Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1998-08-28
2001-11-06
Azpuru, Carlos A. (Department: 2165)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S426000, C424S502000, C428S402210
Reexamination Certificate
active
06312731
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides bioactive agents encapsulated in a rapidly releasing polymeric composition capable of inducing or potentiating an immune response and methods for their use.
BACKGROUND OF THE INVENTION
Cytotoxic T lymphocytes (CTL) play a major role in both regulation of tumor growth and protection against infectious diseases. They recognize antigenic peptides, bound to MHC class I molecules, from either tumor associated antigens or antigens from infectious agents. These peptides are generated in the cytosol and then transferred into the endoplasmic reticulum where they bind to MHC class I molecules. The peptide-class I complex is then transported to the cell surface where it is displayed to CTLs. In order to induce or potentiate CTL responses, it is therefore generally necessary to introduce protein antigens into the cytoplasm.
One approach that has been used to introduce antigens into the MHC class I pathway is the use of recombinant infectious agents such as vaccinia virus, adenovirus, Listeria monocytogenes and other similar vectors. However, a number of safety concerns need to be addressed before infectious agents can have widespread acceptance in vaccine use. Other approaches involve conventional adjuvants, such as alum, or oil based materials, such as Montanide 720 or TiterMax, to deliver antigens in the form of emulsions. However, alum produces weak and variable CTL responses and typically is not effective at inducing immune responses to weak antigens. Oil based adjuvants present a toxicity issue that has not yet been satisfactorily addressed. Consequently, a number of new adjuvants, such as QS21 and AF, have been developed and demonstrate in some cases that they are capable of inducing CTL mediated responses. However, there remains a clear need for a delivery system that is biologically safe while being capable of inducing strong CTL responses against tumor or infectious disease antigens.
The use of microencapsulation to protect sensitive bioactive agents from degradation has become well known. Typically, a bioactive agent is encapsulated within a protective wall material, usually polymeric in nature. The polymer used to encapsulate the bioactive agent is typically a single copolymer or homopolymer. Example polymers for sutures, prostheses and other medical devices as well as drug and antigen carriers are polylactide, polyglycolide, and poly(lactide-co-glycolide). These polymers and copolymers have been utilized to elicit MHC class II responses. For example, U.S. Pat. No. 5,417,986 to Reid et al. discloses the delivery of an antigen using poly(lactide-co-glycolide) microspheres. The microencapsulated antigen was injected into rabbits to produce an antibody response.
Ertl et al. (Vaccine, 1996, vol. 14, no. 9, Peyer's patch 879-885) discloses the use of poly(lactide-co-glycolide) polymers to incorporate linear peptide epitopes as peptide vaccines in order to elicit a MHC class II responses. Hermann et al. (International Journal of Pharmaceutics, 1995, 126, Peyer's patch 129-138) discloses the preparation of biodegradable polyester microspheres of polylactide and poly(lactide-co-glycolide)) containing somatostatin, which is a peptide drug. Thomasin et al. (Journal of Controlled Release, 1996, 41, Peyer's patch 131-145) discloses the degradation of poly(lactide) and poly(lactide-co-glycolide) microspheres and the concurrent release of a natural and a synthetic antigen for eliciting an immune response in mice.
A combination of two or more types of polymeric microspheres that contain a bioactive agent have been made. Such combination microspheres have been shown to elicit MHC class II responses also. Men et al. (Vaccine, 1995, 13(7), Peyer's patch 683-689) discloses the combination, or a mixture, of microspheres that were separately prepared from poly(lactide) and poly(lactide-co-glycolide) respectively with a molecular weight ranging from 12,000 to 129,000 daltons, which contained tetanus toxoid as the bioactive agent. The microspheres elicited a T cell proliferative response and antibody production.
Although previous work in immunological delivery research has achieved delivery of strong antigens to elicit an immune response, such as a CTL response, there is a great need for delivery systems capable of effecting a CTL response to less immunogenic antigens. Such systems can be utilized to develop highly useful, effective vaccines. The present invention fills this need very effectively by providing compositions of an antigen encapsulated in microspheres that rapidly release the antigen once taken up by the cell to elicit a strong CTL response. The compositions are capable of inducing an immune response even against weakly immunogenic antigens. The inventive encapsulated antigens are thus capable of inducing an immune response and, in particular, a CTL response, sufficient for use as effective vaccines. Furthermore, the present invention also fulfills the need for effective vaccines by providing a means to potentiate any immune response by administering to a subject generating the immune response a bioactive agent capable of adjuvant function encapsulated in a microsphere that rapidly releases the bioactive agent. The improved delivery of the bioactive agent stimulates an improved immune response.
SUMMARY OF THE INVENTION
The present invention provides bioactive agents encapsulated in a rapidly releasing polymeric composition capable of inducing or potentiating an immune response and methods for their use.
In accordance with the purpose(s) of this invention, as embodied and broadly described herein, this invention, in one aspect, relates to a composition for inducing a CTL response in a subject, comprising an antigen or a nucleic acid encoding the antigen, encapsulated in a polymeric composition, wherein the polymeric composition comprises a blend of
(a) a polymer present in an amount sufficient to provide structural integrity to the polymeric composition, and
(b) a component selected from the group consisting of a rapidly biodegradable component, a rapidly dissolving component, a rapidly swelling component, and a component that causes osmotic rupture of the encapsulated polymeric composition.
The polymeric composition can further provide kinetics of antigen or nucleic acid release such that a CTL response is measurable within fourteen days of a single administration at a level of at least 30% cytotoxicity. The composition can further comprise a non-antigen bioactive agent capable of inducing or potentiating an immune response, or in particular, a CTL response. The non-antigen bioactive agent can be encapsulated in the polymeric composition or the non-antigen bioactive agent can be present in the composition unencapsulated.
The present invention also provides a composition for inducing a T helper cell response in a subject, comprising an antigen or a nucleic acid encoding the antigen, encapsulated in a polymeric composition, wherein the polymeric composition comprises a blend of
(a) a polymer present in an amount sufficient to provide structural integrity to the polymeric composition, and
(b) a component selected from the group consisting of a rapidly biodegradable component, a rapidly dissolving component, a rapidly swelling component, and a component that causes osmotic rupture of the encapsulated polymeric composition.
The polymeric composition can further provide kinetics of antigen or nucleic acid release such that a T helper cell response is measurable within fourteen days of a single administration at a level of at least two-fold over background as measured by T cell proliferation or cytokine induction.
Also provided is a composition for inducing a neutralizing antibody response in a subject, comprising an antigen or a nucleic acid encoding the antigen, encapsulated in a polymeric composition, wherein the polymeric composition comprises a blend of
(a) a polymer present in an amount sufficient to provide structural integrity to the polymeric composition, and
(b) a component selected from the group consisting of
Raychaudhuri Syamal
Sleath Paul R.
Staas Jay K.
Tice Thomas R.
Azpuru Carlos A.
Needle & Rosenberg P.C.
Southern Research Institute
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