Controlled lipid self-assembly for scalable manufacturing of next-generation immune stimulating complexes
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Description
Published version
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8.15 MB
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Author(s)
Pires, Ivan S
Ni, Kaiyuan
Melo, Mariane Bandeira
Li, Na
Ben-Akiva, Elana
Maiorino, Laura
Dye, Jonathan
Rodrigues, Kristen A
Yun, DongSoo
Kim, Byungji
Date Issued
May 15, 2023
Journal
Chemical Engineering Journal
Publisher
Elsevier BV
Citation
Pires, Ivan S, Ni, Kaiyuan, Melo, Mariane Bandeira, Li, Na, Ben-Akiva, Elana et al. 2023. "Controlled lipid self-assembly for scalable manufacturing of next-generation immune stimulating complexes." Chemical Engineering Journal, 464.
Version
Final published version
Abstract
Immune stimulating complexes (ISCOMs) are safe and effective saponin-based adjuvants formed by the self-assembly of saponin, cholesterol, and phospholipids in water to form cage-like 30-40 nm diameter particles. Inclusion of the Toll-like receptor 4 agonist monophosphoryl lipid A (MPLA) in ISCOM particles yields a promising next-generation adjuvant termed Saponin-MPLA NanoParticles (SMNP). In this work, we detail protocols to produce ISCOMs or SMNP via a tangential flow filtration (TFF) process suitable for scalable synthesis and Good Manufacturing Practice (GMP) production of clinical-grade adjuvants. SMNP or ISCOM components were solubilized in micelles of the surfactant MEGA-10, then diluted below the critical micelle concentration (CMC) of the surfactant to drive ISCOM self-assembly. Assembly of ISCOM/SMNP particles using the purified saponin QS-21 used in clinical-grade saponin adjuvants was found to require controlled stepwise dilution of the initial micellar solution, to prevent formation of undesirable kinetically-trapped aggregate species. An optimized protocol gave yields of ~77% based on the initial feed of QS-21 and the final SMNP particle composition mirrored the feed ratios of the components. Further, samples were highly homogeneous with comparable quality to that of material prepared at lab scale by dialysis and purified via size-exclusion chromatography. This protocol may be useful for clinical preparation of ISCOM-based vaccine adjuvants and therapeutics.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Chemical Engineering
Ragon Institute of MGH, MIT and Harvard
Harvard-MIT Program in Health Sciences and Technology
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Materials Science and Engineering
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DOI of Published Version
https://doi.org/10.1016/j.cej.2023.142664
