Drug – bio-affecting and body treating compositions – Extract – body fluid – or cellular material of undetermined...
Reexamination Certificate
1999-11-09
2001-10-16
Naff, David M. (Department: 1651)
Drug, bio-affecting and body treating compositions
Extract, body fluid, or cellular material of undetermined...
C424S093700, C435S177000, C435S178000, C435S182000, C435S382000, C435S395000
Reexamination Certificate
active
06303151
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the restriction of the proliferation of cells in or capable of rapid log-phase growth which, when their proliferation is physically restricted in a biocompatible, semipermeable material, produce normally unexpressed or increased amounts of a normally expressed factor or factors capable of inhibiting the growth of other rapidly proliferating cells of the same or different types and/or origins. These restricted cells are hereinafter referred to as proliferative cells. A non-limiting list of proliferative cells belonging to this category include neoplastic cells, cancer cells, and non-cancerous cells including, but not limited to, embryonic cells, stem cells, and cells in a post tissue injury regenerative phase including hepatocytes, fibroblasts and epithelial cells. The structures which are one feature of the invention can be used “as is,” or to produce material such as concentrates with a defined approximate molecular weight, which also have an anti-proliferative effect on rapidly proliferating cells associated with diseases or conditions such as, e.g., cancer, or to control growth of cells to prevent certain medical problems that may arise from uncontrolled cell growth, such as the formation of post-operative scars.
BACKGROUND AND PRIOR ART
The encapsulation of various biological materials in biologically compatible materials, which is well documented in the literature, is a technique that has been used for some time, albeit with limited success. Exemplary of the art are U.S. Pat. No. 5,227,298 (Weber, et al.); U.S. Pat. No. 5,053,332 (Cook, et al.); U.S. Pat. No. 4,997,443 (Walthall, et al.); U.S. Pat. No. 4,971,833 (Larsson, et al.); U.S. Pat. No. 4,902,295 (Walthall, et al.); U.S. Pat. No. 4,798,786 (Tice, et al.); U.S. Pat. No. 4,673,566 (Goosen, et al.); U.S. Pat. No. 4,647,536 (Mosbach, et al.); U.S. Pat. No. 4,409,331 (Lim); U.S. Pat. No. 4,392,909 (Lim); U.S. Pat. No. 4,352,883 (Lim); and U.S. Pat. No. 4,663,286 (Tsang, et al.). Also of note is U.S. Pat. No. 5,643,569 to Jain, et al., incorporated by reference herein. Jain, et al. discuss, in some detail, the encapsulation of islets in various biocompatible materials. Islets produce insulin, and the use of the materials disclosed by Jain, et al. in the treatment of diabetes is taught therein. U.S. Pat. No. 5,888,497 to Jain et al. describe implantable agarose coated, agarose beads having cancer cells restricted therein which produce more of a material that suppresses the growth of non-restricted cancer cells than an equal number of the same unrestricted cancer cells.
The Jain, et al. patents discuss, in some detail, the prior approaches taken by the art in transplantation therapy. These are summarized herein as well.
Five major approaches to protecting the transplanted tissue from the host's immune response are known. All involve attempts to isolate the transplanted tissue from the host's immune system. The immunoisolation techniques used to date include: extravascular diffusion chambers, intravascular diffusion chambers, intravascular ultrafiltration chambers, microencapsulation, and macroencapsulation. There are many problems associated with methods of the prior art, including a host fibrotic response to the implant material, instability of the implant material, limited nutrient diffusion across semi-permeable membranes, secretagogue and product permeability, and diffusion lag-time across semi-permeable membrane barriers.
For example, a microencapsulation procedure for enclosing viable cells, tissues, and other labile membranes within a semipermeable membrane was developed by Lim in 1978. (Lim, Research report to Damon Corporation (1978)). Lim used microcapsules of alginate and poly L-lysine to encapsulate islets of Langerhans (referred to as “islets” hereinafter). In 1980, the first successful in vivo application of this novel technique in diabetes research was reported (Lim, et al., Science 210: 908 (1980)). The implantation of these microencapsulated islets resulted in sustaining a euglycemic state in diabetic animals. Other investigators, however, repeating these experiments, found the alginate to cause a tissue reaction and were unable to reproduce Lim, et al.'s results (Lamberti, et al.
Applied Biochemistry and Biotechnology
10: 101 (1984); Dupuy, et al.,
J. Biomed. Material and Res.
22:1061 (1988); Weber, et al.,
Transplantation
49:396 (1990); and Doon-shiong, et al.,
Transplantation Proceedings
22: 754 (1990)). The water solubility of these polymers is now considered to be responsible for the limited stability and biocompatibility of these microcapsules in vivo (Dupuy, et al., supra, Weber et al., supra, Doon-shiong, et al., supra, and Smidsrod,
Faraday Discussion of Chemical Society
57. 263 (1974)).
Iwata et al., (Iwata, et al.
Jour. Biomedical Material and Res.
26: 967 (1992)) utilized agarose for microencapsulation of allogeneic pancreatic islets and discovered that it could be used as a medium for the preparation of microbeads. In their study, 1500-2000 islets were microencapsulated individually in 5% agarose and implanted into streptozotocin-induced diabetic mice. The graft survived for a long period of time, and the recipients maintained normoglycemia indefinitely.
Their method, however, suffers from a number of drawbacks. It is cumbersome and inaccurate. For example, many beads remain partially coated and several hundred beads of empty agarose form. Additional time is thus required to separate encapsulated islets from empty beads. Moreover, most of the implanted microbeads gather in the pelvic cavity, and a large number of islets in completely coated individual beads are required to achieve normoglycemia. Furthermore, the transplanted beads are difficult to retrieve, tend to be fragile, and release islets easily upon slight damage.
A macroencapsulation procedure has also been tested. Macrocapsules of various different materials, such as poly-2-hydroxyethyl-methacrylate, polyvinylchloride-c-acrylic acid, and cellulose acetate were made for the immunoisolation of islets. (See Altman, et al.,
Diabetes
35: 625 (1986); Altman, et al.,
Transplantation: American Society of Artificial Internal Organs
30: 382 (1984); Ronel, et al.,
Jour. Biomedical Material Research
17: 855 (1983); Klomp, et al.,
Jour. Biomedical Material Research
17: 865-871 (1983)). In all these studies, only a transitory normalization of glycemia was achieved.
Archer, et al.,
Journal of Surgical Research
28: 77 (1980), used acrylic copolymer hollow fibers to temporarily prevent rejection of islet xenografts. They reported long-term survival of dispersed neonatal murine pancreatic grafts in hollow fibers which were transplanted into diabetic hamsters. Recently Lacy, et al.,
Science
254: 1782-1784 (1991) confirmed their results, but found the euglycemic state to be a transient phase. They found that when the islets are injected into the fiber, they aggregate within the hollow tube with resultant necrosis in the central portion of the islet masses. The central necrosis precluded prolongation of the graft. To solve this problem, they used alginate to disperse the islets in the fiber. However, this experiment has not been repeated extensively. Therefore, the membrane's function as an islet transplantation medium in humans is questionable.
The Jain, et al. patent discussed supra reports that encapsulating secretory cells in a permeable, hydrophilic gel material results in a functional, non-innunogenic material, that can be transplanted into animals, can be stored for long lengths of time, and is therapeutically useful in vivo. The macroencapsulation of the secretory cells provided a more effective and manageable technique for secretory cell transplantation.
The patent does not discuss at any length the incorporation of cells capable of rapid proliferation.
A survey of the literature on encapsulation of cells reveals that, following encapsulation, cells almost always produce less of materials than they produce when not encapsulated. See Lloyd-George
Asina Shirin
Jain Kanti
Rubin Albert L.
Smith Barry
Stenzel Kurt
Fulbright & Jaworski LLP
Naff David M.
The Rogosin Institute
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