Mastewal Abuhay, PhD

Learn about strategies for purifying bispecific antibodies and antibody fragments having the molecule type and the impurity profile in mind. https://lnkd.in/e5PFqx79

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Fun one for my chemist colleagues out there -innovative solutions for overcoming anti-PEG antibody challenges in LNPs! 🧬 LNP/mRNA are awesome tools, that's undeniable. However, a major hurdle has emerged: the widespread use of LNPs containing polyethylene glycol (PEG) has led to the development of anti-PEG antibodies in over a billion individuals, posing significant risks such as high reactogenicity and potentially life-threatening anaphylaxis. 🔬 Ok, so what is this PEG challenge and why, as a scientist, should care about it? Anti-PEG antibodies can compromise the effectiveness of LNP-based therapies, particularly in intravenously administered products, by triggering inflammation and complement-mediated inactivation. Current efforts to replace PEG with alternatives like polysarcosine (PS) and poly(2-ethyl-2-oxazoline) (PEOZ) have shown promise but are not without drawbacks, including the generation of anti-polymer antibodies and reduced efficacy with chronic use. 💡 A breakthrough with polyamides? This article highlights polyamides with short PEG grafts as a promising alternative. These polymers do not provoke anti-PEG antibody responses even after repeated administrations, thanks to their unique binding characteristics. Specifically, poly(L-glutamic acid) backbone esterified with oligoethylene-oxide grafts (PGE) of 2–5 units can replace PEG in LNPs, maintaining or exceeding the performance of traditional PEG-LNPs. ✨ And the key findings? 1) PGE3-LNPs, with 3-unit ethylene oxide grafts, demonstrated efficient mRNA transfection in vivo, particularly in the liver, and showed superior performance compared to PEG-LNPs during chronic administration. 2) These PGE-LNPs significantly reduce the generation of anti-PEG antibodies, addressing a critical barrier for long-term therapeutic use. 3) Variants with 2, 4, and 5-unit ethylene oxide grafts also achieved efficient cellular transfection, showcasing the broad potential of PGE-LNPs as next-generation stabilizers. 🚀 This study provides compelling evidence that polyamides with short PEG grafts can serve as effective, less immunogenic alternatives to traditional PEG in LNPs, paving the way for safer and more durable mRNA-based therapeutics. As we advance toward a new era of chronic administration of LNP-based therapies, the focus on rational polymer design will be key to unlocking their full potential. Learn more here: https://lnkd.in/eHwY6QtC #LipidNanoparticles #mRNA #DrugDelivery #Immunogenicity #PEGReplacement #Nanotechnology #Biotechnology

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Is AI an end all be all for designing selective SM drugs? Not so Fast! Read this story in depth, and try and hypothesize how would AI be able to help design this type of inhibitor. Hot take: MD simulations are still incredibly powerful tools in the hands of trained biochemists. Hot take #2: Protein DYNAMICS, NOT Protein STRUCTURE is the REAL CHALLENGE.

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In my Biotechnology of Cell Therapies Course at UCLA I teach that we need to improve how we define and assay critical quality attributes (CQAs) of cell therapy products. We need more tools to sort individual cells based on CQAs that directly connect to therapeutic function. 🔬 I am excited to share our latest work that we believe is one of the first times this has been done - and shows that we could dramatically improve cell therapies if we do it! We used #nanovials to sort the cells that secreted the highest levels of extracellular vesicles (EVs) and found these cells were the most therapeutically active in a model system. Please find our new manuscript, published in Nature Communications. 🔗 Link here: https://lnkd.in/gJ5SUhfb ❔ How did this work? Nanovials are cavity-containing microparticles that act as small test tubes for single cells. We confirmed we could capture and label the EVs secreted by cells in Nanovials using imaging cytometry (ImageStream from Cytek Biosciences). We then sorted out mesenchymal stem cells (MSCs) that secreted varying levels of EVs using the SH800S from Sony Biotechnology Inc. to determine if the cells maintained the high-EV-secretion phenotype. We found the phenotype appeared heritable and was associated with particular gene expression signatures. Our collaborators then used this approach to select high-secreting and low-secreting cells to treat an in vivo model of heart damage, where MSC-derived EVs are thought to act therapeutically. High-secreting cells mitigated heart damage more than low-secreting cells, leading to significant improvements in ejection fraction and other metrics of heart function. We encourage others to also repeat this work or related studies for function-based sorting to advance cell therapies. In fact, most cell therapies depend on secreted molecules that play direct roles in therapeutic function (e.g. insulin from islet beta cells, cytokines/granzymes/perforin in immune cell based therapies, growth factors in regenerative cell therapies, etc.). Nanovial formulations like those we used are available from Partillion Bioscience. Of course, this work is the result of an amazing team of researchers: Doyeon Felis Koo, Xiao Cheng, Shreya Udani, SEVANA BAGHDASARIAN, Ke Cheng, Brian Hall, and many more. Many thanks to National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the Chan Zuckerberg Initiative for supporting this work. #extracellularvesicles #celltherapy #singlecell #cytometry #labonaparticle #functionfirst #biotechnology #biotech #bioengineering #qualitybydesign #CQAs

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