Delivery of immunostimulatory monoclonal antibodies by encapsulated hybridoma cells.

Immunostimulatory monoclonal antibodies are immunoglobulins directed toward surface proteins of immune system cells that augment the immune response against cancer in a novel therapeutic fashion. Exogenous administration of the recombinant humanized immunoglobulins is being tested in clinical trials with agents of this kind directed at a variety of immune-controlling molecular targets. In this study, the encapsulation of antibody-producing hybridoma cells was tested in comparison with the systemic administration of monoclonal antibodies. Hybridomas producing anti-CD137 and anti-OX40 mAb were encapsulated in alginate to generate microcapsules containing viable cells that secrete antibody. Immobilized cells in vitro were able to release the rat immunoglobulin produced by the hybridomas into the supernatant. Microcapsules were implanted by injection into the subcutaneous tissue of mice and thereby provided a platform for viable secreting cells, which lasted for more than 1 week. The pharmacokinetic profile of the rat monoclonal antibodies following microcapsule implantation was similar to that attained following an intraperitoneal administration of the purified antibodies. The rat-mouse hybridoma cells did not engraft as tumors in immunocompetent mice, while they lethally xenografted in immunodeficient mice, if not microencapsulated. The antitumor therapeutic activity of the strategy was studied on established CT26 colon carcinomas resulting in complete tumor eradication in an elevated fraction of cases and strong tumor-specific CTL responses with either anti-CD137 or anti-OX40 producing hybridomas, thus offering proof of the concept. This form of administration permitted combinations of more than one immunostimulatory monoclonal antibody to exploit the synergistic effects such as those known to be displayed by anti-CD137 and anti-OX40 mAb.

Encapsulated VEGF-secreting cells enhance proliferation of neuronal progenitors in the hippocampus of AßPP/Ps1 mice.

Vascular endothelial growth factor (VEGF) promotes neurogenesis in the adult hippocampus, but the way in which this process occurs in the Alzheimer's disease (AD) brain is still unknown. We examined the proliferation of neuronal precursors with an ex vivo approach, using encapsulated VEGF secreting cells, in AßPP/PS1 mice, a mouse model of AD. Overexpression of VEGF and VEGF receptor flk-1 was observed in the cerebral cortex from VEGF microcapsules-treated AßPP/PS1 mice at 1, 3 and 6 months after VEGF-microcapsule implantation. Stereological counting of 5-bromodeoxyuridine positive cells revealed that encapsulated VEGF secreting cells significantly enhanced cellular proliferation in the hippocampal dentate gyrus (DG). The number of neuronal precursors in VEGF microcapsules-treated AßPP/PS1 mice was also greater, and this effect remains after 6 months. We also confirmed that encapsulated VEGF secreting cells also stimulated angiogenesis in the cerebral cortex and hippocampal dentate gyrus. In addition, we found that VEGF-microcapsule treatment was associated with a depressed expression and activity of acetylcholinesterase in the hippocampus of AßPP/PS1 mice, a similar pattern as first-line medications for the treatment of AD. We conclude that stereologically-implanted VEGF-microcapsules exert an acute and long-standing neurotrophic effects, and could be utilized to improve potential therapies to control the progression of AD.

[Cell encapsulation for the treatment of central nervous system disorders]. / Encapsulacion de celulas para el tratamiento de enfermedades del sistema nervioso central.

INTRODUCTION: One of the main matters of drug administration into the central nervous system (CNS) is to cross the blood/brain barrier. For this reason, in some cases the drug does not reach the therapeutic level or is necessary to use some special systems to get a right administration. AIM: To present a technological system which allow continuous and direct administration of the drug into the CNS. It consists of enclosing secreting-cells of the desired product within a semipermeable polymeric matrix. Furthermore, this device could be implanted easily into the CNS which improves the access of the drug to the injured places. DEVELOPMENT: During the last years the use of this technology has been researched in the treatment of diverse diseases affecting the CNS. Although it is important to point out that the majority of the studies done have been carried out in experimental animals therefore, it is in experimental state. The aim of this article is to review the current state of the use of cell encapsulation technology as treatment of CNS disorders. CONCLUSION: Taking into account the results obtained in different research works cell encapsulation technology could be a useful strategy to treat CNS disorders. However, some important matters are still to be solved out, before than technology of cell encapsulation could be a reality at clinical level.

The effect of encapsulated VEGF-secreting cells on brain amyloid load and behavioral impairment in a mouse model of Alzheimer's disease.

Cerebrovascular dysfunction contributes to cognitive decline and neurodegeneration in Alzheimer's disease (AD). Vascular endothelial growth factor (VEGF), an angiogenic protein with important neurotrophic and neuroprotective actions, is under investigation as a therapeutic agent for the treatment of neurodegenerative disorders. The aim of this study was to generate encapsulated VEGF-secreting cells and implant them in a transgenic mouse model of AD, the double mutant amyloid precursor protein/presenilin 1 (APP/Ps1) mice, which shows a disturbed vessel homeostasis. We report that, after implantation of VEGF microcapsules, brain Abeta burden, hyperphosphorylated-tau and cognitive impairment attenuated in APP/Ps1 mice. Based on the neurovascular hypothesis, our findings suggest a new potential therapeutic approach that could be developed for AD, to enhance Abeta clearance and neurovascular repair, and to protect the cognitive behavior. Stereologically-implanted encapsulated VEGF-secreting cells could offer an alternative strategy in the treatment of AD.

Cell microencapsulation technology: towards clinical application.

The pharmacokinetic properties of a drug can be significantly improved by the delivery process. Scientists have understood that developing suitable drug delivery systems that release the therapeutically active molecule at the level and dose it is needed and during the optimal time represents a major advance in the field. Cell microencapsulation is an alternative approach for the sustained delivery of therapeutic agents. This technology is based on the immobilization of different types of cells within a polymeric matrix surrounded by a semipermeable membrane for the long-term release of therapeutics. As a result, encapsulated cells are isolated from the host immune system while allowing exchange of nutrients and waste and release of the therapeutic agents. The versatility of this approach has stimulated its use in the treatment of numerous medical diseases including diabetes, cancer, central nervous system diseases and endocrinological disorders among others. The aim of this review article is to give an overview on the current state of the art of the use of cell encapsulation technology as a controlled drug delivery system. The most important advantages of this type of "living" drug release strategy are highlighted, but also its limitations pointed out, and the major challenges to be addressed in the forthcoming years are described.