Title:  Rapid release encapsulated bioactive agents for inducing or potentiating an immune response and methods of using thereof

United States Patent:  6,312,731

Assignee:  Southern Research Institute (Birmingham, AL); Corixa Corporation (Seattle, WA)

Filed:  August 28, 1998

A composition for inducing or potentiating an immune response, preferably a CTL, T helper cell, or neutralizing antibody response in a subject, comprising an antigen and/or a non-antigen bioactive agent capable of inducing or potentiating such an immune response 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 rapidly biodegradable component, a rapidly dissolving component, a rapidly swelling component, or a component that causes osmotic rupture of the encapsulated polymeric composition is disclosed. Single polymer compositions for achieving such an immune response are also disclosed. Methods for inducing or potentiating a CTL, T helper cell or neutralizing antibody response using the above-identified compositions are disclosed.

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 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 the neutralizing antibody response is detectable within fourteen days of a second or subsequent administration.

Additionally 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 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 the neutralizing antibody response is detectable within thirty days of a single administration.

Also provided is a composition for potentiating a preexisting CTL response to an antigen in a subject, comprising a bioactive agent 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 bioactive agent release such that the potentiated CTL response is measurable within fourteen days of a single administration at a level greater than the preexisting CTL response. The bioactive agent can comprise an antigen to which the immune response is induced or potentiated or a nucleic acid functionally encoding such an antigen.

Further provided is a composition for potentiating a preexisting T helper cell response to an antigen in a subject, comprising a bioactive agent 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 bioactive agent release such that the potentiated T helper cell response is measurable within fourteen days of a single administration at a level greater than the preexisting T helper cell response.

Additionally provided is a composition for potentiating a preexisting neutralizing antibody response to an antigen in a subject, comprising a bioactive agent 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 bioactive agent release such that the potentiated neutralizing antibody response is measurable within fourteen days of a second or subsequent administration at a level greater than the preexisting neutralizing antibody response.

Further provided is a composition for potentiating a neutralizing antibody response to an antigen in a subject, comprising a bioactive agent 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 bioactive agent release such that the potentiated neutralizing antibody response is detectable within thirty days of a single administration in at a level greater than the preexisting neutralizing antibody response.

The present invention further provides a method of inducing a CTL response in a subject, comprising administering to the subject an effective amount of a composition 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 providekinetics 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, thereby inducing the CTL response in the subject.

The present invention also provides a method of inducing a T helper cell response in a subject, comprising administering to the subject an effective amount of a composition 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, thereby inducing the T helper cell response in the subject.

Also provided is a method of inducing a neutralizing antibody response in a subject, comprising administering to the subject an effective amount of a composition 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 the neutralizing antibody response is detectable within fourteen days of a second or subsequent administration, thereby inducing the neutralizing antibody response in the subject.

Additionally provided is a method of inducing a neutralizing antibody response in a subject, comprising administering to the subject an effective amount of a composition 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 the neutralizing antibody response is detectable within thirty days of a single administration, thereby inducing the neutralizing antibody response in the subject.

Further provided by the present invention is a method of potentiating a preexisting CTL response to an antigen in a subject, comprising administering to the subject an effective amount of a composition comprising a bioactive agent 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 bioactive agent release such that the potentiated CTL response is measurable within fourteen days of a single administration at a level greater than the preexisting CTL response, thereby potentiating the preexisting CTL response in the subject.

The present invention further provides a method of potentiating a preexisting T helper cell response to an antigen in a subject, comprising administering to the subject an effective amount of a composition comprising a bioactive agent 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 bioactive agent release such that the potentiated T helper cell response is measurable within fourteen days of a single administration at a level greater than the preexisting T helper cell response, thereby potentiating the preexisting T helper response in the subject.

Further provided by the present invention is a method of potentiating a preexisting neutralizing antibody response to an antigen in a subject, comprising administering to the subject an effective amount of a composition comprising a bioactive agent 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 bioactive agent release such that the potentiated neutralizing antibody response is detectable within fourteen days of a second or subsequent administration at a level greater than the preexisting neutralizing antibody response, thereby potentiating the preexisting neutralizing antibody response in the subject.

The present invention also provides a method of potentiating a neutralizing antibody response to an antigen in a subject, comprising administering to the subject an effective amount of a composition comprising a bioactive agent 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 bioactive agent release such that the potentiated neutralizing antibody response is detectable within thirty days of a single administration at a level greater than the preexisting neutralizing antibody response, thereby potentiating the preexisting neutralizing antibody response in the subject.

The invention further relates to a method of inducing a CTL, T helper or neutralizing antibody response in a subject, comprising administering to the subject an effective amount of a composition comprising an antigen or a nucleic acid encoding the antigen, encapsulated in a polymeric composition, wherein the polymeric composition comprises a biodegradable polymer with a molecular weight of less than or equal to 7000 daltons.

The invention further relates to a method of inducing a CTL, T helper or neutralizing antibody response in a subject comprising administering to the subject an effective amount of a composition comprising an antigen or a nucleic acid encoding the antigen, encapsulated in a polymeric composition, wherein the polymeric composition comprises a rapidly biodegradable polymer with an inherent viscosity of less than 0.4 dL/g.

The invention further relates to a method for inducing a CTL, T helper cell or neutralizing antibody response in a subject, comprising administering to the subject an effective amount of a composition comprising an antigen or nucleic acid encoding the antigen, encapsulated in a polymeric composition, wherein the polymeric composition comprises an unblocked polymer of poly(lactide-co-glycolide), polylactide or polyglycolide.

The invention further relates to a method of potentiating a CTL, T helper or neutralizing antibody response in a subject, comprising administering to the subject an effective amount of a composition comprising a bioactive agent encapsulated in a polymeric composition, wherein the polymeric composition comprises a biodegradable polymer with a molecular weight of less than or equal to 7000 daltons.

The invention further relates to a method of potentiating a CTL, T helper or neutralizing antibody response in a subject, comprising administering to the subject an effective amount of a composition comprising a bioactive agent encapsulated in a polymeric composition, wherein the polymeric composition comprises a biodegradable polymer with an inherent viscosity of less than 0.4 dL/g.

The invention further relates to a method for potentiating a CTL, T helper cell or neutralizing antibody response in a subject, comprising a bioactive agent capable of potentiating a CTL, T helper cell or neutralizing antibody response encapsulated in a polymeric composition, wherein the polymeric composition comprises an unblocked polymer of poly(lactide-co-glycolide), polylactide or polyglycolide.

The invention further relates to a composition for inducing a CTL, T helper or neutralizing antibody response in a subject, comprising an effective amount of a composition comprising an antigen or a nucleic acid encoding the antigen, encapsulated in a polymeric composition, wherein the polymeric composition comprises a biodegradable polymer with a molecular weight of less than or equal to 7000 daltons.

The invention further relates to a composition for inducing a CTL, T helper or neutralizing antibody response in a subject, comprising an effective amount of a composition comprising an antigen or a nucleic acid encoding the antigen, encapsulated in a polymeric composition, wherein the polymeric composition comprises a biodegradable polymer with an inherent viscosity of less than 0.4 dL/g.

The invention further relates to a composition for inducing a CTL, T helper cell or neutralizing antibody response in a subject, comprising an effective amount of a composition comprising an antigen or nucleic acid encoding the antigen, encapsulated in a polymeric composition, wherein the polymeric composition comprises an unblocked polymer of poly(lactide-co-glycolide), polylactide or polyglycolide.

The invention further relates to a composition for potentiating a CTL, T helper or neutralizing antibody response in a subject, comprising an effective amount of a composition comprising a bioactive agent encapsulated in a polymeric composition, wherein the polymeric composition comprises a biodegradable polymer with a molecular weight of less than or equal to 7000 daltons.

The invention further relates to a composition for potentiating a CTL, T helper or neutralizing antibody response in a subject, comprising an effective amount of a composition comprising a bioactive agent encapsulated in a polymeric composition, wherein the polymeric composition comprises a biodegradable polymer with an inherent viscosity of less than 0.4 dL/g.

The invention further relates to a composition for potentiating a CTL, T helper cell or neutralizing antibody response in a subject, comprising an effective amount of a composition comprising a bioactive agent encapsulated in a polymeric composition, wherein the polymeric composition comprises an unblocked polymer of poly(lactide-co-glycolide), polylactide or polyglycolide.

Claim 1 of 56 Claims

What is claimed is:

1. A method of inducing or potentiating a CTL response in a subject, comprising administering to the subject an effective amount of a composition 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 thereby inducing or potentiating the CTL response in the subject.

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