Encapsulated cells producing antibodies

Details Encapsulated cells producing antibodies Encapsulated cells producing antibodies

1999-06-21

2002-07-30

Nguyen, Dave T. (Department: 1632)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Capsules

C424S009321, C424S009322, C424S455000, C424S457000, C424S461000, C424S491000, C424S499000

Reexamination Certificate

active

06426088

ABSTRACT:

The present invention relates to encapsulated cells producing antibodies, especially antibodies belonging to the various classes of immunoglobulines; IgM, IgD, IgGs, IgE and IgA, and to the use of such encapsulated cells for implantation in vivo for long term delivery or sustained delivery of antibodies of therapeutic interest.
BACKGROUND
Systemic delivery of cytostatic or cytotoxic tumor-specific antibodies b y engineered cells grafted to patients may be highly valuable for long-term anticancer surveillance treatments to prevent relapse after a primary treatment such as surgery, chemo- or radiotherapy. Such an approach could also be used for treating severe viral diseases, such as AIDS, if virus-neutralizing antibodies or antibodies toxic for virus-producing cells are delivered. In addition, long-term systemic delivery of antibodies may also be useful for more fundamental purposes such as the development of new animal models of autoimmune diseases in which the humoral response contributes to the development of the illness (Rose, N. R. and Bona, C., Immunol. Today, Vol. 14, 426-430 (1993)). Another possible application involve the development of a new cell ablation technique useful for studying in vivo various differentiation pathways and/or the biological importance of specific cell subsets through the release into the blood stream of cytotoxic antibodies recognizing cell type-specific membrane markers. In this situation, antibodies would kill target cells, for instance after a specific differentiation step, immediately following the appearance of cognate antigens at the surface of the differentiating cells.
It has been recently shown that—by using retroviral gene transfer—several cell types (including skin fibroblasts, myogenic cells, hepatocytes and keratinocytes), amenable to genetic modification and grafting to patients, can produce antibodies retaining the specifity and the affinity of the parental antibody (Noel, D et al., Hum. Gene Ther., Vol. 8, 1219-1229 (1997)). Furthermore, the grafting of engineered myogenic cells allows the systemic delivery of cloned antibodies in mouse for at least several months. Although these observations lend support to the idea that engineering of patients' cells may be useful for long-term antibody-based gene therapies, several issues potentially limit the clinical application of such a technology. First, such a therapeutical approach would be labor-intensive and time consuming. Second, stable genetic modification of patients' cells currently utilises ex vivo retroviral infection followed by autologous grafting in order to avoid rejection of non-MHC (MHC=major histocompatibility complex) matched cells b y the immune system. This reduces the versatility of the approach since engineered cells from one individual cannot be used for another. Third, efficient gene transfer and long-term expression of transgenes in cells that can be used in gene therapy protocols are issues that have not yet been completely solved (Crystal, R. G., Science, Vol. 270, 404-410 (1995); Harris, J. D. and Lemoine, N. R., Trends Genet., Vol. 12, 400-405 (1996); Vile, R. G. et al., Mol. Biotechnol., Vol. 5, 139-158 (1996)).
In this context, implantation of engineered cells encapsulated into immunoprotective devices into patients may represent a more versatile and cost-effective approach. On the one hand, it should allow the same batch of non-MHC-matched cells (possibly selected in vitro for optimal antibody expression) to be used for several patients and, on the other hand, implantation of capsules is a very simple surgical operation. In addition, such a technique would also offer the possibility of easy surgical removal of antibody-producing cells in case the treatment needs to be terminated.
For optimal function, the capsule pores must meet two criteria. First, they must be large enough to permit molecules of interest, such as antibodies, to exit and to permit the entry and efficient diffusion of nutrients necessary for cell survival. Second, they must be small enough to prevent the encapsulated cells from leaving the capsules and to prevent entry of host immune system cells.
Encapsulation of cells in permeable structures that allow the release of certain biologically active molecules but protects the cells producing these molecules from the host immune system has met with some success (for a review see Chang, P. L. In Somatic Gene Therapy. P. L. Chang, ed. (CRC Press, Boca Raton), p 203-223 (1995)). Cells that have been genetically modified to produce human growth hormone (hGH) (Tai, I. T. and Sun, A. M., FASEB J. 7, 1061-1069 (1993)) or a secreted form of human adenosine deaminase (Hughes et al., Hum. Gene Ther. 5, 1445-1455 (1994)) have been encapsulated. In both of these studies, cells were encapsulated in poly-L-lysine-alginate microcapsules and the cells were shown to survive for long periods in culture. This was accompanied by long term production of the enzyme or hormone. Further, it was shown that upon transplantation of the microcapsules into mice, the cells remained viable for 1 year and they continued to produce hGH, demonstrating that the capsules protect the transfected cells from destruction by the host immune system. Nevertheless, it was also reported that polylysine-alginate capsules induce an inflammatory response (Pueyo, M. E. et al., J. Biomater. Sci. Polym. Ed., Vol. 5, 197-203 (1993); Vandenbossche, G. M. et al., J. Pharm. Pharmacol., Vol. 45, 115-120 (1993)).
Cell encapsulation has also been reported using other materials. Baby hamster kidney cells genetically modified to produce nerve growth factor have been encapsulated in polyacrylonitrile/vinyl chloride and implanted in rat brain. The encapsulated cells survived for at least 6 months and continued to produce NGF (Winn et al., Proc. Natl.Acad. Sci. USA 91, 2324-2328 (1994) and Deglon et al., Gene Ther., 2, 563 (1995)).
Rat hybridoma cells secreting a mAb directed against murine IL-4 have been encapsulated in alginate and implanted, intraperitoneally and subcutaneously, into mice (Savelkoul, H. F. et al., J. Immunol. Methods, Vol. 170, 185-196 (1994)). However, the levels of antibody delivered in the blood stream declined after 14 days as a consequence of capsule deterioration. Moreover, in this system a 100% incidence of ascite development was observed 30 days post-implantation as a result of cell released from the capsules into the intraperitoneal cavity.
Hepatocytes have successfully been encapsulated in a polyelectrolyte complex of cellulose sulphate and polydimethyldiallyl ammonium (Stange et al., Biomat.Art.Cells & Immob. Biotech. 21, 3443-352 (1993)). More than 90% of the encapsulated hepatocytes retained their viability and in contrast to hepatocytes grown as monolayers, the encapsulated cells showed an increased metabolic activity.
The same encapsulation materials have been used for the encapsulation of antibody producing hybridoma cells (Merten et al. Cytotechnology 7:121-130, 1991).The capsules were prepared from a solution of sodium cellulose sulphate (1.5%) and poly-dimethyl-diallyl-ammoniumchloride (2% solution). The influence of varying encapsulation process parameters on capsule characteristics, cell growth, and monoclonal antibody production were tested and it was demonstrated that encapsulation using sodium cellulose sulphate as polyanion and poly-dimethyl-diallyl-ammonium-chloride as polycation, is a suitable tool for the preparation capsules useful for the cultivation of mammalian cells at high densities.
To summarize of what is known from the state of the art either in vivo implantation of the encapsulated cells producing antibodies for long term delivery and/or sustained release of antibodies for therapy is not described. or even suggested, or implantation of capsules resulted in severe side effects as, e.g., inflammatory responses.
OBJECT OF THE INVENTION
It is, thus, an object of the present invention to provide capsules containing antibody-producing cells, which allow the release of the antibodies from the capsules, and which do not elicit inflammato

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