uses the power of Rosetta to find mutations that retain structure and function and a wide range of methods to see which mutants are least likely to have an immune response. Plus, they use glycan shielding and extended half life. Cyrus is really exceptional.]

Development of chimeras of bacterial KcsA and human Kv1.1, .Kv1.2 and Kv1.3 variants for ease of screening. The authors aimed to develop a tool to screen for Kv1.3 specific blockers using phage display. Bacterial KcsA is easier to produce and handle, and therefore easier to screen against. Some previous work has been performed with chimeras between KcsA and Kv1.x channels, mostly around the extracellular turret domain. Turret only and Turret + Filter chimeras were produced in and purified from E. coli (C41, a strain developed specifically for membrane proteins, was best). Interesting the KcsA tetramer is SDS-resistant, but only some of the chimeras were too. Using previously-identified toxin proteins with a range of potencies, the authors compared IC50 values for the human Kv1.1/2/3 channels (in cells) to ELISA and phage competition assays of the chimeras (in detergent). It was observed that the T+F chimeras were in closer agreement than the T only chimeras. This could be a useful tool to screen for binders to these native ion channels, but it should be noted that these chimeras were not proven to be ion conductive, just that they were able to bind to the known toxin proteins. I'd be very interested to see these proteins used in binding assays. If they are indeed more stable than the human versions, these toxin affinities could be measured by SPR or assessed using cryoEM. VRG Therapeutics, University of Debrecen, Semmelweis University #proteinengineering #drugdiscovery #membraneproteins #biologics #ionchannels #immunology #purification #sdspage #biophysics

📈𝘽𝙞𝙤𝙥𝙝𝙖𝙧𝙢𝙖 𝘽𝙪𝙡𝙡𝙚𝙩𝙞𝙣: 𝙎𝙩𝙖𝙮 𝘼𝙝𝙚𝙖𝙙 𝙬𝙞𝙩𝙝 𝙏𝙝𝙚𝙨𝙚 5 𝙍𝙚𝙖𝙙𝙨 📚 📌 SpringWorks Therapeutics (Nasdaq: SWTX), a commercial-stage biopharmaceutical company specializing in severe rare diseases and cancer, has completed the submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA). The NDA is for mirdametinib, an investigational MEK inhibitor, intended for treating pediatric and adult patients with neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN). 📌  Precision BioSciences, Inc. (Nasdaq: DTIL), an advanced gene editing company using its novel proprietary ARCUS® platform to develop in vivo gene editing therapies, has been added to the Russell Microcap® Index. This inclusion follows the conclusion of the 2024 Russell indexes annual reconstitution, which became effective after the close of U.S. markets on June 28, 2024. 📌 Amneal Pharmaceuticals (Nasdaq: AMRX) has announced the addition of omalizumab, referencing XOLAIR®, to its biosimilar pipeline. Omalizumab is a humanized monoclonal antibody targeting free immunoglobulin E (IgE), used to treat chronic conditions like severe persistent allergic asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), food allergies, and chronic spontaneous urticaria. Developed by Kashiv BioSciences, LLC, the biosimilar is currently in a Phase III clinical trial, which began in Q3 2023. 📌 Humacyte (Nasdaq: HUMA) has received the FDA’s Regenerative Medicine Advanced Therapy (RMAT) designation for their investigational Acellular Tissue Engineered Vessel (ATEV) for advanced peripheral artery disease (PAD). Alongside this, the FDA has cleared a new Investigational New Drug (IND) application for the PAD indication. 📌 Legend Biotech (NASDAQ: LEGN), a global leader in cell therapy, announced positive overall survival results from CARTITUDE-4, an ongoing Phase 3 study evaluating CARVYKTI® (cilta-cel) versus PVd or DPd in adult patients with relapsed and lenalidomide-refractory multiple myeloma. CARVYKTI® showed statistically significant and clinically meaningful improvement in overall survival (OS) in the pre-specified second interim analysis. Safety results aligned with CARVYKTI®'s established profile, with no new safety signals identified. #biotechnews #biotech #biopharma #biopharmanews

Large molecules based treatments have emerged as superior alternative to historically used small molecules based medicines. Since discovery of insulin's therapeutic importance in type-1 diabetes management many protein molecules have been identified with high therapeutic importance. Off all therapeutics proteins monoclonal antibody is leading therapeutic large molecules in terms of number. So far more than 100s unique mAbs have been approved by USFDA for the treatment of various disease including cancer. Same mAbs are also providing a new opportunity for cytotoxic and PROTAC molecules where these molecules are being conjugated to antibody for targeting diseased cell efficiently. This review chronicles both well-established and emerging design strategies that have enabled this paradigm shift by transforming protein-based structures that are often prone to denaturation, degradation, and aggregation in vitro and in vivo into highly effective therapeutics. https://lnkd.in/gpy5W8RN

A recent study unpicks a key immune-mediated mechanism of mutant IDH–blocking drugs such as vorasidenib in the treatment of IDH-mutant glioma.    Figure 1 from the article shows immunity, transcriptional activity, and growth of IDH-mutant tumors.     Mutant isocitrate dehydrogenase (mIDH) catalyzes the conversion of α-ketoglutarate (α-KG) into the R enantiomer of 2-hydroxyglutarate (R-2-HG), which blocks the activity of the DNA demethylase TET2 (Panel A, 1). As a result, the transcription of transposable elements and the DNA-sensing protein cyclic GMP–AMP synthase (cGAS) is blocked (Panel A, 2), which results in hyporesponsiveness to immunostimulatory activity of interferon-γ (Panel A, 3) and decreased antitumor immunity.     When the neomorphic enzymatic activity of mIDH is blocked by the isocitrate dehydrogenase (IDH) inhibitors ivosidenib or vorasidenib, α-KG levels are restored, R-2-HG levels are normalized (Panel B, 1), and TET2 demethylase activity derepressed. This process (Panel B, 2) results in the expression of cGAS and subclasses of transposable elements that are converted to double-stranded DNA (dsDNA) in the cytosol (Panel B, 3).     These double-stranded transposable elements bind and activate the cGAS-STING (stimulator of interferon genes) complex (Panel B, 4), which in turn activates interferon-stimulated genes (ISG) that encode interferons and other cytokines and chemokines (Panel B, 5), which attract T cells that produce interferon-γ (Panel B, 6) and sustain a feed-forward loop of interferon-γ hyperresponsiveness and enhanced antitumor immunity (Panel B, 7 through 10).     The abbreviation cGAMP denotes cyclic guanosine monophosphate–adenosine monophosphate, IRF3 interferon regulatory factor 3, mRNA messenger RNA, and STAT signal transducer and activator of transcription.    Learn more in the Clinical Implications of Basic Research article “Heating Up IDH-Mutant Gliomas” by Michael Platten, MD, and Lukas Bunse, MD, PhD, from Heidelberg University and the DKFZ German Cancer Research Center: https://nej.md/4f3dIMf 

Dear Michael and Lukas, Many thanks for sharing your Perspective article written about a NEJM Group paper regarding ’… #immune-#mediated mechanism of mutant IDH–blocking drugs such as #vorasidenib in the treatment of #IDH-#mutant #glioma.’ Unfortunately, I do not have access to #NEJM articles, but I have been able to read your Post, based on which I would like to raise a couple of thoughts/ideas. 1.      #Gliomas are often #hypoxic. 2.      Hypoxia promotes glioma #stemness and progression, increases resistance to chemo- and radiation therapy, and results in decreased immune response to tumor cells (e.g. it causes proliferation of Treg cells that suppress the immune response). 3.      CURRENT STUDY: ’When the neomorphic enzymatic activity of mIDH is blocked by the isocitrate dehydrogenase (IDH) inhibitors ivosidenib or vorasidenib, #α-#KG levels are restored, R-2-HG levels are normalized (Panel B, 1), and #TET2 #demethylase activity derepressed.   Based on the above points, I wonder whether it would be feasible, worthwhile and safe to:   a)      Decrease the level of #tumor #hypoxia by #hyperbaric #oxygen therapy (as I understand, there are ongoing clinical trials of HBOT in glioma patients) AND/OR b)     Decrease the hypoxic response in the tumor by administering high doses of #vitamin #C (ascorbic acid) by IV infusion. Vitamin C is an important cofactor of 2-Oxoglutarate-dependent dioxygenases (2-OGDD), and high levels of vitamin C stimulate #HIF #hydroxylase activity leading to HIF degradation by #ubiquitination. AND/OR c)      Employ isocitrate dehydrogenase (IDH) inhibitors #ivosidenib or #vorasidenib (as described in your Perspective and the Original article). AND/OR d)     FINALLY, one might want to consider glioma-killing engineered T cells in combination with some of the above-mentioned approaches.   Please see the outstanding article just published: Milos Simic et al. Programming tissue-sensing T cells that deliver therapies to the brain. Science, 6 Dec 2024, Vol 386, Issue 6726, DOI: 10.1126/science.adl42   Best wishes, Joseph Najbauer Selected references:   Park JH and Lee HK. Current Understanding of Hypoxia in Glioblastoma Multiforme and Its Response to Immunotherapy. Cancers 2022, 14, 1176. https://lnkd.in/d4tbyq5V   Carosi F et al. Targeting Isocitrate Dehydrogenase (IDH) in Solid Tumors: Current Evidence and Future Perspectives. Cancers 2024, 16, 2752. https://lnkd.in/dqDv4rVk   Mellinghoff IK et al. Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma. N Engl J Med 2023;389:589-601. DOI: 10.1056/NEJMoa2304194 Kuiper C and Vissers MCM (2014) Ascorbate as a co-factor for Fe- and 2-oxoglutarate dependent dioxygenases: physiological activity in tumor growth and progression. Front. Oncol. 4:359. doi: 10.3389/fonc.2014.00359

Lipid nanoparticle (LNP)–encapsulated mRNA has been used for in vivo production of several secreted protein classes, such as #IgG, and has enabled the development of personalized vaccines in oncology. Establishing the feasibility of delivering complex multi-specific modalities that require higher-order structures important for their function will help expand the use of mRNA/LNP biologic formulations. https://lnkd.in/dxwJNv6y #mRNA #LNP #Antitumor #Cancertreatment #Biologics #formulation #drugdevelopment #engineering

RNA-based therapeutics have gained traction for the prevention and treatment of a variety of diseases. However, their #fragility and #immunogenicity necessitate a drug carrier. Lipid nanoparticles (#LNPs) have emerged as the predominant delivery vehicle for #mRNA therapeutics. An important component of LNPs is the ionizable #lipid (IL), which is protonated in the acidic environment of the endosome, prompting cargo release into the cytosol. There is growing evidence that the structure of IL lipid tails significantly impacts the efficacy of LNP-mediated mRNA translation. Access the article here: https://lnkd.in/ehm6JBKk #LNP #Lipidnanoparticle #RNA #mRNA #Drugdevelopment #Ionizablelipid