CN117320717A - Synthetic nanocarriers comprising immunosuppressants in combination with high affinity IL-2 receptor agonists to enhance immune tolerance - Google Patents
Synthetic nanocarriers comprising immunosuppressants in combination with high affinity IL-2 receptor agonists to enhance immune tolerance Download PDFInfo
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Abstract
Methods and related compositions for administering high affinity IL-2 receptor agonists in combination with immunosuppressants are disclosed. The provided methods and compositions are useful for enhancing regulatory T cells, including antigen specific regulatory T cells.
Description
RELATED APPLICATIONS
The present application claims the following priority benefits in accordance with 35u.s.c. ≡119 (e): U.S. provisional application Ser. No.63/173,333 filed on 4/9 of 2021; U.S. provisional application Ser. No.63/228,931 filed 8/3/2021; U.S. provisional application Ser. No.63/240,749 filed on 9/3 of 2021; U.S. provisional application Ser. No.63/274,626 filed on 11/2 of 2021; U.S. provisional application Ser. No.63/274,706, filed 11/2/2021; U.S. provisional application Ser. No.63/274,673, filed 11/2/2021; and U.S. provisional application Ser. No.63/304,255, filed on 1/28 of 2022, each of which is incorporated herein by reference in its entirety.
Technical Field
The present invention relates, at least in part, to methods for administering high affinity IL-2 receptor agonists in combination with immunosuppressants, and related compositions. The methods and compositions provided herein can be used to enhance regulatory T cell (also referred to herein as Treg) induction, expansion, and/or persistence in a non-antigen specific manner and/or in an antigen specific manner. In some embodiments, the methods and compositions provided herein can be used to enhance antigen-specific immune responses, such as antigen-specific immune responses of regulatory T cells. Thus, in some embodiments, the method may further comprise concomitantly administering an antigen with the high affinity IL-2 receptor agonist and immunosuppressant. In some embodiments, the compositions (e.g., kits) provided herein can include an antigen, for example, for which an antigen-specific tolerogenic immune response is desired. The methods and compositions provided herein may allow a shift to a tolerogenic immune response to occur, such as antigen-specific regulatory T cell production or development, a decrease in cd8+ T cell count in the liver, and/or an increase in CD4-CD 8-double negative cell count in the liver and spleen. The methods and compositions provided herein can be used in subjects that would benefit from the generation and/or enhancement of a tolerogenic immune response (e.g., antigen-specific regulatory T cell immune response), or from the reduction of cytotoxic T cell activity.
Disclosure of Invention
An undesired immune response may be triggered by exposure to a specific antigen, such as a therapeutic macromolecule, an autoantigen or allergen, or an antigen associated with an inflammatory disease, autoimmune disease, organ or tissue rejection, or graft versus host disease. Such undesired immune responses may be reduced by the use of immunosuppressive drugs. However, traditional immunosuppressive drugs are widely available. In addition, immunosuppressive drug therapy is often a life-long recommendation in order to maintain immunosuppression. Unfortunately, the use of widely acting immunosuppressants may also be associated with the risk of serious side effects (e.g. tumors, infections, nephrotoxicity and metabolic disorders).
Thus, new tolerogenic therapies that can induce and expand regulatory T cell production and development, reduce cd8+ T cell numbers, and/or increase double-negative (DN) T cells (e.g., CD4-CD8-T cells) can be beneficial in suppressing unwanted immune responses. High affinity IL-2 receptor agonists may be or are specifically engineered to preferentially bind to and/or activate existing regulatory T cells. Combination therapy with high affinity IL-2 receptor agonists and immunosuppressants (and in some embodiments in the presence or administration of an antigen) may provide an increased tolerogenic immune response, for example, by expanding existing regulatory T cells and/or by inducing and/or expanding regulatory T cells that may be antigen-specific. Surprisingly, it has been found that a combination therapy with a high affinity IL-2 receptor agonist and an immunosuppressant can synergistically induce and/or expand existing regulatory T cells and/or induce and/or expand antigen specific regulatory T cells. It has also been unexpectedly found that combination therapy can prolong the persistence of expanded regulatory T cells. In addition, it has surprisingly been found that combination therapy synergistically induces and/or expands antigen-specific regulatory T cells in the presence of an antigen.
In one aspect, compositions comprising an immunosuppressant (e.g., a synthetic nanocarrier comprising an immunosuppressant) and a high affinity IL-2 receptor agonist are provided. In some embodiments, the composition further comprises an antigen. In some embodiments, the antigen and the high affinity IL-2 receptor agonist are each not co-formulated with an immunosuppressant (e.g., a synthetic nanocarrier comprising an immunosuppressant). In one embodiment of any one of the compositions provided herein, the composition further comprises a pharmaceutically acceptable excipient.
One aspect of the present disclosure provides a dosage form comprising any of the compositions described herein.
In another aspect, methods are provided that include administering to a subject in need thereof a composition comprising an immunosuppressant (e.g., a synthetic nanocarrier comprising an immunosuppressant) and a composition comprising a high affinity IL-2 receptor agonist. In one embodiment, the method further comprises administering to the subject a composition comprising an antigen. In one embodiment, administration of an immunosuppressant (e.g., a synthetic nanocarrier comprising an immunosuppressant) and a high affinity IL-2 receptor agonist is performed to a subject in which an antigen is present and against which a tolerogenic immune response is desired.
In one embodiment of any one of the methods provided herein, the subject is concomitantly administered an immunosuppressant (e.g., a synthetic nanocarrier comprising an immunosuppressant) and a high affinity IL-2 receptor agonist. In one embodiment of any one of the methods provided herein, the subject is concomitantly administered an immunosuppressant (e.g., a synthetic nanocarrier comprising an immunosuppressant), a high affinity IL-2 receptor agonist, and an antigen.
In one embodiment of any one of the methods or compositions provided herein, the antigen induces an undesired immune response in the subject. In one embodiment of any one of the methods or compositions provided herein, the antigen is an antigen against which a tolerogenic immune response is desired.
In another embodiment of any one of the methods provided herein, the administering is performed in an amount effective to produce an increased number (e.g., in percent (or ratio)) of regulatory T cells (e.g., existing and/or induced regulatory T cells), and/or an increased persistence of regulatory T cells and/or a decreased number of hepatic cd8+ T cells and/or an increased double negative CD4-CD8- (DN) T cell count (e.g., in the liver and spleen). In some embodiments, existing and/or induced regulatory T cells may be antigen specific.
In another embodiment of any one of the methods provided herein, the subject has or is at risk of having an inflammatory disease, an autoimmune disease, an allergy, organ or tissue rejection, or graft versus host disease. In another embodiment of any one of the methods provided herein, the subject has undergone or will undergo transplantation. In another embodiment of any one of the methods provided herein, the subject has or is at risk of having an undesired immune response against an antigen being administered or to be administered to the subject.
In another embodiment of any one of the methods or compositions provided herein, the antigen is a therapeutic macromolecule, an autoantigen, or an allergen, or an antigen associated with an inflammatory disease, an autoimmune disease, organ or tissue rejection, or graft versus host disease, or is any one of a therapeutic macromolecule, an autoantigen, or an allergen, or an antigen associated with an inflammatory disease, an autoimmune disease, organ or tissue rejection, or graft versus host disease. In another embodiment of any one of the methods or compositions provided herein, the therapeutic macromolecule is a therapeutic protein or therapeutic polynucleotide.
In another embodiment of any one of the methods or compositions provided herein, the therapeutic protein is for protein replacement or protein supplementation therapy.
In another embodiment of any one of the methods or compositions provided herein, the therapeutic macromolecule comprises an infusible or injectable therapeutic protein, an enzyme cofactor, a hormone, blood or clotting factor, a cytokine, an interferon, a growth factor, a monoclonal antibody, a polyclonal antibody, or a protein associated with Pompe's disease.
In another embodiment of any one of the methods or compositions provided herein, the therapeutic macromolecule is a therapeutic polynucleotide, such as a viral vector (or also referred to herein as a viral transfer vector).
In another embodiment of any one of the methods or compositions provided herein, the immunosuppressant comprises a statin, an mTOR inhibitor, a TGF- β signaling agent, a corticosteroid, a mitochondrial function inhibitor, a P38 inhibitor, an NF- κb inhibitor, an adenosine receptor agonist, a prostaglandin E2 agonist, a phosphodiesterase 4 inhibitor, an HDAC inhibitor, or a proteasome inhibitor. In another embodiment of any one of the methods or compositions provided herein, the mTOR inhibitor is rapamycin (rapamycin) or a rapamycin analog.
In another embodiment of any one of the methods or compositions provided herein, the synthetic nanocarriers comprise lipid nanoparticles, polymer nanoparticles, metal nanoparticles, surfactant-based emulsions, dendrimers, buckyballs, nanowires, virus-like particles, or peptide or protein particles. In another embodiment of any one of the methods or compositions provided herein, the synthetic nanocarriers comprise a lipid nanoparticle. In another embodiment of any one of the methods or compositions provided herein, the synthetic nanocarriers comprise a liposome. In another embodiment of any one of the methods or compositions provided herein, the synthetic nanocarriers comprise a metal nanoparticle. In another embodiment of any one of the methods or compositions provided herein, the metal nanoparticles comprise gold nanoparticles. In another embodiment of any one of the methods or compositions provided herein, the synthetic nanocarriers comprise a polymeric nanoparticle.
In another embodiment of any one of the methods or compositions provided herein, the polymeric nanoparticle comprises a polymer that is a non-methoxy-terminated pluronic (pluronic) polymer. In another embodiment of any one of the methods or compositions provided herein, the polymeric nanoparticle comprises a polyester, a polyester coupled with a polyether, a polyamino acid, a polycarbonate, a polyacetal, a polyketal, a polysaccharide, a polyethyl Oxazolines or polyethylenimines. In another embodiment of any one of the methods or compositions provided herein, the polyester comprises poly (lactic acid), poly (glycolic acid), poly (lactic-co-glycolic acid), or polycaprolactone. In another embodiment of any one of the methods or compositions provided herein, the polymeric nanoparticle comprises a polyester and a polyester coupled to a polyether. In another embodiment of any one of the methods or compositions provided herein, the polyether comprises polyethylene glycol or polypropylene glycol.
In another embodiment of any one of the methods or compositions provided herein, the mean value of the particle size distribution of the synthetic nanocarriers obtained using dynamic light scattering is greater than 100nm in diameter. In another embodiment of any one of the methods or compositions provided herein, the diameter is greater than 110nm, 120nm, 130nm, 140nm, or 150nm. In another embodiment of any one of the methods or compositions provided herein, the diameter is greater than 200nm. In another embodiment of any one of the methods or compositions provided herein, the diameter is greater than 250nm. In another embodiment of any one of the methods or compositions provided herein, the diameter is greater than 300nm. In another embodiment of any one of the methods or compositions provided herein, the diameter is less than 500nm. In another embodiment of any one of the methods or compositions provided herein, the diameter is less than 450nm. In another embodiment of any one of the methods or compositions provided herein, the diameter is less than 400nm. In another embodiment of any one of the methods or compositions provided herein, the diameter is less than 350nm.
In another embodiment of any one of the methods or compositions provided herein, the aspect ratio of the synthetic nanocarriers is greater than or equal to 1:1, 1:1.2, 1:1.5, 1:2, 1:3, 1:5, 1:7, or 1:10.
In another embodiment of any one of the methods or compositions provided herein, the immunosuppressant is present on the synthetic nanocarrier population at an average loading of 0.1% to 50% (w/w). In another embodiment of any one of the methods or compositions provided herein, the immunosuppressant is present at an average loading on the synthetic nanocarrier of 0.1% to 30% (w/w). In another embodiment of any one of the methods or compositions provided herein, the immunosuppressant is present at an average loading of 0.1% to 25% (w/w) on the synthetic nanocarrier. In another embodiment of any one of the methods or compositions provided herein, the loading of immunosuppressant is 0.1% to 10% (w/w). In another embodiment of any one of the methods or compositions provided herein, the immunosuppressant is present on the synthetic nanocarrier at an average loading of 1% to 50% (w/w). In another embodiment of any one of the methods or compositions provided herein, the immunosuppressant is present on the synthetic nanocarrier at an average loading of 1% to 30% (w/w). In another embodiment of any one of the methods or compositions provided herein, the immunosuppressant is present on the synthetic nanocarrier at an average loading of 1% to 25% (w/w). In another embodiment of any one of the methods or compositions provided herein, the loading of immunosuppressant is 1% to 10% (weight/weight). In another embodiment of any one of the methods or compositions provided herein, the immunosuppressant is present on the synthetic nanocarrier at an average loading of 2% to 50% (w/w). In another embodiment of any one of the methods or compositions provided herein, the immunosuppressant is present on the synthetic nanocarrier at an average loading of 2% to 30% (w/w). In another embodiment of any one of the methods or compositions provided herein, the immunosuppressant is present on the synthetic nanocarrier at an average loading of 2% to 25% (w/w). In another embodiment of any one of the methods or compositions provided herein, the loading of immunosuppressant is 2% to 10% (weight/weight). In another embodiment of any one of the methods or compositions provided herein, the immunosuppressant is present on the synthetic nanocarrier at an average loading of 4% to 50% (w/w). In another embodiment of any one of the methods or compositions provided herein, the immunosuppressant is present on the synthetic nanocarrier at an average loading of 4% to 30% (w/w). In another embodiment of any one of the methods or compositions provided herein, the immunosuppressant is present on the synthetic nanocarrier at an average loading of 4% to 25% (w/w). In another embodiment of any one of the methods or compositions provided herein, the loading of immunosuppressant is from 4% to 10% (weight/weight). In another embodiment of any one of the methods or compositions provided herein, the immunosuppressant is present on the synthetic nanocarrier at an average loading of 8% to 50% (w/w). In another embodiment of any one of the methods or compositions provided herein, the immunosuppressant is present on the synthetic nanocarrier at an average loading of 8% to 30% (w/w). In another embodiment of any one of the methods or compositions provided herein, the immunosuppressant is present on the synthetic nanocarrier at an average loading of 8% to 25% (w/w).
In another embodiment of any one of the methods or compositions provided herein, the synthetic nanocarriers comprise a poly (lactic acid) polymer and/or a poly (lactic acid) coupled to a polyethylene glycol polymer.
Drawings
Figures 1A to 1C show the effect of injection of ImmTOR and IL-2 muteins alone and in combination on CD4 (figure 1A), CD25 (figure 1B) and FoxP3 (figure 1C) expression in spleen T cells.
FIGS. 2A-2B show the effect of injection of ImmmTOR and IL-2 muteins alone and in combination on spleen CD8+ (FIG. 2A) and CD4-CD8- (FIG. 2B) T cell counts.
FIGS. 3A to 3C show the effect of injection of ImmTOR and IL-2 muteins alone and in combination on CD4 (FIG. 3A), CD25 (FIG. 3B) and FoxP3 (FIG. 3C) expression in hepatic T cells
Figures 4A to 4B show the effect of injection of ImmTOR and IL-2 muteins alone and in combination on liver cd8+ (figure 4A) and CD4-CD8- (figure 4B) T cell counts.
Figure 5 shows the effect of injection of ImmTOR and IL-2 mutein alone and in combination on Treg counts in the spleen in a 14 day experiment, with measurement time points of 4, 7 and 14 days after treatment.
Fig. 6 is a schematic diagram showing such: the IL-2 mutein is combined with ImmTOR and an antigen to induce and amplify the synergistic effect of tregs specific for the antigen.
Figure 7 shows total Treg counts and OVA-specific Treg counts in the spleen of mice administered ImmTOR, IL-2 muteins and/or ovalbumin.
Fig. 8 shows the results from the following: two doses of AAV8 vector were administered on days 0 and 56, with or without the ImmTOR +/-IL-2 mutein administered on days 0 and 56.
Detailed Description
Before describing the present invention in detail, it is to be understood that this invention is not limited to particular example materials or process parameters, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only, and is not intended to be limiting of the use of alternative terminology for the description of the invention.
All publications, patents, and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety for all purposes.
As used in this specification and the appended claims, a noun without quantitative word modification includes a plural referent unless otherwise specifically stated. For example, reference to "a polymer" includes a mixture of two or more such molecules or a mixture of a single polymer species of different molecular weights, reference to "a synthetic nanocarrier" includes a mixture of two or more such synthetic nanocarriers or a plurality of such synthetic nanocarriers, reference to "a therapeutic molecule" includes a mixture of two or more such therapeutic molecules or a plurality of such therapeutic molecules, reference to "an immunosuppressant" includes a mixture of two or more such immunosuppressant molecules, and the like.
The term "comprises," "comprising," or any other variation thereof, such as "including" or "containing," as used herein, are to be interpreted as including any recited integer (e.g., feature, element, characteristic, property, method/process step, or limitation) or group of integers (e.g., feature, element, characteristic, property, method/process step, or limitation) but not excluding any other integer or group of integers. Thus, the term "comprising" as used herein is inclusive and does not exclude additional unrecited integers or method/process steps.
In some embodiments of any one of the compositions and methods provided herein, "comprise" is replaced with "consisting essentially of. The phrase "consisting essentially of" is used herein to claim the specified integers or steps as well as those that do not materially affect the characteristics or functions of the claimed invention. The term "consisting of" as used herein is used to mean that only the recited whole (e.g., feature, element, characteristic, property, method/process step, or limitation) or a group of whole (e.g., feature, element, characteristic, property, method/process step, or limitation) exists.
A. Introduction to the invention
As previously mentioned, current conventional immunosuppressants are widely available and generally result in an overall systemic down-regulation of the immune system. The methods and compositions provided herein allow for more targeted immunization, and in particular, enhance the production and persistence of regulatory T cells (e.g., cd4+ regulatory T cells), and/or the modulation of cytotoxic cd8+ T cells and/or double negative CD4-CD8- (DN) T cells in an antigen-specific and/or non-antigen-specific manner. Surprisingly, it has been found that synergy can be achieved by practicing the methods or administering the compositions provided herein. For example, it has been unexpectedly discovered that treatment with a combination of a high affinity IL-2 receptor agonist and an immunosuppressant synergistically expands all existing regulatory T cells. It has also been unexpectedly found that combination therapy can prolong the persistence of expanded regulatory T cells. In addition, it has surprisingly been found that combination therapy synergistically induces and/or expands antigen-specific regulatory T cells in the presence of an antigen.
It has also been found that the methods and compositions described herein result in decreased cd8+ T cell counts in the liver and increased DN T cells in the liver and spleen. As described herein, combination therapy with a high affinity IL-2 receptor agonist and an immunosuppressant (and in some embodiments in the presence or administration of an antigen) can provide an improved antigen-specific immune response. Such a combination may expand induced regulatory T cells (which may be antigen specific), reduce cd8+ T cells in the liver and/or increase the number of CD4-CD8-T cells in the liver and/or spleen, thereby increasing the efficacy and persistence of the immune response. Thus, such methods and compositions may result in a reduction of an undesired immune response specific to a particular antigen (e.g., a therapeutic macromolecule, an autoantigen or allergen, or an antigen associated with an inflammatory disease, autoimmune disease, organ or tissue rejection, or graft versus host disease). The methods and compositions described herein can provide an immune response that is tolerogenic to a particular antigen or antigen-specific.
The present invention will now be described in more detail below.
B. Definition of the definition
By "administering" or variations thereof is meant providing a substance to a subject in a pharmacologically useful manner. In some embodiments, the term is intended to include "causing administration (causing to be administered)". By "causing administration" is meant directly or indirectly causing, supervising, encouraging, assisting, inducing or directing the administration of the substance by another party.
In the context of a composition or dosage form for administration to a subject, an "effective amount" refers to an amount of the composition or dosage form that produces one or more desired immune responses in the subject, e.g., an increase in the production or development of a tolerogenic immune response, e.g., regulatory T cells (e.g., cd4+ regulatory T cells, such as those specific for a particular antigen), e.g., a therapeutic macromolecule, an autoantigen or allergen, or an antigen associated with an inflammatory disease, an autoimmune disease, organ or tissue rejection, or graft versus host disease. Thus, in some embodiments, an effective amount is an amount of a composition or combination of compositions provided herein that produces one or more desired immune responses, which may or may not be, for example, an increase in the number or percentage (or ratio) of antigen-specific regulatory T cells (e.g., cd4+ regulatory T cells), and/or a decrease in the number or percentage (or ratio) of hepatic cd8+ T cells, and/or an increase in the count of Double Negative (DN) (CD 4-cd8-) T cells in the liver and/or spleen. The effective amount may be used for in vitro or in vivo purposes. For in vivo purposes, the amount may be an amount that a clinician deems to have clinical benefit for a subject who may experience an undesired immune response against an antigen (e.g., a therapeutic macromolecule, an autoantigen or allergen, or an antigen associated with an inflammatory disease, autoimmune disease, organ or tissue rejection, or graft versus host disease).
An effective amount may be directed to reducing the level of an undesired immune response, but in some embodiments it is directed to completely preventing an undesired immune response. An effective amount may also be related to delaying the onset of an undesired immune response. An effective amount may also be an amount of a composition or combination of compositions provided herein that results in an increase in the production or development or persistence of regulatory T cells (e.g., cd4+) such as antigen-specific regulatory T cells (e.g., cd4+) and/or a decrease in the number of hepatic cd8+ T cells and/or an increase in DN T cell count in the liver and/or spleen. In particular, the increase in production or development may be an increase in the percentage (or ratio) of the number of such cells. The increase may also be an increase in the activity of such cells. The improvement may also be an improvement in the persistence of such cells. An effective amount may also be an amount that results in a desired therapeutic endpoint or a desired therapeutic outcome. An effective amount preferably achieves a tolerogenic immune response in a subject against an antigen. The implementation of any of the foregoing may be monitored by conventional methods.
In some embodiments of any one of the compositions and methods provided, the effective amount is an amount wherein the desired immune response persists in the subject for at least 1 week, at least 2 weeks, or at least 1 month. In other embodiments of any one of the compositions and methods provided, an effective amount is an amount that produces a measurable desired immune response (e.g., a decrease in a measurable immune response (e.g., an immune response to a particular antigen)) for at least 1 week, at least 2 weeks, or at least 1 month.
Of course, the effective amount will depend on the particular subject being treated; the severity of the condition, disease or disorder; individual patient parameters include age, physical condition, size, and weight; duration of treatment; the nature of concurrent therapy (if any); the particular route of administration and like factors within the knowledge and expertise of the health practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with only routine experimentation. It is generally preferred to use the maximum dose, i.e. the highest safe dose according to sound medical judgment. However, one of ordinary skill in the art will appreciate that the patient may adhere to lower doses or tolerable doses for medical reasons, psychological reasons, or virtually any other reason.
In general, the dosage of a high affinity IL-2 receptor agonist, immunosuppressant and/or antigen refers to the amount of the high affinity IL-2 receptor agonist, immunosuppressant and/or antigen. Alternatively, in some embodiments, the dose may be administered based on the amount of synthetic nanocarriers that provide the desired amount of immunosuppressant and/or antigen (e.g., synthetic nanocarriers that comprise immunosuppressant and/or antigen). "antigen-specific" refers to any immune response caused by or resulting in the presence of an antigen or portion thereof that specifically recognizes or binds to a molecule of an antigen. For example, where the immune response is antigen-specific antibody production, antibodies are produced that specifically bind to the antigen. As another example, the immune response is the generation of regulatory T cells (which may be cd4+ regulatory T cells) that bind to antigen that can be presented by an antigen-presenting cell (APC) when presented by the APC.
By "assessing an immune response" is meant any measurement or determination of the level, presence or absence, decrease, increase, etc. of an immune response in vitro or in vivo. Such measurements or determinations may be made on one or more samples obtained from the subject. Such assessment may be performed using any of the methods provided herein or other methods known in the art. The assessment may be an assessment of the number or percentage of regulatory T cells (e.g. cd4+ regulatory T cells, such as those specific for a particular antigen), for example in a sample from the subject.
"attached" or "linked" or "coupled" (etc.) means that one entity (e.g., a portion) is chemically associated with another entity. In some embodiments, the linkage is covalent, meaning that the linkage occurs in the presence of a covalent bond between the two entities. In some non-covalent embodiments, the non-covalent linkage is mediated by non-covalent interactions including, but not limited to, charge interactions, affinity interactions, metal coordination, physical adsorption, host-guest interactions (host-guest interactions), hydrophobic interactions, TT stacking interactions, hydrogen bonding interactions, van der Waals interactions, magnetic interactions, electrostatic interactions, dipole-dipole interactions, and/or combinations thereof. In some embodiments, the encapsulation is a form of attachment.
An "autoimmune disease" is a disease in which the immune system fails to recognize the subject's own organs, tissues or cells and generate an immune response to attack those organs, tissues or cells as if they were foreign antigens. Autoimmune diseases are well known in the art; for example, as disclosed in The Encyclopedia of Autoimmune Diseases, dana k.cassell, noel r.rose, infobase Publishing,14may 2014, the entire contents of which are incorporated by reference as if fully disclosed herein.
As used herein, "average" refers to an arithmetic average, unless otherwise indicated.
By "coformulation" is meant processing of specified substances to produce filled and final pharmaceutical dosage forms, wherein the substances are in intimate physical contact or chemically linked, either covalently or non-covalently. As used herein, "non-coformulation" means that the specified substances are not in intimate physical contact and are not chemically linked. In some embodiments, the high affinity IL-2 receptor agonists, immunosuppressants, and/or antigens described herein are not co-formulated prior to administration to a subject.
As used herein, the term "combination therapy" is intended to define a therapy comprising the use of a combination of two or more substances/agents. Thus, references in this application to "combination therapy", "combination", and "in combination" use of a substance/agent may refer to a substance/agent administered as part of the same overall treatment regimen. Thus, the respective dosimetry of two or more substances/agents may be different: each may be administered at the same time or at different times. Thus, it should be understood that the combined substances/agents may be administered sequentially (e.g., before or after) or simultaneously (in the same pharmaceutical formulation (i.e., together) or in different pharmaceutical formulations (i.e., separately)). In the same formulation, it is referred to as a single (unit) formulation at the same time, while in different pharmaceutical formulations it is not single at the same time. In combination therapy, the dosimetry of each of the two or more substances/agents may also vary depending on the route of administration.
By "concomitant" is meant that two or more substances/agents are administered to a subject in a manner that is correlated in time (preferably sufficiently correlated in time) to provide modulation of an immune response or some other beneficial effect, and even more preferably, the two or more substances/agents are administered in combination. In some embodiments, concomitant administration may encompass administration of two or more substances/agents within a specified period of time (preferably within 1 month, more preferably within 1 week, still more preferably within 1 day, and even more preferably within 1 hour). In some embodiments, the substance/agent may be repeatedly concomitantly administered; it is concomitantly administered at more than one occasion.
"determining" and variations thereof mean determining a factual relationship. The determination may be accomplished in a number of ways, including but not limited to, performing an experiment or making a prediction. For example, the dose of high affinity IL-2 receptor agonist, immunosuppressant and/or antigen can be determined by starting with the test dose and using known scaling techniques, such as isovelocity or isovelocity scaling (allometric or isometric scaling), to determine the dose for administration. This may also be used to determine a scheme as provided herein. In another embodiment, the dose may be determined by testing multiple doses in the subject, i.e., by direct experimentation based on empirical and instructional data. In some embodiments, "determining" and variations thereof include "causing to be determined". "cause determined" means causing, promoting, encouraging, helping, inducing, or directing an entity or coordinating actions with an entity to determine a factual relationship; including directly or indirectly, or explicitly or implicitly.
"dosage form" means a pharmacologically and/or immunologically active substance in a medium, carrier, vehicle or device suitable for administration to a subject. Any of the compositions or dosages provided herein may be in a dosage form.
"dose" refers to a specific amount of a pharmacologically and/or immunologically active substance for administration to a subject at a given time.
"encapsulating" means encapsulating at least a portion of a substance within a synthetic nanocarrier. In some embodiments, the substance is completely encapsulated within the synthetic nanocarrier. In other embodiments, most or all of the encapsulated material is not exposed to the local environment external to the synthetic nanocarriers. In other embodiments, no more than 50%, 40%, 30%, 20%, 10%, or 5% (weight/weight) is exposed to the localized environment. Encapsulation is distinguished from absorption, which is the placement of a substantial portion or all of a substance on the surface of a synthetic nanocarrier and the exposure of the substance to the local environment outside the synthetic nanocarrier.
By "enhancing the number or percentage of regulatory T cells" is meant increasing the number of the cells or percentage (or ratio) of the total cell type in one or more subjects, as determined by taking a sample from one or more subjects and then assaying the sample using a suitable test method. In some embodiments, the percentage of regulatory T cells (e.g., cd4+ regulatory T cells, such as those specific for a particular antigen) is increased by at least 2-fold, 3-fold, 4-fold, 5-fold, or 6-fold or more by practicing the methods provided herein or following administration of the compositions described herein.
Cd4+ regulatory T cells may be characterized as cd4+cd25+foxp3+ cells. The number or percentage of cd4+ regulatory T cells may be assessed by any method described herein or known in the art. For example, cd4+ regulatory T cells in peripheral blood of a subject can be quantified by: peripheral blood samples are obtained from the subject to assess gene expression, protein presence and/or localization of one or more molecules associated with cd4+ regulatory T cells (including but not limited to CD25, foxP3, CCR4, CCR8, CCR5, CTLA4, CD134, CD39 and/or GITR). Any of the foregoing molecules can be assessed by transcriptional analysis (e.g., quantitative RT-PCR, northern blot, microarray, fluorescent in situ hybridization, or RNA sequence); proteins can be detected by western blotting, immunofluorescence microscopy, flow cytometry or ELISA. Cell surface molecules (e.g., CD25, CCR4, CCR8, CCR5, CTLA4, CD134, CD39 and/or GITR) can be assessed by methods such as flow cytometry, cell surface staining, immunofluorescence microscopy, ELISA, and the like. In some embodiments, cd4+ regulatory T cells are detected based on an anergic phenotype (e.g., lack of proliferation following TCR stimulation). In some embodiments, cd4+ regulatory T cells are identified based on resistance to activation-induced cell death or sensitivity to death induced by cytokine deprivation. In some embodiments, cd4+ regulatory T cells may be identified based on the methylation status of the gene encoding FoxP 3; for example, in cd4+ regulatory T cells, it has been found that a portion of the FoxP3 gene is demethylated, which can be detected by DNA methylation analysis (e.g., by PCR or other DNA-based methods). Cd4+ regulatory T cells may be further identified or quantified based on the production of immunosuppressive cytokines, including IL-9, IL-10 or TGF- β. Antigen-specific cd4+ regulatory T cells may be identified and quantified by any method known in the art, for example, by stimulating cells ex vivo with antigen-presenting cells loaded with a particular antigen, and assessing activation of cd4+ regulatory T cells, or evaluating the T cell receptor of cd4+ regulatory T cells. The number or percentage (or ratio) of antigen-specific cd4+ regulatory T cells may be indirectly quantified by assessing one or more functions or activities of cd4+ regulatory T cells that are activated following exposure to an antigen or antigen-containing product.
By "generating" is meant that itself directly or indirectly causes an action, such as the occurrence of an immune response (e.g., tolerogenic immune response).
"high affinity IL-2 receptor agonists" include molecules such as: which selectively binds with high affinity interleukin-2 (IL-2) receptors with high affinity and the biological process triggered is at least similar in nature and intensity to the biological process that would be triggered by binding of wild-type IL-2 to high affinity IL-2 receptors. There are two main forms of IL-2 receptor-high affinity receptor consisting of alpha (or CD 25) chain, beta chain and gamma chain, and low (or medium) affinity receptor consisting of beta and gamma chain only. The high affinity IL-2 receptor agonists described herein selectively bind to high affinity receptors over low affinity receptors. High affinity IL-2 receptor agonists include, but are not limited to, wild-type IL-2, IL-2 muteins, IL-2 mimetics and fusion proteins of any of the foregoing (IL-2 fusion proteins). Wild-type IL-2 can be administered at low doses or in combination with specific monoclonal antibodies (monoclonal antibody, mAbs), wherein the mAb complex that binds IL-2 selectively binds to high affinity IL-2 receptors.
As used herein, "low dose IL-2" refers to any dose of wild-type IL-2 that is considered low by the clinician. Such a dose may be determined in one or more test subjects and applied to a subject in need of treatment. In some embodiments, the dose is observed in a non-human test subject and extrapolated to a human subject. In some embodiments of any one of the methods or compositions provided herein, the low dose of IL-2 is less than 5 million IU/m 2 Less than 4.5 million IU/m 2 Less than 4IU/m 2 Or less than 3IU/m 2 . In some embodiments of any one of the methods or compositions provided herein, the low dose of IL-2 is 300,000IU/m 2 To 3IU/m 2 . In some embodiments of any one of the methods or compositions provided herein, the low dose is an ultra-low dose. As used herein, an "ultra-low dose of IL-2" is any dose of wild-type IL-2 that is considered by a clinician to be an ultra-low dose. In some embodiments of any one of the methods or compositions provided herein, the ultra-low dose of IL-2 is less than 300,000IU/m 2 . In some embodiments of any one of the methods or compositions provided herein, the ultra-low dose of IL-2 is less than 200,000iu/m 2 . In some embodiments of any one of the methods or compositions provided herein, the ultra-low dose of IL-2 is 50,000IU/m 2 Up to 200,000IU/m 2 . In some embodiments, the ultra-low dose of IL-2 is 100,000IU/m 2 。
In some embodiments, the high affinity IL-2 receptor agonist is administered concomitantly with the immunosuppressant and optionally the target antigen. Such administration may expand existing tregs and/or tregs specific for the target antigen. Without wishing to be bound by theory, the use of high affinity IL-2 receptor agonists and immunosuppressants may synergistically induce and/or enhance the expansion of existing tregs (which may include antigen-specific tregs), and may provide a more durable immune tolerance, for example against a target antigen.
Any high affinity IL-2 receptor agonist provided herein may be in the form of a complex of mabs that bind thereto.
An "identified subject" is any action or set of actions that allows a clinician to identify a subject that may benefit from the methods or compositions provided herein. Preferably, the identified subject is a subject in need of a tolerogenic immune response provided herein, e.g., a subject in need of enhanced regulatory T cell production or development or persistence, e.g., enhanced antigen-specific cd4+ regulatory T cell production or development or persistence. An action or group of actions may be performed by itself, directly or indirectly. In one embodiment of any one of the methods provided herein, the method further comprises identifying a subject in need of the methods or compositions provided herein.
An "inflammatory disease" is a disease or disorder characterized by abnormal inflammation (e.g., caused by the immune system attacking a subject's own cells or tissues).
An "IL-2 fusion protein" refers to an engineered protein produced by fusion of an IL-2 molecule (e.g., wild-type IL-2, IL-2 mutein, IL-2 mimetic, etc.) or an active portion thereof with one or more additional peptides or proteins. Such additional peptide or protein may be an antibody or antigen binding fragment thereof. The additional peptide or protein may also be the Fc portion of an IgG antibody, which may be useful, for example, to extend the circulatory half-life of the fusion protein. IL-2 fusion proteins may include IL-2 and anti-IL-2 antibodies or fusion proteins, IL-2-CD25 fusion proteins, and the like.
As used herein, "IL-2 mimetic" refers to an engineered protein or functional fragment thereof designed to achieve the same function as IL-2and selectively bind to a high affinity IL-2 receptor. These proteins generally recapitulate the binding site of IL-2, but differ from IL-2 in terms of topology and/or amino acid sequence. Examples of such IL-2 mimetics are described in Silva, DA., yu, S., ulge, U.S. et al De novo design of potent and selective mimics of IL-2and IL-15.Nature 565,186-191 (2019) https:// doi.org/10.1038/s41586-018-0830-7.
"Interleukin-2 (IL-2) muteins" refer to biologically active derivatives of IL-2 that retain the desired properties of IL-2and selectively bind to high affinity IL-2 receptors. The term includes polypeptides having one or more amino acid-like molecules (including, but not limited to, compounds comprising only amino and or imino molecules), polypeptides containing analogs of one or more amino acids (including, for example, unnatural amino acids, etc.), polypeptides having substituted linkages, as well as other modifications known in the art (both naturally occurring and non-naturally occurring (e.g., synthetic), cyclized, branched molecules, etc.). The term also includes molecules containing one or more N-substituted glycine residues ("peptoids") and other synthetic amino acids or peptides.
Interleukin-2 (IL-2) is a cytokine that plays a critical role in T cell immunity and tolerance. During immunostimulation, IL-2 is an important cytokine that induces differentiation of CD4 and CD 8T cells into effector T cells following antigen-mediated activation. IL-2 also mediates differentiation of CD 8T cells into memory cells. However, IL-2 is also an important cytokine that mediates regulatory T cell (Treg) homeostasis and expansion. Indeed, mice lacking IL-2 may develop fatal autoimmune syndrome. Effector T cells and tregs express different IL-2 receptors. Treg expresses an IL-2 high affinity receptor consisting of three subunits α (or CD 25), β (or CD 122) and γ (or CD 132), whereas memory T cells express a medium affinity receptor consisting of β and γ only. While activated T cells can express CD25 following antigen stimulation, tregs constitutively express high levels of CD25. Thus, tregs are particularly sensitive to IL-2.
IL-2 can be engineered to produce IL-2 muteins. IL-2 muteins can be produced by introducing variations (e.g., mutations) into the amino acid chain of IL-2. Such mutations may be point mutations, in which one (or several) amino acids in the IL-2 chain are deleted, substituted (substituted) or added. For example, IL-2 muteins may be engineered to selectively bind to and activate T-reg. Such IL-2 muteins may have increased affinity for the alpha subunit of the IL-2 receptor and/or reduced affinity for the beta and gamma subunits of the IL-2 receptor as compared to wild-type IL-2. IL-2 muteins can selectively promote expansion of Treg cells and/or reduce agonism on effector T cells
(Front Immunol.2020Apr28;11:638.doi:10.3389/fimmu.2020.00638,Sci Immunol.2020Aug14;5(50):eaba5264.doi:10.1126/sciimmunol.aba5264,Front Immunol.2020Jun5;11:1106.doi:10.3389/fimmu.2020.01106,Trends Immunol.2015Dec;36(12):763-777.doi:10.1016/j.it.2015.10.003,Semin Oncol.2018Jan;45(1-2):95-104.doi:10.1053/j.seminoncol.20018.04.001,US 2017/0037102 A1,J Immunol2019May1;202(1Supplement)68.20.doi).
IL-2 muteins include, but are not limited to
PT101(Pandion Therapeutics/Merck-engineered IL-2mutein fused to and Fc protein backbone;J Immunol2020May1;2041Supplement)237.16);PT002(Pandion Therapeutics/Merck-engineered IL-2mutein with a MAdCAM tether for localization in the gut);
N88D, which corresponds to a point mutation consisting of: substitution of asparagine (N) residue with aspartic acid (D) residue at amino acid 88 and 2:1 stoichiometric IL-2 mutant-Fv fusion protein IgG- (IL-2N 88D) 2 (J.Autoimmun.2018 November 13; 95:1.doi.org/10.1016/j.jaut.2018.10.017); AMG 592 (Amgen-IL-2 mutein-Fc fusion protein); RG7835 (Roche-IL-2 mutein-Fc fusion protein). Other non-limiting examples of IL-2 muteins include, but are not limited to: IL-2 with R38A, F42A, Y A and E62A mutations (J Immunol2013Jun15;190 (12): 6230-8; doi: 10.4049/jimunol.1201895), the P85RIL-2 variant FSD13 (Cell Death Dis 9, 989 (2018). Https:// doi.org/10.1038/s 41419-018-1047-2), no alpha muteins (Oncoiimmunology 2020June2;9:1; doi.org/10.1080/2162402X.2020.1770565), and other structurally modified IL-2 muteins
(Front Immunol2020June5;11 (1106); doi.org/10.3389/fimmu.2020.01106, protein Eng2003Dec;16 (12): 1081-7; doi:10.1093/Protein/gzg 111)
(J Exp Med2020Jan6;217 (1): e20191247; doi:10.1084/jem.20191247, nature484, 529-533 (2012); doi.org/10.1038/aperture 10975, JAutoimrun 2015Jan;56:66-80; doi: 10.1016/j.jaut.2014.10.002).
By "immunosuppressant" is meant a compound that can cause an APC to have an immunosuppressive effect (e.g., tolerogenic effect) or T or B cells to be inhibited. Immunosuppressive action generally refers to the production or expression of cytokines or other factors by APCs that reduce, suppress or prevent an undesired immune response or promote a desired immune response, such as the production or development of regulatory immune responses (e.g., regulatory T cells (e.g., cd4+ regulatory T cells)). When an APC acquires an immunosuppressive function (under immunosuppressive action) on an immune cell that recognizes an antigen presented by the APC, the immunosuppressive action is considered specific to the presented antigen. Without being bound by any particular theory, it is believed that immunosuppression is the result of immunosuppression being delivered to the APC, preferably in the presence of an antigen. In one embodiment, the immunosuppressant is one that causes the APC to promote a regulatory phenotype in one or more immune effector cells. For example, the regulatory phenotype may be characterized by: inhibiting the production, induction, stimulation or recruitment of antigen-specific cd4+ T cells or B cells, inhibiting the production of antigen-specific antibodies, inhibiting the production, induction, stimulation or recruitment of Treg cells (e.g., cd4+cd25highfoxp3+ Treg cells), etc. This may be the result of the conversion of CD4+ T cells or B cells into a regulatory phenotype. This may also be the result of induction of FoxP3 in other immune cells (e.g. cd8+ T cells, macrophages and iNKT cells). In one embodiment, the immunosuppressant is one that affects the response of the APC after the APC processes the antigen. In another embodiment, the immunosuppressant is not an immunosuppressant that interferes with antigen processing. In another embodiment, the immunosuppressant is not an apoptotic signaling molecule. In another embodiment, the immunosuppressant is not a phospholipid.
Immunosuppressants include, but are not limited to: statins; mTOR inhibitors, such as rapamycin or rapamycin analogues; TGF-beta signaling agents; TGF-beta receptor agonists; histone deacetylase inhibitors such as trichostatin A (Trichostatin A); corticosteroids; inhibitors of mitochondrial function, such as rotenone (rotenone); a P38 inhibitor; NF-. Kappa.inhibitors such as 6Bio, dexamethasone (Dexamethasone), TCPA-1, IKK VII; adenosine receptor agonists; prostaglandin E2 agonists (PGE 2), such as Misoprostol; phosphodiesterase inhibitors, such as phosphodiesterase 4 inhibitors (PDE 4), e.g., rolipram (Rolipram); histone Deacetylase (HDAC) inhibitors, proteasome inhibitors; a kinase inhibitor; a G protein-coupled receptor agonist; g protein-coupled receptor antagonists; glucocorticoids; retinoids; a cytokine inhibitor; cytokine receptor inhibitors; cytokine receptor activators; peroxisome proliferator activated receptor antagonists; peroxisome proliferator activated receptor agonists; histone deacetylase inhibitors; calcineurin inhibitors; a phosphatase inhibitor; PI3KB inhibitors such as TGX-221; autophagy inhibitors such as 3-methyladenine; an aromatic hydrocarbon receptor inhibitor; proteasome inhibitor I (PSI); and oxidized ATP, e.g., P2X receptor blockers. Immunosuppressants also include: IDO, vitamin D3, cyclosporines such as cyclosporine a, aromatic receptor inhibitors, resveratrol (resveratrol), azathioprine (Aza), 6-mercaptopurine (6-MP), 6-thioguanine (6-TG), FK506, sanfeverdin a, salmeterol, mycophenolate Mofetil (MMF), aspirin and other COX inhibitors, niflumic acid, estriol and triptolide. In some embodiments, the immunosuppressant may comprise any of the agents provided herein.
The immunosuppressant may be a compound that directly provides immunosuppression to the APC or it may be a compound that indirectly (i.e. after processing in some way after administration) provides immunosuppression. Thus, immunosuppressants comprise prodrug forms of any of the compounds provided herein.
In some embodiments of any one of the methods or compositions provided herein, the immunosuppressant provided herein is formulated with a synthetic nanocarrier. In some preferred embodiments, the immunosuppressant is an element other than the substance constituting the synthetic nanocarrier structure. For example, in one embodiment in which the synthetic nanocarrier is comprised of one or more polymers, the immunosuppressant is a compound that is attached (e.g., coupled) to, in addition to, and to the one or more polymers. As another example, in one embodiment in which the synthetic nanocarrier is comprised of one or more lipids, the immunosuppressant is also a compound in addition to and linked to the one or more lipids. In some embodiments, for example where the substance that synthesizes the nanocarrier also causes immunosuppression, immunosuppressants are elements that exist in addition to the synthetic nanocarrier substance that causes immunosuppression.
Other exemplary immunosuppressants include, but are not limited to, small molecule drugs, natural products, antibodies (e.g., anti-CD 20, CD3, CD4 antibodies), biological agent-based drugs, carbohydrate-based drugs, nanoparticles, liposomes, RNAi, antisense nucleic acids, aptamers, methotrexate, NSAIDs; fingolimod (fingolimod); natalizumab (natalizumab); alemtuzumab (alemtuzumab); anti-CD 3; tacrolimus (tacrolimus) (FK 506), and the like. Other immunosuppressants are known to those skilled in the art, and the invention is not limited in this regard.
In some embodiments of any one of the methods, compositions, or kits provided herein, the immunosuppressant is in a form, e.g., a nanocrystalline form, wherein the form of the immunosuppressant itself is a particle or particle-like. In some embodiments, such forms mimic viruses or other foreign pathogens. Many drugs have been nanocrystallized and suitable methods for producing such drug forms are known to those of ordinary skill in the art. Drug nanocrystals, such as nanocrystalline rapamycin, are known to those of ordinary skill in the art (Katteboinaa, et al 2009, international Journal of PharmTech Resesarch; vol.1, 3; pp.682 to 694). As used herein, "drug nanocrystals" refers to a form of a drug (e.g., immunosuppressant) that does not comprise a carrier or matrix substance. In some embodiments, the drug nanocrystals comprise 90%, 95%, 98%, or 99% or more of the drug. Methods for producing drug nanocrystals include, but are not limited to, milling, high pressure homogenization, precipitation, spray drying, rapid expansion of supercritical solutions (rapid expansion of supercritical solution, RESS), and, Techniques (Baxter Healthcare) and Nanocrystal Technology TM (Elan Corporation). In some embodiments, surfactants or stabilizers may be used for steric or electrostatic stability of the drug nanocrystals. In some embodiments, the nanocrystal or nanocrystal form of an immunosuppressant can be used to increase the solubility, stability, and/or bioavailability of an immunosuppressant (particularly an insoluble or unstable immunosuppressant).
When attached to a synthetic nanocarrier, the "loading" is the amount (weight/weight) of molecules (e.g., immunosuppressants and/or antigens) that can be attached to the synthetic nanocarrier based on the total dry formulation weight of the materials in the overall synthetic nanocarrier. In general, such loadings are calculated as an average across the population of synthetic nanocarriers. In one embodiment, the average loading of the synthetic nanocarriers is from 0.0001% to 99%. In another embodiment, the loading is from 0.1% to 50%. In another embodiment, the loading is from 0.1% to 20%. In another embodiment, the loading is from 0.1% to 25%. In another embodiment, the loading is from 0.1% to 10%. In another embodiment, the loading is from 1% to 10%. In another embodiment, the loading is from 1% to 25% or from 1% to 30%. In another embodiment, the loading is 2% to 25% or 2% to 30%. In another embodiment, the loading is from 4% to 25% or from 4% to 30%. In another embodiment, the loading is 8% to 25% or 8% to 30%. In another embodiment, the loading is 7% to 20%. In another embodiment, the average loading of the population of synthetic nanocarriers is at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 25%, at least 30%, at least 40%, or at least 50%. In another embodiment, the average loading of the population of synthetic nanocarriers is 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20%. In some of the above embodiments, the average loading of the population of synthetic nanocarriers is no more than 25%. In some embodiments, the loading is calculated in a manner otherwise known in the art. In one embodiment of any of the foregoing loading embodiments, the foregoing loading embodiment refers to the loading of the immunosuppressant. In another embodiment of any of the foregoing loading embodiments, the foregoing loading embodiments refer to the loading of the antigen. In one of such embodiments, the loading of antigen (if also included in the synthetic nanocarriers) is from 1% to 10%.
In some embodiments, when the form of the immunosuppressant itself is a particle or particle-like (e.g., nanocrystalline immunosuppressant), the loading of the immunosuppressant is the amount (weight/weight) of immunosuppressant in the form of a particle or the like. In such embodiments, the loading may be approximately 97%, 98%, 99% or more.
"maximum size of the synthetic nanocarrier" means the maximum size of the nanocarrier measured along any axis of the synthetic nanocarrier. "minimum size of a synthetic nanocarrier" means the smallest size of the synthetic nanocarrier measured along any axis of the synthetic nanocarrier. For example, for a spherical synthetic nanocarrier, the largest dimension and the smallest dimension of the synthetic nanocarrier will be substantially the same, and will be the dimension of the diameter thereof. Similarly, for a cubic synthetic nanocarrier, the smallest dimension of the synthetic nanocarrier will be the smallest of its height, width, or length, while the largest dimension of the synthetic nanocarrier will be the largest of its height, width, or length. In one embodiment, at least 75%, preferably at least 80%, more preferably at least 90% of the synthetic nanocarriers in the sample have a minimum size equal to or greater than 100nm, based on the total number of synthetic nanocarriers in the sample. In one embodiment, at least 75%, preferably at least 80%, more preferably at least 90% of the synthesized nanocarriers in the sample have a largest dimension equal to or less than 5 μm based on the total number of synthesized nanocarriers in the sample. Preferably, at least 75%, preferably at least 80%, more preferably at least 90% of the synthetic nanocarriers in the sample have a minimum size of greater than 110nm, more preferably greater than 120nm, more preferably greater than 130nm, and still more preferably greater than 150nm, based on the total number of synthetic nanocarriers in the sample. The aspect ratio of the largest dimension to the smallest dimension of the synthetic nanocarriers can vary depending on the embodiment. For example, the aspect ratio of the largest dimension to the smallest dimension of the synthetic nanocarriers may be varied in the following: 1:1 to 1,000,000:1, preferably 1:1 to 100,000:1, more preferably 1:1 to 10,000:1, more preferably 1:1 to 1000:1, still more preferably 1:1 to 100:1 and still more preferably 1:1 to 10:1. Preferably, at least 75%, preferably at least 80%, more preferably at least 90% of the largest dimension of the synthetic nanocarriers in the sample is equal to or less than 3 μm, more preferably equal to or less than 2 μm, more preferably equal to or less than 1 μm, more preferably equal to or less than 800nm, more preferably equal to or less than 600nm and more preferably also equal to or less than 500nm, based on the total number of synthetic nanocarriers in the sample. In some preferred embodiments, at least 75%, preferably at least 80%, more preferably at least 90% of the synthetic nanocarriers in the sample have a minimum dimension equal to or greater than 100nm, more preferably equal to or greater than 120nm, more preferably equal to or greater than 130nm, more preferably equal to or greater than 140nm, and still more preferably equal to or greater than 150nm, based on the total number of synthetic nanocarriers in the sample. In some embodiments, measurement of the synthetic nanocarrier dimensions (e.g., effective diameter) can be obtained by suspending the synthetic nanocarrier in a liquid (typically aqueous) medium and using dynamic light scattering (dynamic light scattering, DLS) (e.g., using Brookhaven ZetaPALS instruments). For example, the suspension of synthetic nanocarriers can be diluted from an aqueous buffer into pure water to achieve a final synthetic nanocarrier suspension concentration of about 0.01 to 0.1 mg/mL. The diluted suspending agent may be prepared directly inside a suitable cuvette or transferred to a suitable cuvette for DLS analysis. The cuvette may then be placed in DLS, equilibrated to a controlled temperature, and then scanned for a sufficient time based on appropriate inputs of the viscosity of the medium and the refractive index of the sample to obtain a stable and reproducible distribution. The average of the effective diameters or distributions is then reported. Determining the effective size of a high aspect ratio or non-spherical synthetic nanocarrier may require magnification techniques (e.g., electron microscopy) to obtain more accurate measurements. "size" or "diameter" of the synthetic nanocarriers means, for example, an average value of particle size distribution obtained using dynamic light scattering. In some embodiments, the average value of the particle size distribution of the synthetic nanocarriers obtained using dynamic light scattering is greater than 100nm, 150nm, 200nm, 250nm, or 300nm in diameter.
By "non-methoxy terminated polymer" is meant a polymer having at least one end ending with a moiety other than methoxy. In some embodiments, the polymer has at least two ends ending with a moiety other than methoxy. In other embodiments, the polymer does not have a terminus ending with a methoxy group. By "non-methoxy-terminated pluronic polymer" is meant a polymer other than a linear pluronic polymer having methoxy groups at both ends. The polymeric nanoparticles as provided herein may comprise a non-methoxy-terminated polymer or a non-methoxy-terminated pluronic polymer.
By "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" is meant a pharmacologically inert substance that is used with the pharmacologically active substance to formulate the composition. Pharmaceutically acceptable excipients include a variety of substances known in the art including, but not limited to, sugars (e.g., glucose, lactose, etc.), preservatives (e.g., antimicrobial agents), reconstitution aids, colorants, saline (e.g., phosphate buffered saline), and buffers.
"regimen" means the manner of administration to a subject and includes any regimen of administration of one or more substances to a subject. The scheme consists of elements (or variables); thus, a scheme comprises one or more elements. Such elements of the regimen may include the amount administered, the frequency of administration, the route of administration, the duration of administration, the rate of administration, the interval between administrations, combinations of any of the foregoing, and the like. In some embodiments, such regimens may be used to administer one or more compositions of the invention to one or more subjects. The immune response of these subjects can then be evaluated to determine whether the regimen is effective in producing a desired or expected level of immune response or therapeutic effect. Any therapeutic and/or immune effect may be assessed. One or more elements of the regimen may have been previously demonstrated in a subject (e.g., a non-human subject) and subsequently converted to a human regimen. For example, the amount of drug administered demonstrated in a non-human subject may be scaled to be an element of a human regimen using established techniques, such as equivalent scaling (alimetric scaling) or other scaling methods. Any of the methods provided herein or other methods known in the art may be used to determine whether a regimen has the desired effect. For example, a sample may be obtained from a subject to whom a composition provided herein has been administered according to a particular protocol to determine whether a particular immune cell, cytokine, antibody, etc., is reduced, produced, activated, etc. One exemplary protocol is one previously demonstrated to result in an increase in the number or percentage (or ratio) of regulatory T cells (e.g., cd+ regulatory T cells) with the methods or compositions provided herein. Methods that may be used to detect the presence and/or number of immune cells include, but are not limited to, flow cytometry methods (e.g., FACS), ELISpot, proliferative responses, cytokine production, and immunohistochemical methods. Antibodies and other binding reagents for immune cell marker specific staining are commercially available. Such kits typically include staining reagents for the antigen that allow FACS-based detection, isolation and/or quantification that a heterogeneous cell population is a desired cell population. In some embodiments, one or more, or all, or substantially all, of the elements encompassed by the use regimen are administered to another subject a variety of compositions provided herein. In some embodiments, protocols have been shown that use of the methods or compositions as provided herein, result in the development or production of existing and/or antigen-specific regulatory T cells (e.g., cd4+ regulatory T cells).
"providing" means providing an action or a set of actions to be performed by an individual for practicing the desired item or group of items or methods of the present invention. An action or group of actions may be performed by itself, directly or indirectly.
A "providing a subject" is any action or set of actions that a clinician contacts with a subject and applies thereto or performs thereon the methods provided herein. Preferably, the subject is a subject in need of antigen-specific tolerance and/or in need of increased production or development or persistence of regulatory T cells provided herein. An action or group of actions may be performed by itself, directly or indirectly. In one embodiment of any one of the methods provided herein, the method further comprises providing a subject.
By "subject" is meant an animal, including warm-blooded mammals, such as humans and primates; poultry; domesticated domestic or farm animals such as cats, dogs, sheep, goats, cattle, horses and pigs; laboratory animals such as mice, rats and guinea pigs; fish; a reptile; zoo animals and wild animals; etc. In some embodiments, the subject has, or is at risk of having, an inflammatory disease, an autoimmune disease, an allergy, organ or tissue rejection, or graft versus host disease. In other embodiments, the subject has undergone or will undergo transplantation. In other embodiments, the subject has or is at risk of having an undesired immune response against an antigen (e.g., therapeutic macromolecule) being administered or to be administered to the subject.
"synthetic nanocarriers" means discrete objects that are not found in nature and that have at least one dimension that is less than or equal to 5 microns in size. Albumin nanoparticles are typically included as synthetic nanocarriers, however in certain embodiments, the synthetic nanocarriers do not comprise albumin nanoparticles. In some embodiments, the synthetic nanocarriers do not comprise chitosan. In other embodiments, the synthetic nanocarriers are not lipid-based nanoparticles. In other embodiments, the synthetic nanocarriers do not comprise phospholipids.
The synthetic nanocarriers may be, but are not limited to, one or more of the following: lipid-based nanoparticles (also referred to herein as lipid nanoparticles, i.e., nanoparticles whose majority of the substance comprising its structure is lipid), polymer nanoparticles, metal nanoparticles, surfactant-based emulsions, dendrimers, buckyballs, nanowires, virus-like particles (i.e., particles consisting essentially of viral structural proteins but not having infectivity or low infectivity), peptide-or protein-based particles (also referred to herein as protein particles, i.e., particles whose majority of the substance comprising its structure is peptide or protein) (e.g., albumin nanoparticles), and/or nanoparticles produced using a combination of nanomaterials (e.g., lipid-polymer nanoparticles). Synthetic nanocarriers can be a variety of different shapes including, but not limited to, spherical, cubical, pyramidal, rectangular, cylindrical, toroidal, and the like. The synthetic nanocarriers according to the invention comprise one or more surfaces. Exemplary synthetic nanocarriers that may be suitable for use in the practice of the invention include: (1) biodegradable nanoparticles disclosed in U.S. patent 5,543,158 to Gref et al, (2) polymer nanoparticles disclosed in published U.S. patent application 20060002852 to Saltzman et al, (3) nucleic acid-linked virus-like Particles disclosed in published U.S. patent application 20090028910 to DeSimone et al, (4) the disclosure of WO 2009/051837 to von Andrian et al, (5) nanoparticles disclosed in published U.S. patent application 2008/0145441 to Penades et al, (6) protein nanoparticles disclosed in published U.S. patent application 20090226525 to de rism et al, (7) nucleic acid-linked virus-like Particles disclosed in published U.S. patent application 20060222652 to sebbman et al, (8) virus-like Particles disclosed in published U.S. patent application 20060251677 to Bachmann et al, (9) virus-like Particles disclosed in WO2010047839A1 or WO2009106999A2, (10) p.Pacific slide "," green-2010-3 or to pro-3 to pro-tive nanoparticles (2002-37,1746) to apoptosis (13) or to pro-13,1746 to pro-4 of semi-tumor cells (2002-37,1746). In some embodiments, the aspect ratio of the synthetic nanocarriers can be greater than or equal to 1:1, 1:1.2, 1:1.5, 1:2, 1:3, 1:5, 1:7, or greater than 1:10.
In some embodiments, synthetic nanocarriers according to the invention having a minimum dimension of equal to or less than about 100nm, preferably equal to or less than 100nm, do not comprise a surface having hydroxyl groups that activate complement, or alternatively comprise a surface consisting essentially of moieties that are not hydroxyl groups that activate complement. In a preferred embodiment, the synthetic nanocarriers according to the invention having a smallest dimension equal to or smaller than about 100nm, preferably equal to or smaller than 100nm, do not comprise a surface that significantly activates complement or alternatively comprise a surface consisting essentially of a moiety that does not significantly activate complement. In a more preferred embodiment, the synthetic nanocarriers according to the invention having a smallest dimension equal to or less than about 100nm, preferably equal to or less than 100nm, do not comprise a surface that activates complement, or alternatively comprise a surface that consists essentially of a moiety that does not activate complement. In some embodiments, the synthetic nanocarriers exclude virus-like particles. In some embodiments, the aspect ratio of the synthetic nanocarriers can be greater than or equal to 1:1, 1:1.2, 1:1.5, 1:2, 1:3, 1:5, 1:7, or 1:10.
An "antigen" is a natural or synthetic entity that is recognized as a foreign body by antibodies or cells of the immune system and can trigger an immune response. The antigen may be in the form of a peptide, protein, polysaccharide or lipid (e.g., lipopolysaccharide). In some embodiments, the antigen is produced in the subject as a result of normal cellular metabolism. In some embodiments, the antigen is an autoantigen or a natural antigen and may stimulate an autoantibody (or immunoglobulin) in the subject. In some embodiments, the antigen is involved in the pathogenesis of an autoimmune disease. Some non-limiting examples of antigens include therapeutic macromolecules such as those used in protein or enzyme replacement therapy; allergens, such as those found in food products (e.g., peanuts, dairy products, etc.) or other surrounding substances (e.g., pollen, latex, etc.); autoantigens in the case of autoimmune diseases; or other antigens associated with inflammatory diseases, autoimmune diseases, organ or tissue rejection, or graft versus host disease. The antigen may be an antigen to which the subject is exposed or an antigen administered to the subject. The antigen may also be an endogenous antigen.
"therapeutic macromolecule" refers to any protein, carbohydrate, lipid, or nucleic acid that can be administered to a subject and that has a therapeutic effect. In some embodiments, administration of a therapeutic macromolecule to a subject can result in an undesired immune response. In some embodiments, the therapeutic macromolecule may be a therapeutic polynucleotide or a therapeutic protein. In other embodiments, the therapeutic macromolecule comprises an infusible or injectable therapeutic protein, an enzyme cofactor, a hormone, blood or clotting factor, a cytokine, an interferon, a growth factor, a monoclonal antibody, a polyclonal antibody, or a protein associated with pompe disease.
"therapeutic polynucleotide" means any polynucleotide or polynucleotide-based therapy that can be administered to a subject and that has a therapeutic effect. Therapeutic polynucleotides may be produced in, on or by cells, and may also be obtained using cell-free methods or from fully synthetic in vitro methods. Thus, a subject includes any subject in need of treatment with any of the foregoing. Such objects include those that will accept any of the foregoing.
By "therapeutic protein" is meant any protein or protein-based treatment that can be administered to a subject and has a therapeutic effect. Such treatments include protein replacement therapy and protein supplementation therapy. Such treatments also include administration of exogenous or foreign proteins, antibody therapies, and cell or cell-based therapies. Therapeutic proteins include, but are not limited to, infusible or injectable therapeutic proteins, enzymes, enzyme cofactors, hormones, clotting factors, cytokines, growth factors, monoclonal antibodies, antibody-drug conjugates, and polyclonal antibodies.
The therapeutic protein may be in, on or produced by a cell, and may be obtained from or administered in the form of such a cell. In some embodiments, the therapeutic protein is produced in, on, or by: mammalian cells, insect cells, yeast cells, bacterial cells, plant cells, transgenic animal cells, transgenic plant cells, and the like. Therapeutic proteins can be recombinantly produced in such cells. The therapeutic protein may be in, on, or produced by a virus-transformed cell. Thus, a subject includes any subject in need of treatment with any of the foregoing. Such objects include those that will accept any of the foregoing.
An "undesired immune response" refers to any undesired immune response, e.g., an immune response caused by an antigen that promotes or aggravates a disease, disorder, or condition (or symptom thereof) provided herein, and/or is a symptom of a disease, disorder, or condition provided herein. Such an immune response typically has a negative impact on or is a symptom that has a negative impact on the health of the subject.
By "viral transfer vector" is meant a viral vector that has been adapted to deliver a nucleic acid (e.g., transgene) as provided herein and includes such nucleic acid. "viral vector" refers to all viral components of a viral transfer vector. Thus, "viral antigen" refers to the following antigens: the viral component (e.g., capsid protein or coat protein) of a viral transfer vector, and not the nucleic acid (e.g., transgene) or any product encoded thereby, that it delivers. By "viral transfer vector antigen" is meant any of the following antigens: viral transfer vectors, including viral components thereof, as well as delivered nucleic acids (e.g., transgenes) or any expression products thereof. The transgene may be a gene therapy transgene, a gene editing transgene, a transgene that regulates gene expression, or an exon skipping transgene. In some embodiments, the transgene is a transgene encoding a protein provided herein (e.g., a therapeutic protein, a DNA binding protein, or an endonuclease). In other embodiments, the transgene is a transgene encoding a guide RNA, antisense nucleic acid, snRNA, RNAi molecule (e.g., dsRNA or ssRNA), miRNA or triplex forming oligonucleotide (triplex-forming oligonucleotide, TFO), or the like. Viral vectors may be based on, but are not limited to: retroviruses (e.g., murine retrovirus, avian retrovirus, moloney murine leukemia virus (Moloney murine leukemia virus, moMuLV), harvey murine sarcoma virus (Harvey murine sarcoma virus, haMuSV), murine mammary tumor virus (murine mammary tumor virus, muMTV), gibbon ape leukemia virus (gibbon ape leukemia virus, gaLV) and Rous sarcoma virus (Rous sarcoma virus, RSV)), lentiviruses, herpesviruses, adenoviruses, adeno-associated viruses, alphaviruses, and the like. Other examples are provided elsewhere herein or are known in the art. Viral vectors may be based on natural variants, strains, or serotypes of the virus, such as any of those provided herein. Viral vectors may also be based on viruses selected by molecular evolution. The viral vector may also be an engineered vector, a recombinant vector, a mutant vector or a hybrid vector. In some embodiments, the viral vector is a "chimeric viral vector". In such embodiments, this means that the viral vector is composed of viral components derived from more than one virus or viral vector.
C. Composition and method for producing the same
A wide variety of synthetic nanocarriers can be used in accordance with the present invention. In some embodiments, the synthetic nanocarriers are spheres or spheroids. In some embodiments, the synthetic nanocarriers are flat or platy. In some embodiments, the synthetic nanocarriers are cubic or cubic. In some embodiments, the synthetic nanocarriers are ovoids or ellipsoids. In some embodiments, the synthetic nanocarriers are cylinders, pyramids, or pyramids.
In some embodiments, it is desirable to use a population of synthetic nanocarriers that is relatively uniform in size or shape such that each synthetic nanocarrier has similar characteristics. For example, at least 80%, at least 90%, or at least 95% of the smallest dimension or largest dimension of the synthetic nanocarriers fall within 5%, 10%, or 20% of the average diameter or average dimension of the synthetic nanocarriers, based on the total number of synthetic nanocarriers.
The synthetic nanocarriers may be solid or hollow and may comprise one or more layers. In some embodiments, each layer has a unique composition and unique characteristics relative to the other layers. To give just one example, the synthetic nanocarriers may have a core/shell structure, wherein the core is one layer (e.g., a polymer core) and the shell is a second layer (e.g., a lipid bilayer or monolayer). The synthetic nanocarriers may comprise a plurality of different layers.
In some embodiments, the synthetic nanocarriers may optionally comprise one or more lipids. In some embodiments, the synthetic nanocarriers may comprise liposomes. In some embodiments, the synthetic nanocarriers may comprise a lipid bilayer. In some embodiments, the synthetic nanocarriers may comprise a lipid monolayer. In some embodiments, the synthetic nanocarriers may comprise micelles. In some embodiments, the synthetic nanocarriers may comprise a core comprising a polymer matrix surrounded by a lipid layer (e.g., a lipid bilayer, a lipid monolayer, etc.). In some embodiments, the synthetic nanocarriers can comprise a non-polymeric core (e.g., metal particles, quantum dots, ceramic particles, bone particles, viral particles, proteins, nucleic acids, carbohydrates, etc.) surrounded by a lipid layer (e.g., lipid bilayer, lipid monolayer, etc.).
In other embodiments, the synthetic nanocarriers may comprise metal particles, quantum dots, ceramic particles, and the like. In some embodiments, the non-polymeric synthetic nanocarriers are aggregates of non-polymeric components, such as aggregates of metal atoms (e.g., jin Yuanzi).
In some embodiments, the synthetic nanocarriers may optionally comprise one or more amphiphilic entities. In some embodiments, the amphiphilic entity may facilitate the production of synthetic nanocarriers with increased stability, improved uniformity, or increased viscosity. In some embodiments, the amphiphilic entity may be associated with an inner surface of a lipid membrane (e.g., lipid bilayer, lipid monolayer, etc.). Many amphiphilic entities known in the art are suitable for use in preparing synthetic nanocarriers according to the invention. Such amphiphilic entities include, but are not limited to: glycerol phosphate; phosphatidylcholine; dipalmitoyl phosphatidylcholine (DPPC); dioleyl phosphatidylethanolamine (DOPE); dioleylpropyl triethylammonium (DOTMA); di-oleoyl phosphatidylcholine; cholesterol; cholesterol esters; diacylglycerols; succinic diacylglycerol ester; dipeptidyl glycerol (DPPG); hexane decyl alcohol; fatty alcohols such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; surface-active fatty acids, such as palmitic acid or oleic acid; a fatty acid; fatty acid monoglycerides; fatty acid diglycerides; fatty acid amides; sorbitan trioleate Glycocholate; sorbitan monolaurateEster->Polysorbate 20->Polysorbate 60Polysorbate 65->Polysorbate 80->Polysorbate 85->Polyoxyethylene monostearate; a surfactant; a poloxamer; sorbitan fatty acid esters such as sorbitan trioleate; lecithin; lysolecithin; phosphatidylserine; phosphatidylinositol; sphingomyelin; phosphatidylethanolamine (cephalin); cardiolipin; phosphatidic acid; cerebroside; dicetyl phosphate; dipalmitoyl phosphatidylglycerol; stearylamine; dodecylamine; hexadecylamine; acetyl palmitate; glycerol ricinoleate; cetyl stearate; isopropyl myristate; tyloxapol; poly (ethylene glycol) 5000-phosphatidylethanolamine; poly (ethylene glycol) 400 monostearate; a phospholipid; synthetic and/or natural detergents with high surfactant properties; deoxycholate; cyclodextrin; chaotropic salts; an ion pairing agent; and combinations thereof. The amphiphilic entity component may be a mixture of different amphiphilic entities. Those skilled in the art will recognize that this is an exemplary and not comprehensive list of materials having surfactant activity. Any amphiphilic entity can be used to produce the synthetic nanocarriers used in accordance with the invention.
In some embodiments, the synthetic nanocarriers may optionally comprise one or more carbohydrates. The carbohydrate may be natural or synthetic. The carbohydrate may be a derivatized natural carbohydrate. In certain embodiments, the carbohydrate includes a monosaccharide or disaccharide, including but not limited to: glucose, fructose, galactose, ribose, lactose, sucrose, maltose, trehalose, cellobiose, mannose, xylose, arabinose, glucuronic acid, galacturonic acid, mannuronic acid, glucosamine, galactosamine, and neuraminic acid. In certain embodiments, the carbohydrate is a polysaccharide, including but not limited to: pullulan (pullulan), cellulose, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), hydroxy Cellulose (HC), methyl Cellulose (MC), dextran, cyclodextran, glycogen, hydroxyethyl starch, carrageenan, glycosyl (glycon), amylose (amylose), chitosan, N, O-carboxymethyl chitosan, algin and alginic acid, starch, chitin, inulin, konjac, glucomannan, fucan, heparin, hyaluronic acid, curdlan and xanthan gum. In some embodiments, the synthetic nanocarriers do not comprise (or are specifically excluded from) carbohydrates, such as polysaccharides. In certain embodiments, the carbohydrate may include a carbohydrate derivative, such as a sugar alcohol, including, but not limited to: mannitol, sorbitol, xylitol, erythritol, maltitol and lactitol.
In some embodiments, the synthetic nanocarriers may comprise one or more polymers. In some embodiments, the synthetic nanocarriers comprise one or more polymers that are non-methoxy-terminated pluronic polymers. In some embodiments, at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% (weight/weight) of the polymer comprising the synthetic nanocarrier is a non-methoxy-terminated pluronic polymer. In some embodiments, all of the polymers comprising the synthetic nanocarriers are non-methoxy-terminated pluronic polymers. In some embodiments, the synthetic nanocarriers comprise one or more polymers that are non-methoxy-terminated polymers. In some embodiments, at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% (weight/weight) of the polymer comprising the synthetic nanocarrier is a non-methoxy-terminated polymer. In some embodiments, all of the polymers comprising the synthetic nanocarriers are non-methoxy-terminated polymers. In some embodiments, the synthetic nanocarriers comprise one or more polymers that are free of pluronic polymers. In some embodiments, at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% (weight/weight) of the polymer comprising the synthetic nanocarrier does not comprise pluronic polymer. In some embodiments, all of the polymers comprising the synthetic nanocarriers do not comprise pluronic polymers. In some embodiments, such polymers may be surrounded by a coating (e.g., liposome, lipid monolayer, micelle, etc.). In some embodiments, multiple elements of the synthetic nanocarriers can be linked to a polymer.
The immunosuppressants and/or antigens can be attached to the synthetic nanocarriers by any of a variety of methods. In general, the linkage may be the result of binding between the immunosuppressant and/or antigen and the synthetic nanocarriers. Such binding may result in the immunosuppressant and/or antigen being attached to the surface of the synthetic nanocarrier and/or contained (encapsulated) within the synthetic nanocarrier. However, in some embodiments, due to the structure of the synthetic nanocarriers, the immunosuppressants and/or antigens are encapsulated by the synthetic nanocarriers, rather than being bound to the synthetic nanocarriers. In some preferred embodiments, the synthetic nanocarriers comprise a polymer provided herein, and the immunosuppressant and/or antigen is linked to the polymer. In some embodiments of any one of the methods or compositions provided herein, when both the immunosuppressant and the antigen are linked to a synthetic nanocarrier, they can be linked to the same synthetic nanocarrier population or to different synthetic nanocarrier populations.
When the ligation occurs due to binding between the immunosuppressant and/or antigen and the synthetic nanocarriers, the ligation may occur through a coupling moiety. The coupling moiety may be any moiety through which the immunosuppressant and/or antigen is bound to the synthetic nanocarrier. Such moieties include covalent bonds (e.g., amide or ester bonds) and separate molecules that allow the immunosuppressant to bind (covalently or non-covalently) to the synthetic nanocarriers. Such molecules include linkers or polymers or units thereof. For example, the coupling moiety may comprise an immunosuppressant and/or a charged polymer to which the antigen electrostatically binds. As another example, the coupling moiety may comprise a polymer or unit thereof covalently bound thereto.
In some preferred embodiments, the synthetic nanocarriers comprise a polymer provided herein. These synthetic nanocarriers may be complete polymers or they may be a mixture of polymers and other materials.
In some embodiments, the polymers of the synthetic nanocarriers associate to form a polymer matrix. In some of these embodiments, the component (e.g., immunosuppressant and/or antigen) can be covalently associated with one or more polymers of the polymer matrix. In some embodiments, covalent association is mediated by a linker. In some embodiments, the components may be non-covalently associated with one or more polymers of the polymer matrix. For example, in some embodiments, the components may be encapsulated within, surrounded by, and/or dispersed throughout the polymer matrix. Alternatively or additionally, the components may be associated with one or more polymers in the polymer matrix by hydrophobic interactions, charge interactions, van der Waals forces, and the like. A wide variety of polymers and methods for forming polymer matrices therefrom are conventionally known.
The polymer may be a natural or non-natural (synthetic) polymer. The polymer may be a homopolymer or a copolymer comprising two or more monomers. The copolymer may be random, block, or comprise a combination of random and block sequences in terms of sequence. In general, the polymer according to the invention is an organic polymer.
In some embodiments, the polymer comprises a polyester, a polycarbonate, a polyamide, or a polyether, or units thereof. In other embodiments, the polymer comprises poly (ethylene glycol) (PEG), polypropylene glycol, poly (lactic acid), poly (glycolic acid), poly (lactic-co-glycolic acid), or polycaprolactone, or units thereof. In some embodiments, preferably, the polymer is biodegradable. Thus, in these embodiments, preferably, if the polymer comprises a polyether, such as poly (ethylene glycol) or polypropylene glycol or units thereof, the polymer comprises a block copolymer of a polyether and a biodegradable polymer such that the polymer is biodegradable. In other embodiments, the polymer includes more than just polyether or units thereof, such as poly (ethylene glycol) or polypropylene glycol or units thereof.
Further examples of polymers suitable for use in the present invention include, but are not limited to: polyethylene, polycarbonates (e.g., poly (1, 3-dioxane-2-one)), polyanhydrides (e.g., poly (sebacic anhydride)), polypropylene fumerate, polyamides (e.g., polycaprolactam), polyacetals, polyethers, polyesters (e.g., polylactides, polyglycolides, polylactide-co-glycolides, polycaprolactone, polyhydroxyacids (e.g., poly (. Beta. -hydroxyalkanoate))), poly (orthoesters), polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polyureas, polystyrenes, and polyamines, polylysine-PEG copolymers and poly (ethyleneimine), poly (ethyleneimine) -PEG copolymers.
In some embodiments, the polymer according to the present invention comprises a polymer that has been approved by the U.S. food and drug administration (Food and Drug Administration, FDA) for use in humans according to 21c.f.r. ζ177.2600, including but not limited to: polyesters (e.g., polylactic acid, poly (lactic-co-glycolic acid), polycaprolactone, polypentanolide, poly (1, 3-dioxane-2-one)); polyanhydrides (e.g., poly (sebacic anhydride)); polyethers (e.g., polyethylene glycol); polyurethane; a polymethacrylate; a polyacrylate; and polycyanoacrylates.
In some embodiments, the polymer may be hydrophilic. For example, the polymer may comprise anionic groups (e.g., phosphate groups, sulfate groups, carboxylate groups); cationic groups (e.g., quaternary ammonium groups); or polar groups (e.g., hydroxyl, thiol, amine). In some embodiments, the synthetic nanocarriers comprising the hydrophilic polymer matrix create a hydrophilic environment within the synthetic nanocarriers. In some embodiments, the polymer may be hydrophobic. In some embodiments, the synthetic nanocarriers comprising the hydrophobic polymer matrix create a hydrophobic environment within the synthetic nanocarriers. The choice of hydrophilicity or hydrophobicity of the polymer can have an impact on the nature of the material incorporated (e.g., linked) within the synthetic nanocarrier.
In some embodiments, the polymer may be modified with one or more moieties and/or functional groups. Various moieties or functional groups may be used in accordance with the present invention. In some embodiments, the polymer may be modified with polyethylene glycol (PEG), with carbohydrates, and/or with acyclic polyacetals from polysaccharides (papiosov, 2001,ACS Symposium Series,786:301). Certain embodiments may be performed using the general teachings of U.S. patent No. 5543158 to Gref et al or WO publication No. WO 2009/051837 to von Andrian et al.
In some embodiments, the polymer may be modified with lipid or fatty acid groups. In some embodiments, the fatty acid groups may be one or more of butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, or lignoceric acid. In some embodiments, the fatty acid group may be one or more of palmitoleic acid, oleic acid, inverted iso-oleic acid, linoleic acid, alpha-linoleic acid, gamma-linoleic acid, arachidonic acid, gadoleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, or erucic acid.
In some embodiments, the polymer may be a polyester comprising: copolymers comprising lactic acid and glycolic acid units, such as poly (lactic-co-glycolic acid) and poly (lactide-co-glycolide), collectively referred to herein as "PLGA"; and homopolymers comprising glycolic acid units, referred to herein as "PGA", and homopolymers comprising lactic acid units, such as poly-L-lactic acid, poly-D, L-lactic acid, poly-L-lactide, poly-D-lactide, and poly-D, L-lactide, referred to herein collectively as "PLA". In some embodiments, exemplary polyesters include, for example: polyhydroxyacid; PEG copolymers, copolymers of lactide and glycolide (e.g., PLA-PEG copolymers, PGA-PEG copolymers, PLGA-PEG copolymers), and derivatives thereof. In some embodiments, the polyester includes, for example: poly (caprolactone), poly (caprolactone) -PEG copolymers, poly (L-lactide-co-L-lysine), poly (serine esters), poly (4-hydroxy-L-proline esters), poly [ α - (4-aminobutyl) -L-glycolic acid ] and derivatives thereof.
In some embodiments, the polyester may be PLGA. PLGA is a biocompatible and biodegradable copolymer of lactic acid and glycolic acid, and various forms of PLGA are characterized by the ratio of lactic acid to glycolic acid. Lactic acid may be L-lactic acid, D-lactic acid or D, L-lactic acid. The degradation rate of PLGA can be regulated by varying the ratio of lactic acid to glycolic acid. In some embodiments, PLGA to be used according to the present invention is characterized by a lactic acid to glycolic acid ratio of about 85:15, about 75:25, about 60:40, about 50:50, about 40:60, about 25:75, or about 15:85.
In some embodiments, the polymer may be one or more acrylic polymers. In certain embodiments, the acrylic polymer includes, for example: acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymers, poly (acrylic acid), poly (methacrylic acid), alkylamide methacrylate copolymers, poly (methyl methacrylate), poly (methacrylic anhydride), methyl methacrylate, polymethacrylate, poly (methyl methacrylate) copolymers, polyacrylamide, aminoalkyl methacrylate copolymers, glycidyl methacrylate copolymers, polycyanoacrylate, and combinations comprising one or more of the foregoing polymers. The acrylic polymer may comprise a fully polymerized copolymer of acrylate and methacrylate having a low content of quaternary ammonium groups.
In some embodiments, the polymer may be a cationic polymer. In general, cationic polymers are capable of condensing and/or protecting negatively charged strands of nucleic acids. Amine-containing polymers such as poly (lysine) (Zauner et al, 1998,Adv.Drug Del.Rev, 30:97; and Kabanov et al, 1995,Bioconjugate Chem, 6:7), poly (ethyleneimine) (PEI; boussif et al, 1995, proc. Natl. Acad. Sci., USA,1995, 92:7297), and poly (amidoamine) dendrimers (Kukowska-Latallo et al, 1996, proc. Natl. Acad. Sci., USA,93:4897;Tang et al, 1996,Bioconjugate Chem, 7:703; and Haensler et al, 1993,Bioconjugate Chem, 4:372) form an ion pair with nucleic acids at physiological pH. In some embodiments, the synthetic nanocarriers may not include (or may exclude) cationic polymers.
In some embodiments, the polymer may be a degradable polyester with cationic side chains (Putnam et al, 1999,Macromolecules,32:3658;Barrera et al, 1993, J.Am.chem.Soc.,115:11010;Kwon et al, 1989,Macromolecules,22:3250;Lim etal, 1999, J.Am.chem.Soc.,121:5633; and Zhou et al, 1990, macromolecules, 23:3399). Some examples of these polyesters include: poly (L-lactide-co-L-lysine) (Barrera et al, 1993, J.am.chem.Soc., 115:11010), poly (serine esters) (Zhou et al, 1990, macromolecules, 23:3399), poly (4-hydroxy-L-proline esters) (Putnam et al, 1999, macromolecules,32:3658; and Lim et al.,1999, J.am.chem.Soc., 121:5633) and poly (4-hydroxy-L-proline esters) (Putnam et al.,1999, macromolecules,32:3658; and Lim et al.,1999, J.am.chem.Soc., 121:5633).
The nature of these and other polymers and methods for their preparation are well known in the art (see, e.g., U.S. patents
6,123,727;5,804,178;5,770,417;5,736,372;5,716,404;6,095,148;5,837,752;5,902,599;5,696,175;5,514,378;5,512,600;5,399,665;5,019,379;5,010,167;4,806,621;4,638,045; and 4,946,929; wang et al, 2001, j.am.chem.soc.,123:9480; lim et al, 2001, j.am.chem.soc.,123:2460; langer,2000, acc.chem.res.,33:94; langer,1999, J.control.Release,62:7, preparing a base material; and Uhrich et al, 1999, chem. Rev.,99: 3181).
More generally, various methods for synthesizing certain suitable polymers are described in
Concise Encyclopedia of Polymer Science and Polymeric Amines and Ammoniun Sults, ed.by Goethane, pergamon Press,1980; principles of Polymerization by Odian, john Wiley & Sons, fourier Edition,2004; contemporary Polymer Chemistry by Allcock et al, predce-Hall, 1981; deming et al, 1997, nature,390:386; and U.S. patent 6,506,577,6,632,922,6,686,446, 6,818,732.
In some embodiments, the polymer may be a linear or branched polymer. In some embodiments, the polymer may be a dendritic polymer. In some embodiments, the polymers may be substantially crosslinked to each other. In some embodiments, the polymer may be substantially non-crosslinked. In some embodiments, the polymer may be used according to the present invention without a crosslinking step. It should also be appreciated that the synthetic nanocarriers may comprise any of the foregoing block copolymers, graft copolymers, blends, mixtures, and/or adducts, as well as other polymers. Those skilled in the art will recognize that the polymers listed herein represent an exemplary, but not comprehensive, list of polymers that may be used in accordance with the present invention.
In some embodiments, the synthetic nanocarriers do not comprise a polymeric component. In some embodiments, the synthetic nanocarriers may comprise metal particles, quantum dots, ceramic particles, and the like. In some embodiments, the non-polymeric synthetic nanocarriers are aggregates of non-polymeric components, such as aggregates of metal atoms (e.g., jin Yuanzi).
The compositions according to the invention may comprise an element (e.g. an immunosuppressant and/or an antigen) in combination with a pharmaceutically acceptable excipient (e.g. a preservative, buffer, saline or phosphate buffered saline). The compositions may be prepared using conventional pharmaceutical manufacturing and compounding techniques to obtain useful dosage forms. In one embodiment, the compositions (e.g., those comprising immunosuppressants and/or antigens) are suspended in a sterile saline solution for injection along with a preservative.
In some embodiments, when preparing a synthetic nanocarrier as a carrier, a method for linking a component to the synthetic nanocarrier may be useful. If the component is a small molecule, it may be advantageous to attach the component to the polymer prior to assembly of the synthetic nanocarriers. In some embodiments, it may also be advantageous to prepare synthetic nanocarriers having surface groups that are used to attach components to the synthetic nanocarriers by using these surface groups, rather than attaching components to polymers, and then using the polymer conjugates in the construction of the synthetic nanocarriers.
In certain embodiments, the linkage may be a covalent linker. In some embodiments, immunosuppressants according to the present invention may be covalently attached to the external surface by a 1,2, 3-triazole linker formed by a 1, 3-dipolar cycloaddition reaction of an azide group on the nanocarrier surface with an immunosuppressant comprising an alkyne group or by a 1, 3-dipolar cycloaddition reaction of an alkyne on the nanocarrier surface with an immunosuppressant comprising an azide group. Such cycloaddition reactions are preferably carried out in the presence of a Cu (I) catalyst and suitable Cu (I) -ligands and reducing agents to reduce the Cu (II) compound to a catalytically active Cu (I) compound. This Cu (I) -catalyzed azide-alkyne cycloaddition (Cu (I) -catalyzed azide-alkyne cycloaddition, cuAAC) can also be referred to as a click reaction.
Alternatively, the covalent coupling may comprise covalent linkers including amide linkers, disulfide linkers, thioether linkers, hydrazone linkers, hydrazide linkers, imine or oxime linkers, urea or thiourea linkers, amidine linkers, amine linkers, and sulfonamide linkers.
Amide linkers are formed by an amide bond between an amine on one component and a carboxylic acid group on a second component (e.g., a nanocarrier). The amide bond in the linker can be prepared using any conventional amide bond formation reaction with an appropriately protected amino acid and an activated carboxylic acid (e.g., an N-hydroxysuccinimide activated ester).
Disulfide linkers are prepared by forming disulfide (S-S) bonds between two sulfur atoms, for example, in the form of R1-S-R2. Disulfide bonds may be formed by the exchange of a thiol/thiol group (-SH) containing component with another activated thiol on a polymer or nanocarrier or a thiol/thiol group containing nanocarrier with a thiol of an activated thiol containing component.
Triazole linkers (in particular wherein R1 and R2 may be any chemical entityForm 1,2, 3-triazole) is prepared by a 1, 3-dipolar cycloaddition reaction of an azide attached to a first component (e.g., a nanocarrier) with a terminal alkyne attached to a second component. The 1, 3-dipolar cycloaddition reaction is carried out with or without a catalyst, preferably with a Cu (I) -catalyst, which connects the two components via a 1,2, 3-triazole function. This chemistry is described in detail by sharp et al, angel w.chem.int.ed.41 (14), 2596, (2002) and melda, et al, chem.rev.,2008,108 (8), 2952-3015, and is commonly referred to as a "click" reaction or CuAAC.
In some embodiments, polymers are prepared that contain azide or alkyne groups at the ends of the polymer chain. The polymer is then used to prepare synthetic nanocarriers in such a way that a plurality of alkyne or azide groups are located on the surface of the nanocarrier. Alternatively, the synthetic nanocarriers can be prepared by another route and subsequently functionalized with alkyne or azide groups. The components are prepared in the presence of alkyne (if the polymer comprises azide) or azide (if the polymer comprises alkyne) groups. The component is then reacted with the nanocarrier by a 1, 3-dipolar cycloaddition reaction with or without a catalyst that covalently links the component to the particle via a 1, 4-disubstituted 1,2, 3-triazole linker.
Thioether linkers are prepared by forming a sulfur-carbon (thioether) bond, e.g., in the form of R1-S-R2. The thioether may be prepared by alkylating a mercapto/thiol (-SH) group on one component with an alkylating group (e.g., halide or epoxide) on the second component. Thioether linkers can also be formed by Michael addition (Michael addition) of a thiol/thiol group on one component with an electron-deficient alkenyl group on a second component comprising a maleimide group or a vinyl sulfone group as a Michael acceptor. In another approach, thioether linkers can be prepared by free radical mercapto-ene reactions of mercapto/thiol groups on one component with alkenyl groups on a second component.
The hydrazone linker is prepared by the reaction of a hydrazide group on one component with an aldehyde/ketone group on the second component.
The hydrazide linker is formed by the reaction of a hydrazine group on one component with a carboxylic acid group on a second component. Such reactions are typically carried out using a chemistry similar to amide bond formation, wherein the carboxylic acid is activated with an activating reagent.
Imine or oxime linkers are formed by the reaction of amine or N-alkoxyamine (or aminoxy) groups on one component with aldehyde or ketone groups on a second component.
Urea or thiourea linkers are prepared by the reaction of amine groups on one component with isocyanate or thioisocyanate groups on a second component.
The amidine linker is prepared by the reaction of an amine group on one component with an imidoester group on a second component.
Amine linkers are prepared by alkylation of amine groups on one component with an alkylating group (e.g., halide, epoxide, or sulfonate groups) on a second component. Alternatively, amine linkers can also be prepared by reductive amination of the amine groups on one component with aldehyde or ketone groups on the second component using a suitable reducing agent (e.g., sodium cyanoborohydride or sodium triacetoxyborohydride).
Sulfonamide linkers are prepared by the reaction of an amine group on one component with a sulfonyl halide (e.g., sulfonyl chloride) group on a second component.
The sulfone linkages are prepared by michael addition of a nucleophile to vinyl sulfone. The vinyl sulfone or nucleophile may be on the surface of the nanocarrier or attached to the component.
The component may also be conjugated to the nanocarrier by a non-covalent conjugation method. For example, a negatively charged immunosuppressant may be conjugated to a positively charged nanocarrier by electrostatic adsorption. The component comprising the metal ligand may also be conjugated to the nanocarrier comprising the metal complex via a metal-ligand complex.
In some embodiments, the components may be attached to a polymer (e.g., polylactic acid block-polyethylene glycol) prior to assembly of the synthetic nanocarriers, or the synthetic nanocarriers may be formed with reactive or activatable groups on their surfaces. In the latter case, the component may be prepared with groups compatible with the linking chemistry presented by the surface of the synthetic nanocarriers. In other embodiments, the peptide component may be linked to the VLP or liposome using a suitable linker. A linker is a compound or reagent that is capable of coupling two molecules together. In one embodiment, the linker may be a homobifunctional or heterobifunctional reagent as described in Hermanson 2008. For example, VLP or liposome synthetic nanocarriers comprising carboxyl groups on the surface may be treated with homobifunctional linker Adipic Dihydrazide (ADH) in the presence of EDC to form corresponding synthetic nanocarriers having ADH linkers. The resulting ADH-linked synthetic nanocarriers are then conjugated to a peptide component comprising an acid group through the other end of the ADH linker on the nanocarrier to produce the corresponding VLP or liposomal peptide conjugates.
For a detailed description of available conjugation methods, see Hermanson G T "Bioconjugate Techniques", second edition published by Academic Press, inc. In addition to covalent attachment, the components may be attached to the preformed synthetic nanocarriers by adsorption, or they may be attached by encapsulation during formation of the synthetic nanocarriers.
Any of the immunosuppressants provided herein can be used in the provided methods or compositions, and in some embodiments, can be linked to or contained in a synthetic nanocarrier. Immunosuppressants include, but are not limited to: statins; mTOR inhibitors, such as rapamycin or rapamycin analogues; TGF-beta signaling agents; TGF-beta receptor agonists; histone deacetylase (histone deacetylase, HDAC) inhibitors; corticosteroids; inhibitors of mitochondrial function, such as rotenone; a P38 inhibitor; NF- κβ inhibitors; adenosine receptor agonists; prostaglandin E2 agonists; phosphodiesterase inhibitors, such as phosphodiesterase 4 inhibitors; a proteasome inhibitor; a kinase inhibitor; a G protein-coupled receptor agonist; g protein-coupled receptor antagonists; glucocorticoids; retinoids; a cytokine inhibitor; cytokine receptor inhibitors; cytokine receptor activators; peroxisome proliferator activated receptor antagonists; peroxisome proliferator activated receptor agonists; histone deacetylase inhibitors; calcineurin inhibitors; phosphatase inhibitors and oxidized ATP. Immunosuppressants also include: IDO, vitamin D3, cyclosporin a, aromatic receptor inhibitors, resveratrol, azathioprine, 6-mercaptopurine, aspirin (aspirin), niflumic acid, estriol, triptolide (tripolide), interleukins (e.g., IL-1, IL-10), cyclosporin a, sirnas targeting cytokines or cytokine receptors, and the like.
Some examples of statins include: atorvastatin (atorvastatin) Cerivastatin (cerivastatin), fluvastatin (fluvastatin) (-j-in)> XL), lovastatin (lovastatin)> Mevastatin (mevastatin)Pitavastatin (pitavastatin)>Rosuvastatin (rosuvastatin) is added>RosuvastatinAnd simvastatin (simvastatin)>
Some examples of mTOR inhibitors include: rapamycin and analogues thereof (e.g., CCL-779, RAD001, AP23573, C20-methallyl rapamycin (C20-Marap), C16- (S) -butylsulfonylamino rapamycin (C16-BSrap), C16- (S) -3-methylindol rapamycin (C16-iRap) (Bayle et al chemistry & Biology 2006, 13:99-107)), AZD8055, BEZ235 (NVP-BEZ 235), da Huang Gensuan (chrysophanol), defrolimus (MK-8669), everolimus (RAD 0001), KU-0063794, PI-103, PP242, temsirolimus and WYE-354 (available from Selleck, houston, TX, USA).
Some examples of TGF- β signaling agents include: TGF-beta ligands (e.g., activin A, GDF, GDF11, bone morphogenic protein, nodal, TGF-beta) and their receptors (e.g., ACVR1B, ACVR1C, ACVR2A, ACVR2B, BMPR, BMPR1A, BMPR1B, TGF βRI, TGFβRII), R-SMADS/co-SMADS (e.g., SMAD1, SMAD2, SMAD3, SMAD4, SMAD5, SMAD 8) and ligand inhibitors (e.g., follistatin, noggin, chordin, DAN, lefty, LTBP, THBS1, decorin).
Some examples of inhibitors of mitochondrial function include: atractyloside (dipotassium salt), glycine (bongkrekic acid) (tri-ammonium salt), carbonyl cyanide m-chlorophenylhydrazone, carboxyatractyloside (e.g., from gum atractylodes (Atractylis gummifera)), CGP-37157, (-) -roteins (e.g., from silk Mao Mengdou (Mundulea sericea)), F16, hexokinase II VDAC binding domain peptide, oligomycin, roteinone, ru360, SFK1, and valinomycin (e.g., from streptomyces griseus (Streptomyces fulvissimus)) (EMD 4Biosciences, USA).
Some examples of P38 inhibitors include: SB-203580 (4- (4-fluorophenyl) -2- (4-methylsulfinylphenyl) -5- (4-pyridyl) 1H-imidazole), SB-239063 (trans-1- (4 hydroxycyclohexyl) -4- (fluorophenyl) -5- (2-methoxy-pyrimidin-4-yl) imidazole), SB-220025 (5- (2 amino-4-pyrimidinyl) -4- (4-fluorophenyl) -1- (4-piperidinyl) imidazole) and ARRY-797.
Some examples of NF (e.g., NK- κβ) inhibitors include: IFRD1, 2- (1, 8-naphthyridin-2-yl) -phenol, 5-aminosalicylic acid, BAY 11-7082, BAY 11-7085, CAPE (phenethyl caffeate), diethyl maleate, IKK-2 inhibitor IV, IMD 0354, lactomycin, MG-132[ z-Leu-CHO ], nfkb activation inhibitor III, NF-kb activation inhibitor II, JSH-23, parthenolide, phenylarsoid (PAO), PPM-18, pyrrolidinedicarbamic acid ammonium salt, QNZ, RO 106-9920, chinaberramide (rocaglamide), chinaberramide AL, chinaberramide C, chinaberramide I, chinaberramide J, rochollandiol (rocaglaol), (R) -MG-132, sodium salicylate, tripterygide (PG) and wedelolactone (wedelolactone).
Some examples of adenosine receptor agonists include CGS-21680 and ATL-146e.
Some examples of prostaglandin E2 agonists include E-prostaglandin 2 and E-prostaglandin 4.
Some examples of phosphodiesterase inhibitors (non-selective and selective inhibitors) include: caffeine, aminophylline, IBMX (3-isobutyl-1-methylxanthine), parathyroxanthine, pentoxifylline, theobromine, methylated xanthines, vinpocetine (vinnocetine), EHNA (erythro-9- (2-hydroxy-3-nonyl) adenine), anagrelide, enoximone (PERFANN) TM ) Milrinone, levosimendan, pine She Jujian, ibudilast, pirramide, luteolin, drotaverine, roflumilast (DAXAS) TM ,DALIRESP TM ) Sildenafil (sildenafil)Tadalafil (tadalafil)>Vardenafil (vardenafil)>Undenafil (udenafil), avanafil (avanafil), icariin, 4-methylpiperazine and pyrazolopyrimidine-7-1.
Some examples of proteasome inhibitors include: bortezomib (bortezomib), disulfiram (disufiram), epigallocatechin-3-gallate (epigallocatechin-3-gallate) and salinosporamide A (salinosporamide A).
Some examples of kinase inhibitors include: bevacizumab, BIBW 2992 and cetuximabImatinib (imatinib)>Trastuzumab depictingtrastuzumab>Gefitinib (gefitinib)>Ranibizumab (ranibizumab) in the presence of a drug>Pigatanib, sorafenib, dasatinib, sunitinib, erlotinib, nilotinib, lapatinib, panitumumab, vandetanib, E7080, pazopanib, and xylolitinib.
Some examples of glucocorticoids include hydrocortisone (cortisol), cortisone acetate, prednisone (prednisone), prednisolone (prednisolone), methylprednisolone, dexamethasone (dexamethasone), betamethasone (betamethasone), triamcinolone (triamcinolone), beclomethasone (beclomethasone), fludrocortisone acetate, deoxycorticosterone acetate (DOCA), and aldosterone.
Some examples of retinoids include: retinol, retinal, tretinoin (retinoic acid,
) Isotretinoin-> ) Aripitretinoin->Itracenate (TEGISON) TM ) And its metabolite acitretin (acitretin) >Tazarotene (tazarote)>Bexarotene (bexarotene)>And adapalene (adapalene)>/>
Some examples of cytokine inhibitors include: IL1ra, IL1 receptor antagonists, IGFBP, TNF-BF, uromodulin (uromodulin), alpha-2-macroglobulin, cyclosporin A, pentamidine (Pentamidine) and pentoxifylline
Some examples of peroxisome proliferator activated receptor antagonists include GW9662, ppary antagonists III, G335 and T0070907 (EMD 4Biosciences, USA).
Some examples of peroxisome proliferator activated receptor agonists include: pioglitazone, ciglitazone, clofibrate, GW1929, GW7647, L-165,041, LY 171883, PPARgamma activator, fmoc-Leu, troglitazone and WY-14643 (EMD 4Biosciences, USA).
Some examples of histone deacetylase inhibitors include: hydroxamic acids (or hydroxamates) such as koji Gu Liujun a, cyclic tetrapeptides (cyclic tetrapeptide) (e.g. trapoxin B) and depsipeptides, benzamides, electrophiles (electrophilic ketone), fatty acid compounds such as phenyl butyrate and valproic acid, hydroxamic acids such as vorinostat (SAHA), belinostat (PXD 101), LAQ824 and Pan Bisi he (panobinostat) (LBH 589), benzamides such as entinostat (entinostat) (MS-275), 994 and Mo Xisi he (mocetinostat) (MGCD 0103), nicotinamide, derivatives of NAD, dihydrocoumarin, naphthopyranone and 2-hydroxynaphthalene aldehyde.
Some examples of calcineurin inhibitors include: cyclosporine, pimecrolimus (pimecrolimus), cyclosporine (voclosporin) and tacrolimus.
Some examples of phosphatase inhibitors include: BN82002 hydrochloride, CP-91149, calyx sponge carcinoid A (calyculin A), cantharidic acid (cantharidic acid), cantharidin (cantharidin), cypermethrin (cypermethrin), ethyl-3, 4-desmostatin (methyl-3, 4-dephostatin), fosetretin sodium salt (fostriecin sodium salt), MAZ51, methyl-3, 4-desmostatin (methyl-3, 4-dephostatin), NSC 95397, norcantharidin (norcanthorin), okadaic acid (prorocentrum concavum) ammonium salt from thamniosphaga (prorocentrum concavum), okadaic acid potassium salt, okadaic acid sodium salt, phenylarsone oxide, various phosphatase inhibitor mixtures, protease 1C, protease 2A inhibitor protein, protease 2A1, protease 2A2 and sodium orthovanadate.
In some embodiments of any of the methods or compositions provided herein, when the antigen is also administered, the antigen can be linked to (e.g., encapsulated in) the synthetic nanocarrier to which the immunosuppressant is linked or to another population of synthetic nanocarriers that are not linked to the immunosuppressant. In other embodiments, the antigen is not linked to any synthetic nanocarriers. In some embodiments of any of these cases, the antigen may be delivered as the antigen itself or as a fragment or derivative thereof. For example, the therapeutic macromolecule may be delivered as the therapeutic macromolecule itself or as a fragment or derivative thereof.
Therapeutic macromolecules may include therapeutic proteins or therapeutic polynucleotides. Therapeutic proteins include, but are not limited to: infusible therapeutic proteins, enzymes, enzyme cofactors, hormones, coagulation factors, cytokines and interferons, growth factors, monoclonal and polyclonal antibodies (e.g., which are administered to a subject as an alternative therapy) and proteins associated with pompe disease (e.g., acid glucosidase alpha, rhGAA (e.g., myozyme) and Lumizyme (Genzyme)) therapeutic proteins also include proteins involved in the coagulation cascade.
Some examples of therapeutic proteins for enzyme replacement therapy of subjects with lysosomal storage disorders include, but are not limited to, imiphosase (e.g., CEREZYME) for the treatment of Gaucher's disease TM ) A-galactosidase A (a-gal A) (e.g., galactosidase beta, FABRYZYME) for the treatment of Brix disease TM ) Acid alpha-Glucosidase (GAA) (e.g., acid glucosidase alpha, LUMIZYME) for treating pompe disease TM ,MYOZYME TM ) Arylsulfatase B (e.g., laronidase), ALDURAZYME for the treatment of mucopolysaccharidosis TM The method comprises the steps of carrying out a first treatment on the surface of the Ai Duliu enzyme (idursulfase), ELAPRASE TM The method comprises the steps of carrying out a first treatment on the surface of the Arylsulfatase B, NAGLAZYME TM ) Pegolozyme (krystaxxa) and pegsicticase.
Some examples of enzymes include oxidoreductases, transferases, hydrolases, lyases, isomerases, asparaginase, uricases, glycosidases, asparaginase, uricases, proteases, nucleases, collagenases, hyaluronidases, heparinases, heparanases, lysins, and ligases.
Additional therapeutic proteins include, for example, engineered proteins such as Fc fusion proteins, bispecific antibodies, multispecific antibodies, nanobodies, antigen-binding proteins, antibody fragments, and protein conjugates, such as antibody drug conjugates.
Therapeutic polynucleotides include, but are not limited to: nucleic acid aptamers such as piptanib (Macugen, pegylated anti-VEGF aptamer), antisense therapeutics such as antisense polynucleotides or oligonucleotides (e.g., antiviral drugs Fomivirsen (Fomivirsen) or mipramine (Mipomersen), antisense therapeutics targeting messenger RNAs of apolipoprotein B to reduce cholesterol levels); small interfering RNAs (sirnas) (e.g., dicer substrate siRNA molecules (dsirnas) that are asymmetric double stranded RNAs of 25 to 30 base pairs that mediate RNAi with extremely high potency, or modified messenger RNAs (mmrnas), such as those disclosed in us patent application 2013/0115272 to de Fougerolles et al and us patent application 2012/0251618 to Schrum et al.
Additional therapeutic macromolecules useful in accordance with some aspects of the present invention will be apparent to those skilled in the art, and the invention is not limited in this regard.
In some embodiments, components such as antigens, high affinity IL-2 receptor agonists or immunosuppressants may be isolated. Isolated means that the element is isolated from its natural environment and present in a sufficient amount to allow its identification or use. This means, for example, that the element can be (i) selectively produced by expression cloning or (ii) purified by chromatography or electrophoresis. The isolated elements may be, but need not be, substantially pure. Since the separate element may be mixed with pharmaceutically acceptable excipients in a pharmaceutical formulation, the element may constitute only a small portion of the weight of the formulation. Nevertheless, the element is isolated in that it has been separated from substances in the living system that can be associated with it, i.e. from other lipids or proteins. Any of the elements provided herein may be isolated and contained in a composition or used in a method in isolated form.
D. Methods of making and using compositions and related methods
Synthetic nanocarriers can be prepared using a wide variety of methods known in the art. For example, the synthetic nanocarriers can be formed by, for example, the following methods: nano-precipitation, flow focusing using fluidic channels, spray drying, single and double emulsion solvent evaporation, solvent extraction, phase separation, milling, microemulsification operations, microfabrication, nano-fabrication, sacrificial layers, simple and complex coacervation, and other methods known to those of ordinary skill in the art. Alternatively or additionally, aqueous and organic solvent synthesis for monodisperse semiconductor, conductive, magnetic, organic and other nanomaterials has been described (Pellegrino et al, 2005,Small,1:48;Murray et al, 2000, ann.rev. Mat. Sci.,30:545; and Trindade et al, 2001, chem. Mat., 13:3843). Additional methods have been described in the literature (see, e.g., doubrow, eds., "Microcapsules and Nanoparticles in Medicine and Pharmacy," CRC Press, boca Raton,1992;Mathiowitz et al, 1987,J.Control.Release,5:13;Mathiowitz et al.1987,Reactive Polymers,6:275; and Mathiolitz et al, 1988,J.Appl.Polymer Sci, 35:755; U.S. Pat. Nos. 5578325 and 6007845;P.Paolicelli et al, "Surface-modified PLGA-based Nanoparticles that can Efficiently Associate and Deliver Virus-like Particles" nanomedicine.5 (6): 843-853 (2010)).
A variety of materials may be encapsulated into the synthetic nanocarriers as desired using a variety of methods including, but not limited to: ascete et al, "Synthesis and characterization of PLGA nanoparticles" j.biomatter.sci.polymer Edn, volume 17, stage 3, pages 247 to 289 (2006); avgoutakis "Pegylated Poly (Lactide) and Poly (Lactide-Co-glycoide) nanopartics: preparation, properties and Possible Applications in Drug Delivery" Current Drug Delivery 1:321-333 (2004); reis et al, "Nanomedicine I.methods for preparation of drug-loaded polymeric nanoparticles" Nanomedicine 2:8-21 (2006); paolicelli et al, "Surface-modified PLGA-based Nanoparticles that can Efficiently Associate and Deliver Virus-like Particles" nanomedicine.5 (6): 843-853 (2010). Other methods suitable for encapsulating the substance into the synthetic nanocarriers may be used, including but not limited to the method disclosed in U.S. patent 6,632,671 to Unger at 14/10/2003.
In certain embodiments, the synthetic nanocarriers are prepared by a nano-precipitation method or spray drying. The conditions used to prepare the synthetic nanocarriers can be varied to produce particles having a desired size or property (e.g., hydrophobicity, hydrophilicity, external morphology, "viscosity," shape, etc.). The method of preparing the synthetic nanocarriers and the conditions of use (e.g., solvent, temperature, concentration, air flow, etc.) may depend on the composition of the substance and/or polymer matrix to be coupled to the synthetic nanocarriers.
If the size range of the synthetic nanocarriers prepared by any of the above methods is outside of the desired range, the synthetic nanocarriers may be resized, for example, using a sieve.
The elements (i.e., components) of the synthetic nanocarriers may be linked to the entire synthetic nanocarrier, for example, by one or more covalent bonds, or may be linked by means of one or more linkers. Additional methods of functionalizing synthetic nanocarriers can be adapted from published U.S. patent application 2006/0002852 to Saltzman et al, published U.S. patent application 2009/0028910 to DeSimone et al, or published International patent application WO/2008/127532A1 to Murthy et al.
Alternatively or additionally, the synthetic nanocarriers may be directly or indirectly linked to the component via non-covalent interactions. In some non-covalent embodiments, the non-covalent linkage is mediated by non-covalent interactions including, but not limited to, charge interactions, affinity interactions, metal coordination, physical adsorption, host-guest interactions (host-guest interaction), hydrophobic interactions, TT stacking interactions, hydrogen bonding interactions, van der Waals interactions, magnetic interactions, electrostatic interactions, dipole-dipole interactions, and/or combinations thereof. Such a connection may be disposed on an outer or inner surface of the synthetic nanocarrier. In some embodiments, encapsulation and/or absorption is the form of attachment. In some embodiments, the synthetic nanocarriers may be combined with the antigen by mixing in the same carrier or delivery system.
The compositions provided herein may comprise inorganic or organic buffers (e.g., sodium or potassium salts of phosphoric acid, carbonic acid, acetic acid, or citric acid) and pH modifiers (e.g., hydrochloric acid, sodium or potassium hydroxide, citrate or acetate salts, amino acids, and salts thereof), antioxidants (e.g., ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene 9-10 nonylphenol, sodium deoxycholate), solution and/or freeze/lyophilization stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic regulators (e.g., salts or sugars), antibacterial agents (e.g., benzoic acid, phenols, gentamicin), antifoaming agents (e.g., polydimethylsiloxane (e.g., thiomerosal, 2-phenoxyethanol, EDTA), polymeric stabilizers and modifiers (e.g., polyvinylpyrrolidone, poloxamer 488, carboxymethylcellulose), and co-solvents (e.g., glycerol, polyethylene glycol, ethanol).
The composition according to the invention may comprise pharmaceutically acceptable excipients. The compositions may be prepared using conventional pharmaceutical manufacturing and compounding techniques to obtain useful dosage forms. Techniques suitable for use in the practice of the present invention can be found in Handbook of Industrial Mixing: science and Practice, edward L.Paul, victor A.Atiemo-Obeng, and Suzanne M.Kresta,2004John Wiley&Sons,Inc; and Pharmacutinics, the Science of Dosage Form Design,2nd Ed.M.E.Auten, editions 2001,Churchill Livingstone. In one embodiment, the composition is suspended with a preservative in a sterile injectable saline solution.
It should be understood that the compositions of the present invention may be prepared in any suitable manner and that the present invention is in no way limited to compositions that may be produced using the methods described herein. The selection of an appropriate manufacturing method may require attention to the characteristics of the particular part concerned.
In some embodiments, the composition is prepared under aseptic conditions or terminally sterilized. This ensures that the resulting composition is sterile and non-infective, thus improving safety when compared to non-sterile compositions. This provides a valuable safety measure, especially when the subject receiving the composition is immune-deficient, suffering from infection and/or susceptible to infection. In some embodiments, the composition may be lyophilized and stored in suspension or as a lyophilized powder, depending on the formulation strategy for extended periods of time without losing activity.
Administration according to the present invention may be by a variety of routes including, but not limited to, subcutaneous, intravenous, intraperitoneal, intramuscular, transmucosal, transdermal or intradermal routes. In a preferred embodiment, administration is via the subcutaneous route of administration. The compositions mentioned herein may be manufactured and prepared for application using conventional methods, in some embodiments with concomitant application.
The compositions of the present invention may be administered in an effective amount (e.g., an effective amount as described elsewhere herein). According to the invention, dosage forms may contain various amounts of high affinity IL-2 receptor agonists, immunosuppressants and/or antigens. The amount of high affinity IL-2 receptor agonist, immunosuppressant and/or antigen present in the dosage form may vary depending on the nature of the high affinity IL-2 receptor agonist, immunosuppressant and/or antigen, the therapeutic benefit to be achieved, and other such parameters. In some embodiments, a dose-range study may be performed to determine the optimal therapeutic amount of high affinity IL-2 receptor agonist, immunosuppressant, and/or antigen present in the dosage form. In some embodiments, the high affinity IL-2 receptor agonist, immunosuppressant, and/or antigen is present in the dosage form in an amount effective to produce a tolerogenic immune response to the antigen after administration to a subject, e.g., according to the methods provided herein. In some preferred embodiments, the high affinity IL-2 receptor agonist, immunosuppressant, and/or antigen is present in the dosage form in an amount effective to enhance the production or development or persistence of regulatory T cells (e.g., cd4+ regulatory T cells), e.g., when concomitantly administered to a subject as provided herein. Conventional dose-range studies and techniques can be used in a subject to determine the amount of high affinity IL-2 receptor agonist, immunosuppressant, and/or antigen effective to produce a desired immune response. Dosage forms may be administered at a variety of frequencies. In other embodiments, the high affinity IL-2 receptor agonist, immunosuppressant and/or antigen is present in the dosage form in an amount effective to reduce the number of cytotoxic cd8+ T cells in the liver and/or to increase the number of double negative CD4-CD8- (DN) T cells in the liver and/or spleen.
Another aspect of the present disclosure relates to a kit. In some embodiments, the kit comprises an immunosuppressant and a high affinity IL-2 receptor agonist. In some embodiments, the kit further comprises an antigen. In one embodiment, the immunosuppressant is attached to a synthetic nanocarrier. In another embodiment, the antigen may be linked to a synthetic nanocarrier comprising an immunosuppressant or other synthetic nanocarrier (in some embodiments). The immunosuppressant, the high affinity IL-2 receptor agonist, and any other components may be contained in separate containers in a kit. In some embodiments, the container is a vial or ampoule. In some embodiments, the immunosuppressant, the high affinity IL-2 receptor agonist, and any other components are contained in a solution separate from the container, such that the immunosuppressant, the high affinity IL-2 receptor agonist, and any other components can be added to the container at a later time. In some preferred embodiments, the immunosuppressant, the high affinity IL-2 receptor agonist, and any other components are not co-formulated with one another prior to administration. In some embodiments, the immunosuppressant, the high affinity IL-2 receptor agonist, and any other components are each in a separate container in lyophilized form, such that they can be reconstituted at a later time. In some embodiments, the kit further comprises instructions for reconstitution, mixing, administration, and the like. In some embodiments, the instructions include a description of the methods described herein. The instructions may be in any suitable form, for example as printed inserts or labels. In some embodiments, the kit further comprises one or more syringes or other devices for administering immunosuppressants, high affinity IL-2 receptor agonists, and any other components.
Examples
Example 1: immmTOR and IL-2 mutein combinations
Mice were used to evaluate the effect of injection of ImmTOR (rapamycin-encapsulating polymer (PLA/PLA-PEG) synthetic nanocarriers) and/or IL-2 muteins (Khoryati, et al science immunology|report,5, eba5264 (2020)) on the expression levels of FoxP3 or additional Treg markers in the liver and spleen. Animals were divided into four groups, numbered 1 to 4 (3 mice/group). Group 1 animals received a single retroorbital injection of 300 μg ImmTOR. Animals in group 2 received one intraperitoneal injection of 9. Mu.g IL-2 mutein. Animals in group 3 received one intraperitoneal injection of 9 μg of IL-2 mutein followed by one retroorbital injection of 300 μg of ImmmmmTOR. Animals of group 4 were untreated and served as controls to define a flow cytometry baseline. Spleen and liver tissue was harvested 7 days after treatment and treated for flow cytometry measurements.
Spleen T cells
Cd4+ T cells were harvested from spleens from the 4 groups of animals described above. For IL-2 mutein injections (animals group 2), a significant increase in CD25 and FoxP3 expression was observed relative to the control group (animals group 4) and thus Treg counts were increased and further increased when IL-2 mutein injections were combined with ImmTOR injections (animals group 3), in particular with respect to FoxP3 expression (fig. 1B and 1C). IL-2 mutein administration (group 2) slightly increased DN T cell count relative to the control group (group 4).
Liver T cell
Cd4+ T cells were collected from the livers of animals of all four experimental groups. When both IL-2 mutein and ImmTOR were injected (group 3), CD25 expression and FoxP3 expression were significantly increased in liver CD 4T cells, indicating an increase in liver Treg counts relative to baseline (fig. 3B and 3C).
All three treatment groups showed a significant decrease in liver cd8+ T cells compared to the control group, indicating that both ImmTOR and IL-2 muteins have downregulating effects, both alone and in combination. Group 3 showed a slight decrease in cd8+ T cell count compared to groups 1 and 2, respectively, indicating that injection of both ImmTOR and IL-2 muteins was more effective in reducing cd8+ T cell levels (fig. 4A). Both group 1 (ImmTOR alone) and group 3 (combined IL-2 mutein with ImmTOR) showed a significant increase in liver DN T cell count compared to baseline (fig. 4B).
Example 2: sustained induction of Treg with ImmTOR and IL-2 mutein combinations
Mice were used to evaluate the effect of injection of ImmTOR (rapamycin-encapsulating polymer (PLA/PLA-PEG) synthetic nanocarriers) and/or IL-2 muteins on the number of cd4+cd25+foxp3+ tregs in the spleen. Animals were divided into four groups, numbered 1 to 4. Group 1 animals received a single retroorbital injection of 300 μg ImmTOR. Animals in group 2 received one intraperitoneal injection of 9. Mu.g IL-2 mutein. Animals in group 3 received one intraperitoneal injection of 9 μg of IL-2 mutein followed by one retroorbital injection of 300 μg of ImmmmmTOR. Animals of group 4 were untreated and served as controls to define a flow cytometry baseline. Spleen tissue was harvested 4, 7 and 14 days after treatment and treated for flow cytometry measurements. Cd4+ T cells were harvested from spleens from the 4 groups of animals described above.
On day 4 after treatment, animals treated with IL-2 mutein alone (group 2) and with IL-2 mutein and ImmTOR (group 3) had significantly higher spleen cd4+cd25+foxp3+ Treg counts compared to baseline. Notably, animals in group 2 had the highest counts, with Treg counts that were more than 6-fold higher (27% of cd4+ cells) compared to baseline (4% of cd4+ cells), while animals in group 3 were 3.5-fold higher (14% of cd4+ cells). IL-2 muteins non-selectively amplify all pre-existing tregs, which accounts for the high Treg counts in animals of group 2. Animals in group 3 had the highest Treg levels at day 7 and day 14 after treatment, significantly higher than Treg counts in all three other groups. Treg levels from animals in group 2 were higher than baseline on day 7, but returned to baseline on day 14. These results indicate that the combination of ImmTOR with IL-2 muteins is more effective in inducing robust and sustained increases in Treg counts.
Example 3: synergistic Activity of ImmTOR in combination with IL-2 muteins
Mice received one retroorbital injection of 300 μg ImmTOR, one intraperitoneal injection of 9 μg IL-2 mutein, and/or one intraperitoneal injection of 100 μg ovalbumin. Total spleen Treg counts and Ovalbumin (OVA) -specific Treg counts were measured, as shown in fig. 7, with the control group not receiving any immunosuppressant, IL-2 mutein or ovalbumin in order to determine a baseline for comparison with the other experimental groups.
The results showed that animals receiving ImmTOR and ovalbumin had significantly higher OVA-specific Treg counts relative to baseline, but did not show a significant increase in total spleen Treg counts. This suggests that administration of a combination of ImmTOR with ovalbumin induces specialization of tregs to OVA-specific tregs. The combination of ImmTOR with IL-2 mutein alone increased total Treg counts, but did not affect OVA-specific Treg levels. In contrast, animals receiving a combination of IL-2 mutein, immTOR and ovalbumin exhibited significantly higher OVA-specific tregs and significantly higher total spleen Treg counts compared to baseline, indicating a synergistic activity of IL-2 mutein and ImmTOR in inducing a tolerogenic response against ovalbumin antigen.
Example 4: synthesis of synthetic nanocarriers containing immunosuppressants (prophetic)
Synthetic nanocarriers that contain immunosuppressants (e.g., rapamycin) can be produced using any method known to those of ordinary skill in the art. Preferably, in some embodiments of any one of the methods or compositions provided herein, the synthetic nanocarriers comprising immunosuppressant are produced by any one of U.S. publication No. us2016/0128986 A1 and U.S. publication No. us 2016/01289887 A1, such production methods and resulting synthetic nanocarriers described are incorporated herein by reference in their entirety. In any of the methods or compositions provided herein, the synthetic nanocarriers comprising an immunosuppressant are synthetic nanocarriers so incorporated.
Example 5: combination of immTOR with Terogenic nanoparticles and IL-2 muteins induces massive expansion of antigen-specific regulatory T cells
Biodegradable ImmTOR nanoparticles encapsulating rapamycin (PLA/PLA-PEG synthetic nanocarriers encapsulating rapamycin) (inhibitors of the mTOR pathway) have the ability to reduce the immunogenicity of AAV vectors and enable re-administration. However, delayed immune responses can lead to breakthrough of anti-AAV antibodies in some animals, particularly at higher vector doses. The combination of ImmTOR with regulatory T cells (Treg) -selective interleukin 2 (IL-2) mutant molecules (IL-2 muteins) has been studied. Teg-selective IL-2 muteins have been shown to amplify all pre-existing Tregs, unlike ImmTOR, which induces antigen-specific Treg.
ImmTOR has been found to act synergistically with IL-2 muteins. The same day as IL-2 mutein administration of single dose ImmTOR resulted in an increase in total Treg. However, expansion of antigen-specific tregs may be preferable to expansion of total tregs. The ability of ImmTOR plus antigen in combination with IL-2 muteins to induce and/or amplify antigen-specific tregs was evaluated. Ovalbumin-specific OTII T cells were adoptively transferred into mice and then treated with ovalbumin and ImmmTOR and/or IL-2 muteins. As expected, immtor+ovalbumin did not amplify total Treg, but increased the percentage of foxp3+otii cells from about 3% to 15%. IL-2 mutein + ovalbumin resulted in a more modest increase, similar to that observed with ovalbumin alone (about 6%). However, the combination of immtor+il-2 mutein+ovalbumin showed a significant synergy, with about 45% of the Foxp3 expressing OTII cells.
A combination of ImmTOR and IL-2 muteins was tested to see if it could achieve a more durable inhibition of the antibody response against the co-administered AAV gene therapy vector. Mice were treated with two doses of AAV8 vector on days 0 and 56, with or without the ImmTOR +/-IL-2 mutein administered on days 0 and 56. Treatment with IL-2 muteins showed a modest decrease in anti-AAV IgG antibodies (fig. 8). Mice treated with ImmTOR showed dose-dependent inhibition of anti-AAV antibodies, and therapeutic doses of ImmTOR (200 μg) inhibited antibody formation until day 75 (19 days after the second dose of AAV). However, by day 91, some mice exhibited delayed development of anti-AAV antibodies. In contrast, the combination of immtor+il-2 muteins completely inhibited antibody formation until day 117. These results indicate that the combination of ImmTOR with IL-2 muteins can provide more durable antigen-specific immune tolerance to mitigate the immunogenicity of AAV gene therapy vectors.
Claims (53)
1. A composition comprising:
(a) Immunosuppressants (e.g., synthetic nanocarriers comprising the immunosuppressants);
(b) High affinity IL-2 receptor agonists, and
(b) Optionally, an antigen.
2. The composition of claim 1, further comprising a pharmaceutically acceptable excipient.
3. The composition of claim 1 or claim 2, wherein the antigen is encapsulated in the synthetic nanocarrier.
4. A dosage form comprising the composition of any one of claims 1 to 3.
5. A method comprising administering to a subject in need thereof:
(a) Immunosuppressants (e.g., synthetic nanocarriers comprising the immunosuppressants);
(b) High affinity IL-2 receptor agonists, and
(b) Optionally, an antigen.
6. The method of claim 5, wherein the immunosuppressant and the high affinity IL-2 receptor agonist and optionally antigen are concomitantly administered.
7. The method of any one of claims 5 to 6, wherein (a), (b) and optionally (c) are administered in an amount effective to enhance regulatory T cells (e.g., cd4+), such as antigen-specific regulatory T cells (e.g., cd4+).
8. The method of any one of claims 5 to 7, wherein the subject has or is at risk of having an inflammatory disease, an autoimmune disease, an allergy or a graft versus host disease.
9. The method of any one of claims 5 to 8, wherein the subject has or is at risk of having an undesired immune response against an antigen being administered or to be administered to the subject.
10. The method of claim 9, wherein the antigen is a therapeutic macromolecule.
11. The method of any one of claims 5 to 9, wherein the subject has or is at risk of having an undesired immune response to an antigen to which the subject is or will be exposed.
12. The method or composition of any one of the preceding claims, wherein the immunosuppressant comprises a statin, an mTOR inhibitor, a TGF- β signaling agent, a corticosteroid, a mitochondrial function inhibitor, a P38 inhibitor, an NF- κb inhibitor, an adenosine receptor agonist, a prostaglandin E2 agonist, a phosphodiesterase 4 inhibitor, an HDAC inhibitor, or a proteasome inhibitor.
13. The method or composition of claim 12, wherein the mTOR inhibitor is rapamycin or a rapamycin analog.
14. The method or composition of any of the preceding claims, wherein the synthetic nanocarrier comprises a lipid nanoparticle, a polymer nanoparticle, a metal nanoparticle, a surfactant-based emulsion, a dendrimer, a buckyball, a nanowire, a virus-like particle, or a peptide or protein particle.
15. The method or composition of claim 14, wherein the synthetic nanocarriers comprise polymeric nanoparticles.
16. The method or composition of claim 14 or 15, wherein the polymer nanoparticle comprises a polyester, a polyester coupled with a polyether, a polyamino acid, a polycarbonate, a polyacetal, a polyketal, a polysaccharide, a polyethylOxazolines or polyethylenimines.
17. The method or composition of claim 16, wherein the polyester comprises poly (lactic acid), poly (glycolic acid), poly (lactic-co-glycolic acid), or polycaprolactone.
18. The method or composition of claim 16 or 17, wherein the polymer nanoparticle comprises a polyester and a polyester coupled to a polyether.
19. The method or composition of any of claims 16 to 18, wherein the polyether comprises polyethylene glycol or polypropylene glycol.
20. The method or composition of any of the above claims, wherein the average value of the particle size distribution of the synthetic nanocarriers obtained using dynamic light scattering is greater than 100nm in diameter.
21. The method or composition of claim 20, wherein the diameter is greater than 150nm.
22. The method or composition of claim 21, wherein the diameter is greater than 200nm.
23. The method or composition of claim 22, wherein the diameter is greater than 250nm.
24. The method or composition of claim 23, wherein the diameter is greater than 300nm.
25. The method or composition of any of claims 20 to 24, wherein the diameter is less than 500nm.
26. The method or composition of any of claims 20 to 24, wherein the diameter is less than 450nm.
27. The method or composition of any of claims 20 to 24, wherein the diameter is less than 400nm.
28. The method or composition of any of claims 20 to 24, wherein the diameter is less than 350nm.
29. The method or composition of any of claims 20 to 23, wherein the diameter is less than 300nm.
30. The method or composition of any of claims 20 to 22, wherein the diameter is less than 250nm.
31. The method or composition of claim 20 or 21, wherein the diameter is less than 200nm.
32. The method or composition of any of the above claims, wherein the aspect ratio of the synthetic nanocarriers is greater than or equal to 1:1, 1:1.2, 1:1.5, 1:2, 1:3, 1:5, 1:7, or 1:10.
33. The method or composition of any of the above claims, wherein the immunosuppressant contained in the synthetic nanocarrier has an average loading on the synthetic nanocarrier of 1% to 40% (w/w).
34. The method or composition of claim 33, wherein the loading is 1% to 30%.
35. The method or composition of claim 34, wherein the loading is 1% to 25%.
36. The method or composition of claim 33, wherein the loading is 2% to 40%.
37. The method or composition of claim 36, wherein the loading is 2% to 30%.
38. The method or composition of claim 37, wherein the loading is 2% to 25%.
39. The method or composition of claim 33, wherein the loading is 4% to 40%.
40. The method or composition of claim 39, wherein the loading is from 4% to 30%.
41. The method or composition of claim 40, wherein the loading is from 4% to 25%.
42. The method or composition of claim 33, wherein the loading is 8% to 40%.
43. The method or composition of claim 42, wherein the loading is 8% to 30%.
44. The method or composition of claim 43, wherein the loading is 8% to 25%.
45. The method or composition of any one of the preceding claims, wherein the high affinity IL-2 receptor agonist is wild-type IL-2, an IL-2 mutein, an IL-2 mimetic, or an IL-2 fusion protein.
46. The method or composition of any one of the preceding claims, wherein the frequency, dosage, timing, and/or pattern of administration of the synthetic nanocarriers comprising the immunosuppressant is according to any one of the regimens provided herein.
47. The method or composition of any one of the preceding claims, wherein the frequency, dose, timing, and/or pattern of administration of the high affinity IL-2 receptor agonist is according to any one of the regimens provided herein.
48. The method or composition of any of the preceding claims, wherein the frequency, dosage, timing, and/or pattern of optional antigen administration is according to any of the regimens provided herein.
49. The method or composition of any of the preceding claims, wherein the antigen is a therapeutic macromolecule, such as a therapeutic polynucleotide, such as a viral vector.
50. The method or composition of claim 49, wherein when the antigen is a viral vector, the synthetic nanocarrier comprising the immunosuppressant, high affinity IL-2 receptor agonist (e.g., IL-mutein), and viral vector are concomitantly administered every month.
51. The method or composition of claim 50, wherein said concomitant administration is performed at least twice.
52. The method or composition of claim 50 or 51, wherein the dose of the synthetic nanocarrier, high affinity IL-2 receptor agonist (e.g., IL-mutein), and/or viral vector comprising the immunosuppressant is any of the corresponding doses provided herein.
53. The method or composition of claim 50 or 51, wherein the dose of synthetic nanocarriers comprising immunosuppressant is any of the doses provided herein.
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