Drug – bio-affecting and body treating compositions – Nonspecific immunoeffector – per se ; or nonspecific... – Synthetic polymer or copolymer
Reexamination Certificate
1999-03-25
2001-03-27
Salimi, Ali R. (Department: 1648)
Drug, bio-affecting and body treating compositions
Nonspecific immunoeffector, per se ; or nonspecific...
Synthetic polymer or copolymer
C424S204100, C424S001110, C424S209100, C435S005000, C536S001110, C514S075000, C514S110000, C514S114000, C514S137000
Reexamination Certificate
active
06207171
ABSTRACT:
Current research in vaccine development has focused on treatment requiring a single administration, since the major disadvantage of many currently available vaccines is that repeated administrations are required. The ability now exists to provide the controlled release of proteins through microencapsulation of proteins in water soluble polymers thus making single administration vaccines possible. Microencapsulation has been applied to the development of vaccines for administration by both parenteral and mucosal routes. A frequent choice of carrier used in these vaccines is poly (d,1-lactide-co-glycolide) (PLGA), a biodegradable polyester that has a long history of medical use in erodible sutures, bone plates and other temporary prostheses. Adaptation of PLGA for the controlled release of antigen has been described (Eldrige, J. H. et al.,
Curr. Top. Microbiol. Immunol.,
146:59-66 (1989); Eldrige, J. H. et al.,
Infect. Immun.,
59:2978-2986 (1991)). The entrapment of antigens in PLGA microspheres of 1 to 10 microns in diameter has been shown to enhance immune responses. However, the PLGA system requires the use of organic solvents and long preparation times for microencapsulation of antigens, which may adversely affect the immunogenicity of the antigens, particularly labile antigens.
Ionically cross-linkable water soluble polymers, poly[di(carboxylatophenoxy)phosphazene]s (PCPPs) have been developed (Allcock, H. R. and S. Swan,
Macromolecules,
22:75-79 (1989)). In the soluble state, PCPP has been demonstrated to have adjuvant activity (U.S. Pat. No. 5,494,673) and has enhanced the immunogenicity of various antigens (Payne, L. G. et al.,
Vaccine,
16:92-98(1998)). Generally, the addition of PCPP to antigen preparations has enhanced functional hemagglutination inhibition (HAI) antibody response and has enhanced IgM, IgG, and IgG1 ELISA antibody titers over the levels elicited by vaccine alone. PCPP as an adjuvant has been demonstrated to be as efficient as or to outperform complete Freund's adjuvant. The immunogenicity of antigens as diverse as tetanus toxoid, hepatitis B surface antigen,
Hemophilus influenzae
type b polyribosribotolphosphate, herpes simplex virus type 2 glycoprotein D and HIV env has been dramatically enhanced in the presence of soluble PCPP (Payne, L. G. et al.,
Modulation of the Immune Response to Vaccine Antigens,
Lars Haaheim, ed, Geneva (1997); Lu, Y. et al.,
J. AIDS Human Retrovirol.,
12:99-106 (1996)).
Polymeric hydrogel microspheres can be prepared from PCPP which encapsulate antigens and that, throughout their preparation, are exposed only to an aqueous environment (Cohen, S. et al.,
J. Am. Chem. Soc.,
112:78320-7833 (1990); Payne, L. G. et al.,
Adv. Exp. Med. Biol.,
McGee, J. R. and J. Mestecky, eds, New York (1994)). In microencapsulation, the antigen is entrapped in the microsphere matrix during the generation of the microspheres. Water soluble PCPP and antigen solution are formulated into hydrogel microspheres by cross-linking carboxyl groups with divalent cations (Payne, 1994). Gelation by ionic crosslinking of the aqueous based polymer solution at room temperature has eliminated long exposure to organic solvents, elevated temperatures and drying required for polymers dissolved in organic solvents, thus maintaining antigenic integrity.
These microspheres are suitable for parenteral or mucosal immunization (Payne, L. G. et al.,
Vaccine Design,
Powell, M. F. and M. J. Neuman, eds, New York (1995)). The hydrogel properties of these microspheres allow a sustained antigen release to maximally stimulate the immune response over a long period.
Two methods have been developed to generate PCPP microspheres: a spray method (see U.S. Pat. No. 5,529,777) and an aqueous coacervation method (see U.S. patent application Ser. No. 08/675,713). We have previously demonstrated that antigens encapsulated in ionically-crosslinked PCPP microspheres formed by a spray methodology were able to induce an immune response when administered by a mucosal route. Microencapsulated proteins produced by coacervation methodology eliminates the use of organic solvents and heat used in preparing PLGA microspheres, and avoids the complicated manufacturing equipment and generation of aerosols required for producing spray microspheres.
SUMMARY OF THE INVENTION
It is an object of the present invention to produce an antigen-microsphere formulation by adsorbing the antigen onto preformed microspheres. The present invention describes a polymeric microsphere structure that can efficiently adsorb and/or absorb antigen from a solution. The novel antigen/microsphere formulations provide enhanced immune responses in animals to the antigen. Applicants have found that an immune response against antigen is enhanced by administration of polyphosphazene microspheres in which the antigen is simply absorbed, adsorbed or linked to the surface of the microsphere after production of the microsphere.
REFERENCES:
patent: 5494673 (1996-02-01), Andrianov et al.
patent: 5529777 (1996-06-01), Andrianov et al.
patent: 5562909 (1996-10-01), Allcock et al.
patent: 5855895 (1999-01-01), Andrianov et al.
O'Hagan, et al.,Vaccine,vol. 7, pp. 213-216 (Jun. 1989).
O'Hagan, et al.,Vaccine,vol. 7, pp. 421-424 (Oct. 1989).
Payne et al. 1998, Vaccine, vol. 16, No. 1, pp. 92-98, Jan. 1998.*
Andrianov et al, 1998, Biomaterials, vol. 19, pp. 109-115, Jan. 1998.
Jenkins Sharon A.
Payne Lendon G.
Woods Angela L.
AVANT Immunotherapeutics, Inc.
Lillie Raymond J.
Olstein Elliot M.
Salimi Ali R.
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