(19) United States
`(2) Patent Application Publication (10) Pub. No.: US 2015/0140036 A1
`(43) Pub. Date:
`May 21, 2015
`Mannicket al.
`
`US 20150.140036A1
`
`(54)
`
`(71)
`
`(72)
`
`(73)
`
`LOW, IMMUNE ENHANCING, DOSE MTOR
`INHIBITORS AND USES THEREOF
`
`Applicants: Joan Mannick, Cambridge, MA (US);
`David Glass, Cambridge, MA (US);
`Leon Murphy, Cambridge, MA (US)
`
`Inventors: Joan Mannick, Cambridge, MA (US);
`David Glass, Cambridge, MA (US);
`Leon Murphy, Cambridge, MA (US)
`
`Assignee: NOVARTIS INSTITUTES FOR
`BIOMEDICAL RESEARCH, INC.,
`Cambridge, MA (US)
`
`(21)
`
`Appl. No.: 14/540,867
`
`(22)
`
`Filed:
`
`Nov. 13, 2014
`
`(60)
`
`Related U.S. Application Data
`Provisional application No. 62/052,629, filed on Sep.
`19, 2014, provisional application No. 62/027,121,
`filed on Jul. 21, 2014, provisional application No.
`
`61/903,636, filed on Nov. 13, 2013, provisional appli
`cation No. 62/076,142, filed on Nov. 6, 2014.
`Publication Classification
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`(51) Int. Cl.
`A61R 39/39
`G0IN 33/68
`A61R 39/09
`CI2N 7/00
`A61 K 45/06
`A61 K 39/145
`(52) U.S. CI.
`CPC ................. A61K39/39 (2013.01); A61K 45/06
`(2013.01); A61K39/145 (2013.01); A61 K
`39/092 (2013.01); C12N 7/00 (2013.01); G0IN
`33/6854 (2013.01); A61K2039/55511
`(2013.01)
`
`ABSTRACT
`(57)
`The present invention relates, in part, to compositions and
`methods for enhancement of an immune response by partial
`mTOR inhibition, e.g., with low, immune enhancing, doses of
`an mTOR inhibitor, such as RAD001.
`
`Ex. 1106-0001
`
`

`

`Patent Application Publication May 21, 2015 Sheet 1 of 8
`
`US 2015/0140036 A1
`
`##3. A
`
`
`
`i
`
`
`
`i
`
`&######3
`
`Vaccine
`: Straits
`
`* vaccine
`
`*:::::::... 3.;
`
`Strains
`
`$383 & &
`ºº::::::::::
`
`Ex. 1106-0002
`
`

`

`Patent Application Publication May 21, 2015 Sheet 2 of 8
`
`US 2015/0140036 A1
`
`*
`
`
`
`AH1N1
`
`Ö 0.5 mg daily
`+ 5 mg weekiy
`20 mg weekiy
`
`Evero?raas Concentration ing?mily
`
`Ex. 1106-0003
`
`

`

`Patent Application Publication
`
`May 21, 2015 Sheet 3 of 8
`
`US 2015/0140036 A1
`
`
`
`-----
`
`--
`
`Aºni Heterologous
`& Aft:382
`Strains
`
`3.5 mg da?y
`
`5 mg weekiy
`ºfte:{{{{{{{{f
`
`29 tº weeky
`
`Ex. 1106-0004
`
`

`

`Patent Application Publication May 21, 2015 Sheet 4 of 8
`
`US 2015/0140036 A1
`
`i
`
`i3
`
`
`
`| i
`
`s
`
`---
`
`---
`
`RADoo!
`0.5 mg daily
`
`RAD001
`RAD001
`5 mg weekly 20 mg weekly
`
`-->**
`
`#3:30:a::g
`
`§§§33
`0.5 mg daily
`
`RADool
`#
`5 mg weekly 20 mg weekly
`
`*?acebo
`
`
`
`Ex. 1106-0005
`
`

`

`Patent Application Publication May 21, 2015 Sheet 5 of 8
`
`US 2015/0140036 A1
`
`& 8
`
`& 33
`
`
`
`
`
`
`
`
`
`
`
`Ex. 1106-0006
`
`

`

`Patent Application Publication May 21, 2015 Sheet 6 of 8
`
`US 2015/0140036 A1
`
`
`
`4 3.§:- -
`
`-- 3 §
`
`Ex. 1106-0007
`
`

`

`Patent Application Publication May 21, 2015 Sheet 7 of 8
`
`US 2015/0140036 A1
`
`H6. 7
`
`Suhgecia ra;3<:::*£.ir3g am imraaaa
`in emiiitgr to
`.................................................................................
`
`S£«g:2}§g:{:t3 2*-egygmcriéng;
`§acr$a.gg, 3;; ewe-zr-gig
`..........................................................................................................................H
`
`
`P§ae::e%;~:t«
`ilfiimg
`i2£%mg
`W3
`am?
`33;} mg
`
`Ex. 1 106-0008
`
`Ex. 1106-0008
`
`

`

`Patent Application Publication May 21, 2015 Sheet 8 of 8
`
`US 2015/0140036 A1
`
`.
`i
`
`
`
`
`
`
`
`23
`* {{ags;
`
`Ex. 1106-0009
`
`

`

`US 2015/014003.6 A1
`
`May 21, 2015
`
`LOW, IMMUNE ENHANCING, DOSE MTOR
`INHIBITORS AND USES THEREOF
`[0001] This application claims priority to U.S. Ser. No.
`61/903,636, filed Nov. 13, 2013, U.S. Ser. No. 62/027,121,
`filed Jul. 21, 2014, U.S. Ser. No. 62/052,629, filed Sep. 19,
`2014, and U.S. Ser. No. 62/076,142, filed Nov. 6, 2014, the
`entire contents of each of these applications are incorporated
`herein by reference.
`
`BACKGROUND
`
`[0002] Functional and effective T-cell responses play an
`important role in effective immune responses, for example,
`against infectious diseases and cancer. However, under cer
`tain conditions, such as chronic infection or cancer, effector T
`cells can be suppressed by various immunosuppressive
`mechanisms, including programmed death ligand-1 (PD-L1)/
`programmed death-1 (PD-1) interaction, leading to T-cell
`exhaustion (Pen et al. Gene Therapy 21, 262-271, 2014). It is
`thought that PD-L1 is normally expressed by most cell types,
`while its receptor PD-1 is only present on certain immune
`cells, such as activated T cells and regulatory T (Treg) cells. It
`is also thought that PD-L1/PD-1 binding is important in the
`maintenance of peripheral T-cell tolerance, preventing auto
`immune responses. On the other hand, high levels of PD-1
`expression generally correlate with loss of T cell function,
`leading to increased viral load in cases of viral infection (Pen
`et al. Gene Therapy 21, 262-271, 2014).
`
`SUMMARY OF THE INVENTION
`[0003] Methods and compositions disclosed herein are
`based, at least in part, on the discovery that partial mTOR
`inhibition, e.g., with low, immune enhancing, doses of an
`mTOR inhibitor, e.g., an allosteric mTOR inhibitor, such as
`RAD001, is effective to improve immune function in a sub
`ject. While not wishing to be bound by theory, it is believed
`that treatment with a low, immune enhancing, dose (e.g., a
`dose that is insufficient to completely suppress the immune
`system but sufficient to improve immune function) of an
`mTOR inhibitor is accompanied by a decrease in PD-1 posi
`tive immune effector cells, e.g., T cells, an increase in PD-1
`negative immune effector cells, e.g., T cells, or an increase in
`the ratio of in PD-1 negative immune effector cells, e.g., T
`cells/PD-1 positive immune effector cells, e.g., T cells. PD-1
`positive T cells, but not PD-1 negative T cells, can be
`exhausted by engagement with cells which express a PD-1
`ligand, e.g., PD-L1 or PD-L2. Thus, embodiments of the
`invention are based, at least in part, on the recognition that
`partial mTOR inhibition, e.g., with low, immune enhancing,
`dose of an mTOR inhibitor, is associated with a reduction in
`the percentage of programmed death (PD)-1 positive CD4
`and CD8 T lymphocytes.
`[0004] Accordingly, in one aspect, the present invention
`relates to a method of promoting an immune response in a
`subject, e.g., a human subject, comprising,
`[0005] administering to the subject a low, immune enhanc
`ing, dose of an mTOR inhibitor, e.g., RAD001 or rapamycin,
`[0006] thereby enhancing or promoting an immune
`response in the subject.
`[0007] In an embodiment, a low, immune enhancing, dose
`of an mTOR inhibitor, e.g., RAD001 or rapamycin and an
`antigen are administered as a vaccine.
`
`[0008] In an embodiment, a low, immune enhancing, dose
`ofan mTOR inhibitor, e.g., RAD001 or rapamycin is admin
`istered as an adjuvant composition or compound.
`[0009| Exemplary mTOR inhibitors are described herein,
`e.g., in the section below entitled “mTOR INHIBITORS..”
`[0010] In an embodiment, the mTOR inhibitor is an allos
`teric mTOR inhibitor. In an embodiment, the mTOR inhibitor
`is a RAD001. In an embodiment, the mTOR inhibitor is
`rapamycin.
`[0011] In an embodiment, the mTOR inhibitor is a catalytic
`inhibitor, e.g., a kinase inhibitor. In an embodiment, the
`kinase inhibitoris selective for mTOR. In an embodiment, the
`kinase inhibitor is selected from BEZ235 and CCG168.
`[0012] In an embodiment, the low, immune enhancing,
`dose comprises a plurality of mTOR inhibitors. In an embodi
`ment, the low, immune enhancing, dose comprises an allos
`teric and a catalytic mTOR inhibitor.
`[0013] In an embodiment, the low, immune enhancing,
`dose of an mTOR inhibitor is administered for an amount of
`time sufficient for one or more of the following to occur:
`[0014] i) a decrease in the number of PD-1 positive immune
`effector cells;
`[0015] ii) an increase in the number of PD-1 negative
`immune effector cells;
`[0016] iii) an increase in the ratio of PD-1 negative immune
`effector cells/PD-1 positive immune effector cells;
`[0017] iv) an increase in the number of naive T cells;
`[0018] v) an increase in the expression of one or more of the
`following markers: CD62L”, CD127”, CD27", and
`BCL2, e.g., on memory T cells, e.g., memory T cell precur
`sors;
`[0019) vi) a decrease in the expression of KLRG1, e.g., on
`memory T cells, e.g., memory T cell precursors; or
`[0020) vii) an increase in the number of memory T cell
`precursors, e.g., cells with any one or combination of the
`following characteristics: increased CD62L* increased
`CD127”, increased CD27", decreased KLRG1, and
`increased BCL2;
`and whereini), ii), iii), iv), v), vi), or vii) occurs e.g., at least
`transiently, e.g., as compared to a non-treated subject.
`[0021] In an embodiment, the method of treating, e.g., pro
`moting an immune response in, a subject, e.g., a human
`subject, comprises inhibiting a negative immune response
`mediated by the engagement of PD-1 with PD-L1 or PD-L2.
`[0022] In an embodiment, the method of treating, e.g., pro
`moting an immune response in, a subject, e.g., a human
`subject, comprises increasing the number of T cells capable
`of proliferation.
`[0023] In an embodiment, the method of treating, e.g., pro
`moting an immune response in, a subject, e.g., a human
`subject, comprises increasing the number of T cells capable
`of cytotoxic function, secreting cytokines, or activation.
`[0024] In an embodiment, the method of treating, e.g., pro
`moting an immune response in, a subject, e.g., a human
`subject, comprises increasing the number of T cells capable
`of providing T cell help to B cells.
`[0025] In an embodiment, the administering of the low,
`immune enhancing, dose of an mTOR inhibitor results in the
`partial, but not total, inhibition of mTOR for at least 1, 5, 10,
`20, 30, or 60 days.
`[0026] In an embodiment, the administering of the low,
`immune enhancing, dose of an mTOR inhibitor results in the
`partial, but not total, inhibition of mTOR as long as enhance
`ment of the immune response is needed.
`
`Ex. 1106-0010
`
`

`

`US 2015/014003.6 A1
`
`May 21, 2015
`
`[0027] In an embodiment, the low, immune enhancing,
`dose of an mTOR inhibitor is associated with mTOR inhibi
`tion of at least 5% but no more than 90%, e.g., as measured by
`p70S6K inhibition. In an embodiment, the mTOR inhibitor
`comprises RAD001. (Methods for evaluation of the level of
`inhibition of mTOR are described herein, e.g., in the section
`below entitled “EVALUATION OF mTOR INHIBITION”)
`[0028] In an embodiment, the low, immune enhancing,
`dose of an mTOR inhibitor is associated with mTOR inhibi
`tion of at least 10% but no more than 80%, e.g., as measured
`by p70S6K inhibition. In an embodiment, the mTOR inhibi
`tor comprises RAD001.
`[0029] In an embodiment, the low, immune enhancing,
`dose of an mTOR inhibitor is associated with mTOR inhibi
`tion of at least 10% but no more than 40%, e.g., as measured
`by p70S6K inhibition. In an embodiment, the mTOR inhibi
`tor comprises RAD001.
`[0030] In an embodiment, administering to the subject a
`low, immune enhancing, dose of an mTOR inhibitor com
`prises administering, e.g., once per week, e.g., in an immedi
`ate release dosage form, 0.1 to 20, 0.5 to 10, 2.5 to 7.5, 3 to 6,
`or about 5, mgs of RAD001.
`[0031] In an embodiment, administering to the subject a
`low, immune enhancing, dose of an mTOR inhibitor com
`prises administering, once per week, in an immediate release
`dosage form, about 5 mgs of RAD001.
`[0032] In an embodiment, administering to the subject a
`low, immune enhancing, dose of an mTOR inhibitor com
`prises administering, e.g., once per week, e.g., in an immedi
`ate release dosage form, an amount of an mTOR inhibitor
`other than RAD001, that is bioeduivalent to a one per week,
`immediate release dosage form of 0.1 to 20, 0.5 to 10, 2.5 to
`7.5, 3 to 6, or about 5 mgs of RAD001.
`[0033] In an embodiment, administering to the subject a
`low, immune enhancing, dose of an mTOR inhibitor com
`prises administering, once per week, in an immediate release
`dosage form, an amount of an mTOR inhibitor other than
`RAD001, that is bioeduivalent to a once per week, immediate
`release dosage form of about 5 mgs of RAD001.
`[0034] In an embodiment, administering to the subject a
`low, immune enhancing, dose of an mTOR inhibitor com
`prises administering, e.g., once per week, e.g., in a sustained
`release dosage form, 0.3 to 60, 1.5 to 30, 7.5 to 22.5, 9 to 18,
`or about 15 mgs of RAD001.
`[0035) In an embodiment, administering to the subject a
`low, immune enhancing, dose of an mTOR inhibitor com
`prises administering, once per week, in a sustained release
`dosage form, about 15 mgs of RAD001.
`[0036) In an embodiment, administering to the subject a
`low, immune enhancing, dose of an mTOR inhibitor com
`prises administering, e.g., once per week, e.g., in a sustained
`release dosage form, an amount of an mTOR inhibitor other
`than RAD001, that is bioeduivalent to a once per week, sus
`tained release dosage form of 0.3 to 60, 1.5 to 30, 7.5 to 22.5,
`9 to 18, or about 15 mgs of RAD001.
`[0037] In an embodiment, administering to the subject a
`low, immune enhancing, dose of an mTOR inhibitor com
`prises administering, once per week, in a sustained release
`dosage form, an amount of an mTOR inhibitor other than
`RAD001, that is bioeduivalent to a once per week sustained
`release dosage form of about 15 mgs of RAD001.
`[0038] In an embodiment, administering to the subject a
`low, immune enhancing, dose of an mTOR inhibitor com
`prises administering, e.g., once per day, e.g., in an immediate
`
`release dosage form, 0.005 to 1.5, 0.01 to 1.5, 0.1 to 1.5, 0.2
`to 1.5, 0.3 to 1.5,0.4 to 1.5, 0.5 to 1.5,0.6 to 1.5,0.7 to 1.5,0.8
`to 1.5, 1.0 to 1.5, 0.3 to 0.6, or about 0.5 mgs of RAD001.
`[0039] In an embodiment, administering to the subject a
`low, immune enhancing, dose of an mTOR inhibitor com
`prises administering once per day, in an immediate release
`dosage form, about 0.5 mgs of RAD001.
`[0040] In an embodiment, administering to the subject a
`low, immune enhancing, dose of an mTOR inhibitor com
`prises administering, e.g., once per day, e.g., in an immediate
`release dosage form, an amount of an mTOR inhibitor other
`than RAD001, that is bioeduivalent to a once per day, imme
`diate release dosage form of 0.005 to 1.5, 0.01 to 1.5, 0.1 to
`1.5, 0.2 to 1.5, 0.3 to 1.5, 0.4 to 1.5, 0.5 to 1.5, 0.6 to 1.5, 0.7
`to 1.5, 0.8 to 1.5, 1.0 to 1.5, 0.3 to 0.6, or about 0.5 mgs of
`RAD001.
`[0041] In an embodiment, administering to the subject a
`low, immune enhancing, dose of an mTOR inhibitor com
`prises administering, once per day, in an immediate release
`dosage form, an amount of an mTOR inhibitor other than
`RAD001, that is bioeduivalent to a once per day, immediate
`release dosage form of about 0.5 mgs of RAD001.
`[0042] In an embodiment, administering to the subject a
`low, immune enhancing, dose of an mTOR inhibitor com
`prises administering, e.g., once per day, e.g., in a sustained
`release dosage form, 0.015 to 4.5, 0.03 to 4.5, 0.3 to 4.5,0.6
`to 4.5,0.9 to 4.5, 1.2 to 4.5, 1.5 to 4.5, 1.8 to 4.5, 2.1 to 4.5, 2.4
`to 4.5, 3.0 to 4.5, 0.9 to 1.8, or about 1.5 mgs of RAD001.
`[0043] In an embodiment, administering to the subject a
`low, immune enhancing, dose of an mTOR inhibitor com
`prises administering, e.g., once per day, e.g., in a sustained
`release dosage form, an amount of an mTOR inhibitor other
`than RAD001, that is bioeduivalent to a once per day, sus
`tained release dosage form of 0.015 to 4.5, 0.03 to 4.5, 0.3 to
`4.5, 0.6 to 4.5, 0.9 to 4.5, 1.2 to 4.5, 1.5 to 4.5, 1.8 to 4.5, 2.1
`to 4.5, 2.4 to 4.5, 3.0 to 4.5, 0.9 to 1.8, or about 1.5 mgs of
`RAD001.
`[0044] In an embodiment, administering to the subject a
`low, immune enhancing, dose of an mTOR inhibitor com
`prises administering, e.g., once per week, e.g., in a sustained
`release dosage form, 0.1 to 30, 0.2 to 30, 2 to 30, 4 to 30, 6 to
`30, 8 to 30, 10 to 30, 1.2 to 30, 14 to 30, 16 to 30, 20 to 30, 6
`to 12, or about 10 mgs of RAD001.
`[0045] In an embodiment, administering to the subject a
`low, immune enhancing, dose of an mTOR inhibitor com
`prises administering, e.g., once per week, e.g., in a sustained
`release dosage form, an amount of an mTOR inhibitor other
`than RAD001, that is bioeduivalent to a once per week, sus
`tained release dosage form of 0.1 to 30, 0.2 to 30, 2 to 30, 4 to
`30, 6 to 30, 8 to 30, 10 to 30, 1.2 to 30, 14 to 30, 16 to 30, 20
`to 30, 6 to 12, or about 10 mgs of RAD001.
`[0046) In an embodiment, the mTOR inhibitor is RAD001
`and the dose provides for a trough level of RAD001 in a range
`of between about 0.1 and 3 ng/ml, between 0.3 or less and 3
`ng/ml, or between 0.3 or less and 1 ng/ml.
`[0047] In an embodiment, the mTOR inhibitoris other than
`RAD001 and the dose is bioeduivalent to a dose of RAD001
`that provides for a trough level of RAD001 in a range of
`between about 0.1 and 3 ng/ml, between 0.3 or less and 3
`ng/ml, or between 0.3 or less and 1 ng/ml.
`[0048] In an embodiment the subject has cancer. Exem
`plary cancers are described herein, e.g., in the section below
`entitled “DISORDERS Cancer.” In an embodiment, the sub
`ject has cancer, but is not otherwise immunocompromised,
`
`Ex. 1106-0011
`
`

`

`US 2015/014003.6 A1
`
`May 21, 2015
`
`e.g., is not HIV+, does not have AIDS, or is not immunosce
`nescent. In an embodiment, the subject has cancer, but, except
`for that due to any anti-cancer treatment, is not otherwise
`immunocompromised, e.g., is not HIV+, does not have AIDS,
`or is not immunoscenescent.
`[0049] In an embodiment, the subject has cancer and the
`method comprises promoting the subject’s immune response
`to the cancer. In an embodiment, the subject was selected on
`the basis of having cancer. In an embodiment, the subject was
`selected on the basis of being in need of, or likely to benefit
`from, promotion of the immune response. In an embodiment,
`a cell of the cancer expresses PD-L1 or PD-L2. In an embodi
`ment, a cell in the cancer microenvironment expresses PD-L1
`or PD-L2.
`[0050] In an embodiment, the cancer comprises a solid
`tumor. In an embodiment, the cancer is a hematological can
`cer. In an embodiment, the cancer is a leukemia. In an
`embodiment, the cancer is melanoma.
`[0051] In an embodiment, promoting an immune response
`in a subject comprises preparing the subject, e.g., a subject
`having cancer, for an additional treatment that suppresses the
`immune system or kills T cells, e.g., administration of a drug,
`e.g., a chemotherapeutic, or radiation. In an embodiment, the
`low, immune enhancing dose, of an mTOR inhibitor, e.g.,
`RAD001, reduces immune suppression associated with the
`additional treatment.
`[0052] In an embodiment, the method further comprises
`administering an additional treatment, e.g., a chemotherapeu
`tic, radiation, a cellulartherapy, bone marrow transplant to the
`subject. In an embodiment the additional treatment comprises
`a combination of drugs or treatments as described herein, see,
`e.g., the section below entitled “COMBINATION TREAT
`MENTS.” In an embodiment, the method further comprises
`administering an additional treatment that kills T cells, e.g.,
`radiation or cytotoxic chemotherapy. In an embodiment, the
`low, immune enhancing, dose of mTOR inhibitor is admin
`istered prior to, with, or after the initiation of the additional
`treatment. In an embodiment, the method further comprises
`administering an additional treatment for the cancer.
`[0053] In an embodiment, the method further comprises
`administering an additional treatment that suppresses the
`immune system, e.g., administration of a drug, e.g., a chemo
`therapeutic, or radiation. In an embodiment, the low, immune
`enhancing, dose of mTOR inhibitor, e.g., RAD001, is admin
`istered prior to, with, or after the initiation of the additional
`treatment that suppresses the immune system. While not
`wishing to be bound by theory, it is believed that the low,
`immune enhancing dose of an mTOR inhibitor, allows for a
`broader range of therapeutic options. Without wishing to be
`bound by theory, it is believed that this is due to the improve
`ment in the subject’s immune responsiveness. In an embodi
`ment, the low, immune enhancing dose of an mTOR inhibitor,
`can allow for more aggressive administration of the addi
`tional treatment. Thus, in an embodiment, the unit dosage,
`total dosage, frequency of administration, or number of
`administrations, is increased. In an embodiment, the increase
`is relative to a reference administration, e.g., the standard of
`care that is provided in the absence of a low, immune enhanc
`ing, dose of mTOR inhibitor. In an embodiment, the increase
`is relative to an administration that would give the maximum
`tolerable or acceptable levels of immune suppression, in the
`absence of a low, immune enhancing, dose of mTOR inhibi
`tor. In anotherembodiment, the immune enhancing dose of an
`mTOR inhibitor, can allow for less aggressive administration
`
`of the additional treatment. Thus, in an embodiment, the unit
`dosage, total dosage, frequency of administration, or number
`of administrations, is decreased. In an embodiment, the
`decrease is relative to a reference administration, e.g., the
`standard of care that is provided in the absence of a low,
`immune enhancing, dose of mTOR inhibitor. In an embodi
`ment, the decrease is relative to an administration that would
`give the maximum tolerable or acceptable levels of immune
`suppression, in the absence of a low, immune enhancing, dose
`of mTOR inhibitor.
`[0054] In an embodiment, the subject is immunocompro
`mised. In an embodiment, the subject is HIV+ or has AIDs.
`[0055] Thus, in an embodiment, promoting an immune
`response in a subject comprises promoting the immune
`response of an immunocompromised subject, e.g., a subject
`having an immunodeficiency, e.g., a hereditary or acquired
`immunodeficiency, e.g., a virally-mediated immunodefi
`ciency, e.g., a subject that is HIV+, or a subject having AIDS.
`In an embodiment, the method further comprises administer
`ing an additional treatment for the immunodeficiency, e.g., an
`antiviral agent. In an embodiment, the subject is HIV+ or has
`AIDS and the additional treatment comprises administering
`an anti-viral agent, e.g., a nucleoside reverse transcriptase
`inhibitor, e.g., abacavir, didanosine, emtricitabine, lamivu
`dine, stavudine, tenofovir, zalcitabine, or zidovudine, or com
`binations thereof, e.g. combivir (zidovudine and lamivudine),
`trizivir (zidovudine, lamivudine and abacavir), epzicom (aba
`cavir and lamivudine) and truvada (tenofovir and lamivu
`dine). In an embodiment, the additional treatment comprises
`administering a protease inhibitor, e.g., amprenavir, agen
`erase, atazanavir, fosamprenavir, indinavir, lopinavir,
`ritonavir, or saquinavir, or a combination thereof. In an
`embodiment, the low, immune enhancing, dose of mTOR
`inhibitor, e.g., RAD001, is administered prior to, with, or
`after the initiation of the additional treatment. While not
`wishing to be bound by theory, it is believed that the low,
`immune enhancing dose of an mTOR inhibitor, allows for a
`broader range of therapeutic options. Without wishing to be
`bound by theory, it is believed that this is due to the improve
`ment in the subject’s immune responsiveness. In an embodi
`ment, the low, immune enhancing dose of an mTOR inhibitor,
`can allow for more aggressive administration of the addi
`tional treatment. Thus, in an embodiment, the unit dosage,
`total dosage, frequency of administration, or number of
`administrations, is increased. In an embodiment, the increase
`is relative to a reference administration, e.g., the standard of
`care that is provided in the absence of a low, immune enhanc
`ing, dose of mTOR inhibitor. In an embodiment, the increase
`is relative to an administration that would give the maximum
`tolerable or acceptable levels of a side effect, in the absence of
`a low, immune enhancing, dose of mTOR inhibitor. In another
`embodiment, the immune enhancing dose of an mTOR
`inhibitor, can allow for less aggressive administration of the
`additional treatment. Thus, in an embodiment, the unit dos
`age, total dosage, frequency of administration, or number of
`administrations, is decreased. In an embodiment, the
`decrease is relative to a reference administration, e.g., the
`standard of care that is provided in the absence of a low,
`immune enhancing, dose of mTOR inhibitor. In an embodi
`ment, the decrease is relative to an administration that would
`give the maximum tolerable or acceptable levels of a side
`effect, in the absence of a low, immune enhancing, dose of
`mTOR inhibitor.
`
`Ex. 1106-0012
`
`

`

`US 2015/014003.6 A1
`
`May 21, 2015
`
`[0056] In an embodiment, the subject has an infectious
`disease, e.g., hepatitis, e.g., hepatitis A, B or C, or other
`pathogenic infection. Exemplary pathogenic infections are
`described herein, e.g., in the section below entitled “DISOR
`DERS Pathogenic Infections.” In an embodiment, the subject
`has an infectious disease or has a pathogenic infection, but is
`not otherwise immunocompromised, e.g., is not immunose
`neScent.
`[0057] In an embodiment, the subject has an impaired
`immune response. In an embodiment, the subject is immun
`OSeneScent.
`[0058] In an embodiment, the subject has an age related
`condition. In an embodiment, the age related condition is
`selected from the group consisting of sarcopenia, skin atro
`phy, muscle wasting, brain atrophy, atherosclerosis, arterio
`sclerosis, pulmonary emphysema, osteoporosis, osteoarthri
`tis, high blood pressure, erectile dysfunction, dementia,
`Huntington’s disease, Alzheimer’s disease, cataracts, age
`related macular degeneration, prostate cancer, stroke, dimin
`ished life expectancy, impaired kidney function, and age
`related hearing loss, aging-related mobility disability (e.g.,
`frailty), cognitive decline, age-related dementia, memory
`impairment, tendon stiffness, heart dysfunction such as car
`diac hypertrophy and systolic and diastolic dysfunction,
`immunosenescence, cancer, obesity, and diabetes.
`[0059] In an embodiment, the method comprises enhancing
`an immune response to an antigen in the subject. In an
`embodiment the method comprises providing or administer
`ing to the subject a low, immune enhancing, dose of an mTOR
`inhibitor, e.g., RAD001 or rapamycin as an adjuvant compo
`sition or compound. In an embodiment the method comprises
`providing or administering to the subject a low, immune
`enhancing, dose of an mTOR inhibitor, e.g., RAD001 or
`rapamycin, and the antigen, as a, or in combination with a
`vaccine. In an embodiment the antigen is a cancer antigen. In
`an embodiment the antigen is an infectous disease-, viral,
`bacterial, protozoan, microbial, pathogen-, or parasite-, anti
`gen. In an embodiment, the method further comprises admin
`istering an antigen or a vaccine to the subject. In an embodi
`ment, prior to the step of administering, the method
`comprises a step of identifying a subject having an impaired
`immune response to an antigen.
`[0060] In an embodiment, a relatively low baseline or pre
`immunization level or titer of antibody to the antigen is pre
`dictive of a greater mTOR inhibitor-, e.g., RAD001-, associ
`ated increase in antibody titer for an antigen. In an
`embodiment, the subject is evaluated for level or titer of
`antibody to the antigen prior to administration of an antigenor
`vaccine. In an embodiment evaluation comprises acquiring,
`e.g., directly orindirectly acquiring, a measurement of titer or
`level of antibody. The titer or level of antibody can be com
`pared with a reference value. Relatively low titer, e.g., titer
`below or equal to a reference value, is indicative of a greater
`mTOR inhibitor-, e.g., RAD001-, associated increase in anti
`body titer. Thus, baseline or pre-immunization titer can be
`used to select patients for low, immune enhancing, dose of
`mTOR inhibitor, e.g., in combination with vaccination or
`administration of antigento stimulate animmune response. In
`an embodiment, responsive to a determined level or titer of
`antibody, a subject is classified as to the likelihood of ben
`efiting from administration of a low, immune enhancing, dose
`of mTOR inhibitor, e.g., prior to or with administration of a
`vaccine or antigen. In an embodiment, responsive to a deter
`mined level or titer of antibody, e.g., a level or titer that is at or
`
`below a reference value, a subject is selected for, or admin
`istered, a low, immune enhancing, dose of mTOR inhibitor,
`prior to or with administration of a vaccine or antigen. In an
`embodiment, responsive to a determined level or titer of anti
`body, e.g., a level or titer that is above a reference value, a
`subject is selected for, or administered an alternative therapy,
`e.g., administration of a vaccine or antigen, without the
`administration of a low, immune enhancing, dose of mTOR
`inhibitor.
`[0061] In an embodiment, the subject is infected with, or at
`risk for infection with, an influenza virus, e.g., an influenza A
`or B virus.
`[0062] In an embodiment, the method comprises enhancing
`an immune response to an influenza virus, e.g., an influenza A
`or B virus. Influenza A viruses are characterized by one or
`both of two glycoproteins, a hemagglutinin (HA)polypeptide
`and a neuraminidase (NA) polypeptide, which are are dis
`played on the surface of the virus. There are 17 HA antigens,
`denoted H1-17, and nine different NA antigens, denoted
`N1-9.
`[0063] In such embodiments the antigen or vaccine com
`prises an influenza antigen, e.g., an influenza A or B antigen.
`In an embodiment the antigen comprises an HA antigen, e.g.,
`any of H1-17. In an embodiment the antigen is selected from
`H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2
`H7N3, H10N7, or HTN9.
`[0064] In an embodiment, the antigen is selected from
`H1N1, H2N3, and B influenza subtypes. In an embodiment,
`the antigen is a pneumococcal antigen.
`[0065] In an embodiment, the antigen and the mTOR
`inhibitor are co-administered. In an embodiment, the antigen
`and the mTOR inhibitor are administered sequentially. In an
`embodiment, the subject is less than 65 years old.
`[0066] In an embodiment, a relatively low baseline or pre
`immunization level or titer of influenza antibody is predictive
`of a greater mTOR inhibitor-, e.g., RAD001-, associated
`increase in antibody titer for the influenza virus, e.g., an
`influenza A virus. In an embodiment, the subject is evaluated
`for anti-influenza antibody titer prior to administration of an
`antigen or vaccine. In an embodiment, evaluation comprises
`acquiring, e.g., directly or indirectly acquiring, a measure
`ment of anti-influenza antibody titer. The titer of antibody can
`be compared with a reference value. Relatively low titer, e.g.,
`titer at or below a reference value, e.g., less than or equal to a
`titer of 1:40 (e.g., as measured herein), is indicative of a
`greater mTOR inhibitor-, e.g., RAD001-, associated increase
`in antibody titer. Thus, baseline or pre-immunization titer can
`be used to select patients for low, immune enhancing, dose of
`mTOR inhibitor, e.g., in combination with vaccination or
`administration of antigen to protect against influenza, e.g.,
`influenza A. In an embodiment, responsive to a determined
`antibody titer, a subject is classified as to the likelihood of
`benefiting from administration of a low, immune enhancing,
`dose of mTOR inhibitor, e.g., prior to or with administration
`of a vaccine or antigen. In an embodiment, responsive to a
`determined antibody titer, e.g., a titer that is at or below a
`reference value, a subject is selected for, or administered, a
`low, immune enhancing, dose of mTOR inhibitor, prior to or
`with administration of a vaccine or antigen. In an embodi
`ment, responsive to a determined antibody titer, e.g., a titer
`that is above a reference value, a subject is selected for, or
`administered an alternative therapy, e.g., administration of a
`vaccine or antigen without the administration of a low,
`immune enhancing, dose of mTOR inhibitor.
`
`Ex. 1106-0013
`
`

`

`US 2015/014003.6 A1
`
`May 21, 2015
`
`[0067] In an embodiment, the subject does not receive a
`vaccine, e.g., does not receive a vaccine while the mTOR
`inhibitor is present at levels which promote the immune
`response. In an embodiment, the vaccine is an anti-cancer
`vaccine or a vaccine against an infectious agent. In an
`embodiment the vaccine is a therapeutic vaccine for a neuro
`logical disorder, e.g., Alzheimers.
`[0068] In an embodiment, the subject does not receive a
`vaccine, e.g., a cancer vaccine, within 10, 20, 30, 40, 50, 60,
`70, 80, or 90 days prior