Basics of advanced therapy medicinal product development in academic pharma and the role of a GMP simulation unit.

Following successes of authorized chimeric antigen receptor T-cell products being commercially marketed in the United States and European Union, product development of T-cell-based cancer immunotherapy consisting of cell-based advanced therapy medicinal products (ATMPs) has gained further momentum. Due to their complex characteristics, pharmacological properties of living cell products are, in contrast to classical biological drugs such as small molecules, more difficult to define. Despite the availability of many new advanced technologies that facilitate ATMP manufacturing, translation from research-grade to clinical-grade manufacturing in accordance with Good Manufacturing Practices (cGMP) needs a thorough product development process in order to maintain the same product characteristics and activity of the therapeutic product after full-scale clinical GMP production as originally developed within a research setting.

Enzyme-induced shedding of a poly(amino acid)-coating triggers contents release from dioleoyl phosphatidylethanolamine liposomes.

The enzymatically degradable poly(amino acid)-lipid conjugate poly(hydroxyethyl l-glutamine)-N-succinyl-dioctadecylamine (PHEG-DODASuc) has been shown to effectively prolong liposome circulation times. In this paper, we investigated whether PHEG-DODASuc can stabilize liposomes composed of the fusogenic, non-bilayer-forming lipid dioleoyl phosphatidylethanolamine (DOPE). Moreover, we evaluated the release of an entrapped compound after enzyme-induced shedding of the PHEG-coating, interbilayer contact and membrane destabilizing phase changes.

Temperature-sensitive poly(N-(2-hydroxypropyl)methacrylamide mono/dilactate)-coated liposomes for triggered contents release.

We prepared thermosensitive poly( N-(2-hydroxypropyl)methacrylamide mono/dilactate) (pHPMA mono/dilactate) polymer and studied temperature-triggered contents release from polymer-coated liposomes. HPMA mono/dilactate polymer was synthesized with a cholesterol anchor suitable for incorporation in the liposomal bilayers and with a cloud point (CP) temperature of the polymer slightly above normal body temperature (42 degrees C). Dynamic light scattering (DLS) measurements showed that whereas the size of noncoated liposomes remained stable upon raising the temperature from 25 to 46 degrees C, polymer-coated liposomes aggregated around 43 degrees C.

Long-circulating, pH-sensitive liposomes sterically stabilized by copolymers bearing short blocks of lipid-mimetic units.

A major hurdle towards in vivo utilization of pH-sensitive liposomes is their prompt sequestration by reticuloendothelial system and hence short circulation time. Prolonged circulation of liposomes is usually achieved by incorporation of pegylated lipids, which have been frequently reported to deteriorate the acid-triggered release. In this study we evaluate the ability of four novel nonionic copolymers, bearing short blocks of lipid-mimetic units to provide steric stabilization of DOPE:CHEMs liposomes.

Effect of liposome characteristics and dose on the pharmacokinetics of liposomes coated with poly(amino acid)s.

Long-circulating liposomes, such as PEG-liposomes, are frequently studied for drug delivery and diagnostic purposes. In our group, poly(amino acid) (PAA)-based coatings for long-circulating liposomes have been developed. These coatings provide liposomes with similar circulation times as compared to PEG-liposomes, but have the advantage of being enzymatically degradable.