NZ750444B2 - Use of plinabulin in combination with immune checkpoint inhibitors - Google Patents
Use of plinabulin in combination with immune checkpoint inhibitors Download PDFInfo
- Publication number
- NZ750444B2 NZ750444B2 NZ750444A NZ75044416A NZ750444B2 NZ 750444 B2 NZ750444 B2 NZ 750444B2 NZ 750444 A NZ750444 A NZ 750444A NZ 75044416 A NZ75044416 A NZ 75044416A NZ 750444 B2 NZ750444 B2 NZ 750444B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- cancer
- immune checkpoint
- antibody
- checkpoint inhibitor
- plinabulin
- Prior art date
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Abstract
Disclosed herein are compositions comprising Plinabulin and one or more immune checkpoint inhibitors for treating cancer. Some embodiments relate to methods of treating cancer by co-administering Plinabulin and one or more immune checkpoint inhibitors such as CTLA4 (cytotoxic T lymphocyte antigen-4), PD-1 (programmed cell death protein 1), PD-L1 (programmed cell death ligand 1), PD-L2(programmed cell death ligand 2), PD-L3(programmed cell death ligand 3), PD-L4(programmed cell death ligand 4), LAG-3 (lymphocyte activation gene-3), and TIM-3 (T cell immunoglobulin and mucin protein-3). Some of the immune checkpoint inhibitors can be an antibody such as PD-1 antibody, PD-L1 antibody, PD-L2 antibody, PD-L3 antibody, PD-L4 antibody, CTLA-4 antibody, LAG3 antibody, B7-H3 antibody, B7-H4 antibody, KIR antibody and TIM3 antibody. , PD-1 (programmed cell death protein 1), PD-L1 (programmed cell death ligand 1), PD-L2(programmed cell death ligand 2), PD-L3(programmed cell death ligand 3), PD-L4(programmed cell death ligand 4), LAG-3 (lymphocyte activation gene-3), and TIM-3 (T cell immunoglobulin and mucin protein-3). Some of the immune checkpoint inhibitors can be an antibody such as PD-1 antibody, PD-L1 antibody, PD-L2 antibody, PD-L3 antibody, PD-L4 antibody, CTLA-4 antibody, LAG3 antibody, B7-H3 antibody, B7-H4 antibody, KIR antibody and TIM3 antibody.
Description
USE OF PLINABULIN IN COMBINATION WITH IMMUNE CHECKPOINT
INHIBITORS
INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS
This application claims the benefit of U.S. Provisional Application No.
62/115,468, filed February 12, 2015, and U.S. Provisional Application No. 62/255,259, filed
November 13, 2015, the disclosures of which are incorporated herein by reference in their
entireties.
BACKGROUND
Field
The present invention relates to the field of chemistry and medicine. More
particularly, the present invention relates to Plinabulin, compositions containing Plinabulin,
and its use in treatment.
Description of the Related Art
Human cancers harbor numerous genetic and epigenetic alterations,
generating neoantigens potentially recognizable by the immune system (Sjoblom et al, 2006).
The adaptive immune system, comprised of T and B lymphocytes, has powerful anti-cancer
potential, with a broad capacity and exquisite specificity to respond to diverse tumor
antigens.
Recent cancer immunotherapy research has focused substantial effort on
approaches that enhance anti-tumor immunity by adoptive-transfer of activated effector cells,
immunization against relevant antigens, providing non-specific immune- stimulatory agents
such as cytokines, or removing inhibitors to anti-cancer effector cells. Efforts to develop
specific immune checkpoint inhibitors have begun to provide new immunotherapeutic
approaches for treating cancer, including the development of an antibody, ipilimumab, that
binds to and inhibits Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) for the treatment of
patients with advanced melanoma (Hodi et al., 2010). While cancer remains as an incurable
disease for the great majority of patients, there exists a particular need for developing
effective therapeutic agents that can be used in cancer immunotherapy.
SUMMARY OF THE INVENTION
Some embodiments relate to a pharmaceutical composition including
Plinabulin and one or more immune checkpoint inhibitor.
Some embodiments relate to a method for treating cancer, the method
including co-administering Plinabulin and one or more immune checkpoint inhibitor to a
subject in need thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
shows the expression of DC maturation markers CD40, CD80,
CD86, and MHCII in dendritic cells treated with Plinabulin at various concentrations and
with LPS control; shows the viability of dendritic cells treated with Plinabulin and
LPS.
shows the expression of the CD40 marker in dendritic cells
treated with Plinabulin, Paclitaxel, Etoposide, or control; shows the expression of
the CD80 marker in dendritic cells treated with Plinabulin, Paclitaxel, Etoposide, or control;
shows the expression of the CD86 marker in dendritic cells treated with Plinabulin,
Paclitaxel, Etoposide, or control; shows the expression of the MHCII marker in
dendritic cells treated with Plinabulin, Paclitaxel, Etoposide, or control.
shows the production of IL-1β in dendritic cells treated with
Plinabulin, Paclitaxel. Etoposide, and control; shows the production of IL-6 marker
in dendritic cells treated with Plinabulin, Paclitaxel. Etoposide, and control; shows
the production of IL-12p40 in dendritic cells treated with Plinabulin, Paclitaxel. Etoposide,
and control.
FIGS. 4A-4C show the plinabulin-induced enhancement of the anti-tumor
effect of the PD-1 antibody plus CTLA-4 antibody in the MC-38 tumor model in immune
competent mice. FIG 4A shows the effect on tumor growth; FIG 4B shows the effect on the
mean tumor weight at necropsy; Fig 4C shows the time for tumors to reach 10 fold of their
starting volume.
FIGS. 5A-5C show the results of Fluorescence-activated cell sorting
(FACS) analysis of the tumors at necropsy from the study described in Example 6.
shows the effect on Treg cells; FIG 5B shows the ratio of CD8+ cells to Treg cells; FIG 5C
shows the effect on macrophages.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Plinabulin, (3Z,6Z)Benzylidene{[5-(2-methylpropanyl)-1H-
imidazolyl]methylene}-2,5-piperazinedione, is a synthetic analog of the natural compound
phenylahistin. Plinabulin can be readily prepared according to methods and procedures
detailed in U.S. Patent Nos. 7,064,201 and 7,919,497, which are incorporated herein by
reference in their entireties. In some embodiments, Plinabulin can efficiently promote antigen
uptake and migration of dendritic cells to lymph nodes where tumor-specific antigens are
presented by dendritic cells to prime immune effector cells. Exposure of dendritic cells to
Plinabulin can induce maturation of dendritic cells and significantly increase their capacity to
prime T cells. In some embodiments, Plinabulin can mediate tumor size reduction through
immune modulation of the tumor microenvironment to promote anti-tumor immune
enhancing effects. In some embodiments, substantial therapeutic synergies can be achieved
when combining Plinabulin with immune checkpoint inhibitors.
Some embodiments relate to the use of Plinabulin in combination with one
or more immune checkpoint inhibitors, such as inhibitors of CTLA4 (cytotoxic T lymphocyte
antigen-4), PD-1 (programmed cell death protein 1), PD-L1 (programmed cell death ligand
1), PD-L2(programmed cell death ligand 2), PD-L3(programmed cell death ligand 3), PD-
L4(programmed cell death ligand 4), LAG-3 (lymphocyte activation gene-3), and TIM-3 (T
cell immunoglobulin and mucin protein-3). In some embodiments, the immune checkpoint
inhibitor is a binding ligand of PD-1. In some embodiments, the immune checkpoing
inhibitor is a binding ligand of CTLA-4.
PD-1 is a key immune checkpoint receptor expressed by activated T and B
cells and mediates immunosuppression. PD-1 is a member of the CD28 family of receptors,
which includes CD28, CTLA-4, ICOS, PD-1, and BTLA. The term "PD-1" as used herein
includes human PD-1 (hPD-1), variants, isoforms, and species homologs of hPD-1, and
analogs having at least one common epitope with hPD-1.
Various cell surface glycoprotein ligands for PD-1 have been identified,
including PD-L1, PD-L2, PD-L3, and PD-L4, that are expressed on antigen- presenting cells
as well as many human cancers and have been shown to downregulate T cell activation and
cytokine secretion upon binding to PD-1. The term "PD-L1" as used herein includes human
PD-L1 (hPD-Ll), variants, isoforms, and species homologs of hPD-Ll, and analogs having at
least one common epitope with hPD-Ll. The term "PD-L2" as used herein includes human
PD-L2 (hPD-L2), variants, isoforms, and species homologs of hPD-L2, and analogs having at
least one common epitope with hPD-L2. The term "PD-L3" as used herein includes human
PD-L3 (hPD-L3), variants, isoforms, and species homologs of hPD-L3, and analogs having at
least one common epitope with hPD-L3. The term "PD-L4" as used herein includes human
PD-L4 (hPD-L4), variants, isoforms, and species homologs of hPD-L4, and analogs having at
least one common epitope with hPD-L4.
CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) is a protein
receptor that, functioning as an immune checkpoint, downregulates the immune system.
CTLA4 is found on the surface of T cells, is also a member of the immunoglobulin (Ig)
superfamily; CTLA-4 comprises a single extracellular Ig domain. CTLA-4 transcripts have
been found in T cell populations having cytotoxic activity, suggesting that CTLA-4 might
function in the cytolytic response.
Definitions
Unless defined otherwise, all technical and scientific terms used herein
have the same meaning as is commonly understood by one of ordinary skill in the art to
which this disclosure belongs. All patents, applications, published applications, and other
publications are incorporated by reference in their entirety. In the event that there is a
plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
The term “pharmaceutically acceptable carrier” or “pharmaceutically
acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial
and antifungal agents, isotonic and absorption delaying agents and the like. The use of such
media and agents for pharmaceutically active substances is well known in the art. Except
insofar as any conventional media or agent is incompatible with the active ingredient, its use
in the therapeutic compositions is contemplated. In addition, various adjuvants such as are
commonly used in the art may be included. Considerations for the inclusion of various
components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.)
(1990); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 8th Ed.,
Pergamon Press, which is incorporated herein by reference in its entirety. The
pharmaceutically acceptable excipient can be a monosaccharide or monosaccharide
derivative.
“Subject” as used herein, means a human or a non-human mammal, e.g.,
a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g.,
a chicken, as well as any other vertebrate or invertebrate.
The term “mammal” is used in its usual biological sense. Thus, it
specifically includes, but is not limited to, primates, including simians (chimpanzees, apes,
monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rodents, rats,
mice, guinea pigs, or the like.
An “effective amount” or a “therapeutically effective amount” as used
herein refers to an amount of a therapeutic agent that is effective to relieve, to some extent, or
to reduce the likelihood of onset of, one or more of the symptoms of a disease or condition,
and can include curing a disease or condition.
“Treat,” “treatment,” or “treating,” as used herein refers to administering a
compound or pharmaceutical composition to a subject for prophylactic and/or therapeutic
purposes. The term “prophylactic treatment” refers to treating a subject who does not yet
exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of,
a particular disease or condition, whereby the treatment reduces the likelihood that the patient
will develop the disease or condition. The term “therapeutic treatment” refers to
administering treatment to a subject already suffering from a disease or condition.
As used herein, the term “chemotherapeutic agent” refers to an agent that
reduces, prevents, mitigates, limits, and/or delays the growth of metastases or neoplasms, or
kills neoplastic cells directly by necrosis or apoptosis of neoplasms or any other mechanism,
or that can be otherwise used, in a pharmaceutically-effective amount, to reduce, prevent,
mitigate, limit, and/or delay the growth of metastases or neoplasms in a subject with
neoplastic disease. Chemotherapeutic agents include but are not limited to, for example,
fluoropyrimidines; pyrimidine nucleosides; purine nucleosides; anti-folates, platinum-based
agents; anthracyclines/anthracenediones; epipodophyllotoxins; camptothecins; hormones;
hormonal complexes; antihormonals; enzymes, proteins, peptides and polyclonal and/or
monoclonal antibodies; vinca alkaloids; taxanes; epothilones; antimicrotubule agents;
alkylating agents; antimetabolites; topoisomerase inhibitors; antivirals; and various other
cytotoxic and cytostatic agents.
Administration and Pharmaceutical Compositions
Some embodiments relate to a pharmaceutical composition, comprising
Plinabulin and one or more immune checkpoint inhibitor.
In some embodiments, the immune checkpoint inhibitor is an inhibitor of
PD-1, PD-L1, PD-L2, PD-L3, PD-L4, CTLA-4, LAG3, B7-H3, B7-H4, KIR or TIM3. In
some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor. In some
embodiments, the immune checkpoint inhibitor is a binding ligand of PD-L1. In some
embodiments, the immune checkpoint inhibitor is a PD-L1 inhibitor. In some embodiments,
the immune checkpoint inhibitor is a PD-L2 inhibitor or a combined PD-L1/PD-L2 inhibitor.
In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor.
In some embodiments, the composition described herein includes a first
immune checkpoint inhibitor and a second immune checkpoint inhibitor, wherein the first
immune checkpoint inhibitor is different from the second immune checkpoint inhibitor. In
some embodiments, the first and the second immune checkpoint inhibitor is independently an
inhibitor of PD-1, PD-L1, PD-L2, PD-L3, PD-L4, CTLA-4, LAG3, B7-H3, B7-H4, KIR or
TIM3. In some embodiments, the first immune checkpoint inhibitor is a PD-1 inhibitor, and
the second immune checkpoint inhibitor is a CTLA-4 inhibitor. In some embodiments, the
first immune checkpoint inhibitor is a PD-L1 inhibitor, and the second immune checkpoint
inhibitor is a CTLA-4 inhibitor. In some embodiments, the first immune checkpoint inhibitor
is a PD-L2 inhibitor, and the second immune checkpoint inhibitor is a CTLA-4 inhibitor.
In some embodiments, the immune checkpoint inhibitor can be a small
peptide agent that can inhibit T cell regulation function. In some embodiments, the immune
checkpoint inhibitor can be a small molecule (e.g. less than 500 Daltons) that can inhibit T
cell regulation function. In some embodiments, the immune checkpoint inhibitor can be a
molecule providing co-stimulation of T-cell activation. In some embodiments, the immune
checkpoint inhibitor can be a molecule providing co-stimulation of natural killer cell
activation. In some embodiments, the immune checkpoint inhibitor can be an antibody. In
some embodiments, the immune checkpoint inhibitor is a PD-1 antibody. In some
embodiments, the immune checkpoint inhibitor is a PD-L1 antibody. In some embodiments,
the immune checkpoint inhibitor is a PD-L2 antibody. In some embodiments, the immune
checkpoint inhibitor is a PD-L3 antibody. In some embodiments, the immune checkpoint
inhibitor is a PD-L4 antibody. In some embodiments, the immune checkpoint inhibitor is a
CTLA-4 antibody. In some embodiments, the immune checkpoint inhibitor is an antibody of
CTLA-4, LAG3, B7-H3, B7-H4, KIR, or TIM3.
The antibody can be selected from α-CD3-APC, α-CD3-APC-H7, α-CD4-
ECD, α-CD4-PB, α-CD8-PE-Cy7, α-CDPerCP-Cy5.5, α-CD11c-APC, α-CD11b-PE-Cy7,
α-CD11b-AF700, α-CD14-FITC, α-CD16-PB, α-CD19-AF780, α-CD19-AF700, α-CD20-
PO, α-CD25-PE-Cy7, α-CD40-APC, α-CD45-Biotin, Streptavidin-BV605, α-CD62L-ECD,
α-CD69-APC-Cy7, α-CD80-FITC, α-CD83-Biotin, Streptavidin-PE-Cy7, α-CD86-PE-Cy7,
α-CD86-PE, α-CD123-PE, α-CD154-PE, α-CD161-PE, α-CTLA4-PE-Cy7, α-FoxP3-AF488
(clone 259D), IgG1-isotype-AF488, α-ICOS (CD278)-PE, α-HLA-A2-PE, α-HLA-DR-PB, α-
HLA-DR-PerCPCy5.5, α-PD1-APC, VISTA, co-stimulatory molecule OX40, and CD137.
A variety of antibodies (Abs) can be used in the composition described
herein, including antibodies having high-affinity binding to PD-1 PD-Ll, PD-L2, PD-L3, or
PD-L4. Human mAbs (HuMAbs) that bind specifically to PD-1 (e.g., bind to human PD-1
and may cross-react with PD-1 from other species, such as cynomolgus monkey) with high
affinity have been disclosed in U.S. Patent No. 8,008,449, which is incorporated herein by
reference in its entirety. HuMAbs that bind specifically to PD-Ll with high affinity have been
disclosed in U.S. Patent No. 7,943,743, which is incorporated herein by reference in its
entirety. Other anti-PD-1 mAbs have been described in, for example, U.S. Patent Nos.
6,808,710, 7,488,802 and 8,168,757, and PCT Publication No. , all of
which are incorporated herein by reference in their entireties. Anti-PD-Ll mAbs have been
described in, for example, U.S. Patent Nos. 7,635,757 and 8,217,149, U.S. Publication No.
2009/0317368, and PCT Publication Nos. and , all of
which are incorporated herein by reference in their entireties.
In some embodiments, the anti-PD-1 HuMAbs can be selected from 17D8,
2D3, 4H1, 5C4 (also referred to herein as nivolumab), 4A1 1, 7D3 and 5F4, all of which are
described in U.S. Patent No. 8,008,449. In some embodiments, the anti-PD-1 HuMAbs can
be selected from 3G10, 12A4 (also referred to herein as BMS-936559), 10A5, 5F8, 10H10,
1B12, 7H1, 1 1E6, 12B7, and 13G4, all of which are described in U.S. Patent No. 7,943,743.
In some embodiments, the composition can further include one or more
pharmaceutically acceptable diluents. In some embodiments, the pharmaceutically
acceptable diluent can include Kolliphor HS15® (Polyoxyl (15)-hydroxystearate). In some
embodiments, the pharmaceutically acceptable diluent can include propylene glycol. In some
embodiments, the pharmaceutically acceptable diluents can include kolliphor and propylene
glycol. In some embodiments, the pharmaceutically acceptable diluents can include kolliphor
and propylene glycol, wherein the kolliphor is about 40% by weight and propylene glycol is
about 60% by weight based on the total weight of the diluents. In some embodiments, the
composition can further include one or more other pharmaceutically acceptable excipients.
Standard pharmaceutical formulation techniques can be used to make the
pharmaceutical compositions described herein, such as those disclosed in Remington's The
Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005),
incorporated herein by reference in its entirety. Accordingly, some embodiments include
pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of
Plinabulin or pharmaceutically acceptable salts thereof; (b) an immune checkpoint inhibitor
and (c) a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
Other embodiments include co-administering Plinabulin and one or more
immune checkpoint inhibitor in separate compositions. Thus, some embodiments include a
first pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount
of Plinabulin or pharmaceutically acceptable salts thereof and (b) a pharmaceutically
acceptable carrier, diluent, excipient or combination thereof; and a second pharmaceutical
composition comprising: (a) one or more immune checkpoint inhibitor and (b) a
pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
Administration of the pharmaceutical compositions described herein can
be via any of the accepted modes of administration for agents that serve similar utilities
including, but not limited to, orally, sublingually, buccally, subcutaneously, intravenously,
intranasally, topically, transdermally, intradermally, intraperitoneally, intramuscularly,
intrapulmonarilly, vaginally, rectally, or intraocularly. Oral and parenteral administrations
are customary in treating the indications that are the subject of the preferred embodiments.
The term “pharmaceutically acceptable carrier” or “pharmaceutically
acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial
and antifungal agents, isotonic and absorption delaying agents and the like. The use of such
media and agents for pharmaceutically active substances is well known in the art. Except
insofar as any conventional media or agent is incompatible with the active ingredient, its use
in the therapeutic compositions is contemplated. In addition, various adjuvants such as are
commonly used in the art may be included. Considerations for the inclusion of various
components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.)
(1990); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 8th Ed.,
Pergamon Press, which is incorporated herein by reference in its entirety.
Some examples of substances, which can serve as pharmaceutically-
acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose;
starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium
carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt;
gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate;
vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of
theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene
glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl
sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants;
preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.
The compositions described herein are preferably provided in unit dosage
form. As used herein, a "unit dosage form" is a composition containing an amount of a
compound or composition that is suitable for administration to an animal, preferably mammal
subject, in a single dose, according to good medical practice. The preparation of a single or
unit dosage form however, does not imply that the dosage form is administered once per day
or once per course of therapy. Such dosage forms are contemplated to be administered once,
twice, thrice or more per day and may be administered as infusion over a period of time (e.g.,
from about 30 minutes to about 2-6 hours), or administered as a continuous infusion, and
may be given more than once during a course of therapy, although a single administration is
not specifically excluded. The skilled artisan will recognize that the formulation does not
specifically contemplate the entire course of therapy and such decisions are left for those
skilled in the art of treatment rather than formulation.
The compositions useful as described above may be in any of a variety of
suitable forms for a variety of routes for administration, for example, for oral, sublingual,
buccal, nasal, rectal, topical (including transdermal and intradermal), ocular, intracerebral,
intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of
administration. The skilled artisan will appreciate that oral and nasal compositions include
compositions that are administered by inhalation, and made using available methodologies.
Depending upon the particular route of administration desired, a variety of pharmaceutically-
acceptable carriers well-known in the art may be used. Pharmaceutically-acceptable carriers
include, for example, solid or liquid fillers, diluents, hydrotropies, surface-active agents, and
encapsulating substances. Optional pharmaceutically-active materials may be included,
which do not substantially interfere with the inhibitory activity of the compound or
composition. The amount of carrier employed in conjunction with the compound or
composition is sufficient to provide a practical quantity of material for administration per unit
dose of the compound. Techniques and compositions for making dosage forms useful in the
methods described herein are described in the following references, all incorporated by
reference herein: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes,
editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel,
Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).
Various oral dosage forms can be used, including such solid forms as
tablets, capsules (e.g. solid gel capsules and liquid gel capsules), granules and bulk powders.
Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or
multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents,
coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid oral
dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or
suspensions reconstituted from non-effervescent granules, and effervescent preparations
reconstituted from effervescent granules, containing suitable solvents, preservatives,
emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents
and flavoring agents.
The pharmaceutically-acceptable carriers suitable for the preparation of
unit dosage forms for peroral administration is well-known in the art. Tablets typically
comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as
calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch,
gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants
such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be
used to improve flow characteristics of the powder mixture. Coloring agents, such as the
FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as
aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for
chewable tablets. Capsules typically comprise one or more solid diluents disclosed above.
The selection of carrier components depends on secondary considerations like taste, cost, and
shelf stability, which are not critical, and can be readily made by a person skilled in the art.
Peroral compositions also include liquid solutions, emulsions,
suspensions, and the like. The pharmaceutically-acceptable carriers suitable for preparation
of such compositions are well known in the art. Typical components of carriers for syrups,
elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene
glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents
include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and
sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical
preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may
also contain one or more components such as sweeteners, flavoring agents and colorants
disclosed above.
Such compositions may also be coated by conventional methods, typically
with pH or time-dependent coatings, such that the subject composition is released in the
gastrointestinal tract in the vicinity of the desired topical application, or at various times to
extend the desired action. Such dosage forms typically include, but are not limited to, one or
more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl
cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.
Compositions described herein may optionally include other drug actives.
Other compositions useful for attaining systemic delivery of the subject
compounds include sublingual, buccal and nasal dosage forms. Such compositions typically
comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and
binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and
hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and
flavoring agents disclosed above may also be included.
A liquid composition, which is formulated for topical ophthalmic use, is
formulated such that it can be administered topically to the eye. The comfort may be
maximized as much as possible, although sometimes formulation considerations (e.g. drug
stability) may necessitate less than optimal comfort. In the case that comfort cannot be
maximized, the liquid may be formulated such that the liquid is tolerable to the patient for
topical ophthalmic use. Additionally, an ophthalmically acceptable liquid may either be
packaged for single use, or contain a preservative to prevent contamination over multiple
uses.
For ophthalmic application, solutions or medicaments are often prepared
using a physiological saline solution as a major vehicle. Ophthalmic solutions may
preferably be maintained at a comfortable pH with an appropriate buffer system. The
formulations may also contain conventional, pharmaceutically acceptable preservatives,
stabilizers and surfactants.
Preservatives that may be used in the pharmaceutical compositions
disclosed herein include, but are not limited to, benzalkonium chloride, PHMB,
chlorobutanol, thimerosal, phenylmercuric, acetate and phenylmercuric nitrate. A useful
surfactant is, for example, Tween 80. Likewise, various useful vehicles may be used in the
ophthalmic preparations disclosed herein. These vehicles include, but are not limited to,
polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl
cellulose, hydroxyethyl cellulose and purified water.
Tonicity adjustors may be added as needed or convenient. They include,
but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and
glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
Various buffers and means for adjusting pH may be used so long as the
resulting preparation is ophthalmically acceptable. For many compositions, the pH will be
between 4 and 9. Accordingly, buffers include acetate buffers, citrate buffers, phosphate
buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations
as needed.
Ophthalmically acceptable antioxidants include, but are not limited to,
sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and
butylated hydroxytoluene.
Other excipient components, which may be included in the ophthalmic
preparations, are chelating agents. A useful chelating agent is edetate disodium, although
other chelating agents may also be used in place or in conjunction with it.
For topical use, creams, ointments, gels, solutions or suspensions, etc.,
containing the composition disclosed herein are employed. Topical formulations may
generally be comprised of a pharmaceutical carrier, co-solvent, emulsifier, penetration
enhancer, preservative system, and emollient.
For intravenous administration, the compositions described herein may be
dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or dextrose
solution. Suitable excipients may be included to achieve the desired pH, including but not
limited to NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In various
embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7.
Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium
formaldehyde, sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable
excipients found in the final intravenous composition may include sodium or potassium
phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol,
and dextran. Further acceptable excipients are described in Powell, et al., Compendium of
Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and
Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and
Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are
incorporated herein by reference in their entirety. Antimicrobial agents may also be included
to achieve a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric
nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and
chlorobutanol.
The compositions for intravenous administration may be provided to
caregivers in the form of one more solids that are reconstituted with a suitable diluent such as
sterile water, saline or dextrose in water shortly prior to administration. In other
embodiments, the compositions are provided in solution ready to administer parenterally. In
still other embodiments, the compositions are provided in a solution that is further diluted
prior to administration. In embodiments that include administering a combination of a
compound described herein and another agent, the combination may be provided to
caregivers as a mixture, or the caregivers may mix the two agents prior to administration, or
the two agents may be administered separately.
The actual dose of the active compounds described herein depends on the
specific compound, and on the condition to be treated; the selection of the appropriate dose is
well within the knowledge of the skilled artisan. In some embodiments, a daily dose of
Plinabulin may be from about 0.25 mg/kg to about 120 mg/kg or more of body weight, from
about 0.5 mg/kg or less to about 70 mg/kg, from about 1.0 mg/kg to about 50 mg/kg of body
weight, or from about 1.5 mg/kg to about 10 mg/kg of body weight. Thus, for administration
to a 70 kg person, the dosage range would be from about 17 mg per day to about 8000 mg per
day, from about 35 mg per day or less to about 7000 mg per day or more, from about 70 mg
per day to about 6000 mg per day, from about 100 mg per day to about 5000 mg per day, or
from about 200 mg to about 3000 mg per day.
In some embodiments, the compositions described herein can be used in
combination with other therapeutic agents. In some embodiments, the compositions described
herein can be administered or used in combination with treatments such as chemotherapy,
radiation, and biologic therapies.
Method of Treatment
Some embodiments relate to a method for treating cancer using the
pharmaceutical composition described herein to a subject in need thereof. Some
embodiments relate to a method for treating cancer, comprising co-administering Plinabulin
and one or more immune checkpoint inhibitor to a subject in need thereof. In some
embodiments, the subject can be an animal, e.g., a mammal, a human. In some embodiments,
the subject is a human.
Some embodiments relate to methods of providing co-stimulation of T-cell
activation against cancer by co-administering plinabulin and one or more immune checkpoint
inhibitor. Some embodiments relate to methods of providing co-stimulation of natural killer
cells against cancer by co-administering plinabulin and one or more immune checkpoint
inhibitor.
In some embodiments, the cancer comprises cancer cells expressing a
binding ligand of PD-1. In some embodiments, the binding ligand of PD-1 is PD-L1. In
some embodiments, the binding ligand of PD-1 is PD-L2.
In some embodiments, the method of treating cancer described herein
further includes identifying cancer cells expressing a binding ligand of PD-1. In some
embodiments, the method of treating cancer described herein further includes identifying
cancer cells expressing PD-L1. In some embodiments, the method of treating cancer
described herein further includes identifying cancer cells expressing PD-L2. In some
embodiments, the method of treating cancer described herein further includes identifying
cancer cells expressing PD-L3 or PD-L4.
In some embodiments, identifying cancer cells expressing a binding ligand
of PD-1 includes using an assay to detect the presence of the binding ligand. Examples of
applicable assay include but are not limited to PD-L1 IHC 22C3 pharmDx kit and PD-L1
IHC 28-8 pharmDx available from Dako.
In some embodiments, the cancer comprises cancer cells expressing a
binding ligand of CTLA-4. In some embodiments, the binding ligand of CTLA-4 is B7.1 or
B7.2.
In some embodiments, the method of treating cancer described herein
further includes identifying cancer cells expressing a binding ligand of CTLA-4. In some
embodiments, the method of treating cancer described herein further includes identifying
cancer cells expressing B7.1 or B7.2.
In some embodiments, the immune checkpoint inhibitor is nivolumab,
pembrolizumab, pidilizumab, ipilimumab, dacarbazine, BMS 936559, atezolizumab,
durvalimumab, or any combinations thereof.
In some embodiments, cancer is head and neck cancer, lung cancer,
stomach cancer, colon cancer, pancreatic cancer, prostate cancer, breast cancer, kidney
cancer, bladder cancer, ovary cancer, cervical cancer, melanoma, glioblastoma, myeloma,
lymphoma, or leukemia. In some embodiments, the cancer is renal cell carcinoma, malignant
melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, Hodgkin’s lymphoma or
squamous cell carcinoma. In some embodiments, the cancer is selected from breast cancer,
colon cancer, rectal cancer, lung cancer, prostate cancer, melanoma, leukemia, ovarian
cancer, gastric cancer, renal cell carcinoma, liver cancer, pancreatic cancer, lymphomas and
myeloma. In some embodiments, the cancer is a solid tumor or hematological cancer.
In some embodiments, the cancer does not have any cells expressing PD-1,
PD-L1, or PD-L2 at detectable levels.
In some embodiments, the cancer is selected from breast cancer, colon
cancer, rectal cancer, lung cancer, prostate cancer, melanoma, leukemia, ovarian cancer,
gastric cancer, renal cell carcinoma, liver cancer, pancreatic cancer, lymphomas and
myeloma. In some embodiments, the cancer is a solid tumor or hematological cancer.
Some embodiments relate to a method of inducing dendritic cell
maturation in a cancer patient, comprising administering to a composition comprising
Plinabulin to a cancer patient.
Some embodiments relate to a method of disrupting cancer associated
tumor vasculature in a subject comprising co-administering to the subject a compound of
plinabulin and one or more immune checkpoint inhibitor.
Various cancers are associated the formation of tumor vasculature. In
some embodiments, the cancer is selected from the group consisting of a melanoma, a
pancreatic cancer, a colorectal adenocarcinoma, a brain tumor, acute lymphoblastic leukemia,
chronic lymphocytic leukemia, hormone refractory metastatic prostate cancer, metastatic
breast cancer, non-small cell lung cancer, renal cell carcinoma, head and neck cancer,
prostate cancer, colon cancer, anaplastic thyroid cancer.
Some embodiments include co-administering a composition, and/or
pharmaceutical composition described herein, with an additional medicament. For example,
as described above, some embodiments include co-administering Plinabulin with one or more
immune checkpoint inhibitor. By “co-administration,” it is meant that the two or more agents
are administered in such a manner that administration of one or more agent has an effect on
the efficacy and/or safety of the one or more other agent, regardless of when or how they are
actually administered. In one embodiment, the agents are administered simultaneously. In
one such embodiment, administration in combination is accomplished by combining the
agents in a single dosage form. In another embodiment, the agents are administered
sequentially. In one embodiment the agents are administered through the same route, such as
orally or intravenously. In another embodiment, the agents are administered through different
routes, such as one being administered orally and another being administered i.v. In some
embodiments, the time period between administration of one or more agent and
administration of the co-administered one or more agent can be about 1 hour, 2 hours, 3
hours, 5 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 24 hours, 36 hours,
48 hours, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 14 days, 21 days, 28 days, or 30
days.
In some embodiments, the treatment cycle can include co-administering
Plinabulin and one or more immune checkpoint inhibitors in combination with administering
Plinabulin alone or administering one or more checkpoint inhibitor alone. In some
embodiments, plinabulin and one or more immune checkpoint inhibitor are co-administered
on day 1, followed by administration of plinabulin alone after 1 day, 2 days, 3 days, 4 days, 5
days, 6 days, 7 days, 2 weeks, or 3 weeks, and then followed by co-administration of
plinabulin and one or more immune checkpoint inhibitor after 1 day, 2 days, 3 days, 4 days, 5
days, 6 days, 7 days, 2 weeks, or 3 weeks. In some embodiments, plinabulin and one or more
immune checkpoint inhibitor are administered simultaneously on day 1, followed by
administration of plinabulin or one or more immune checkpoint inhibitor alone on a day
selected between day 2 and day 31, and then followed by co-administration of plinabulin and
one or more immune checkpoint inhibitor on a day selected between day 3 and day 31. In
some embodiments, plinabulin and one or more immune checkpoint inhibitor are co-
administered on day 1, followed by administration of plinabulin alone on day 8, and then
followed by co-administration of plinabulin and one or more immune checkpoint inhibitor on
day 15. In some embodiments, the treatment cycle can be repeated two or more times.
Examples of additional medicaments include other chemotherapeutic
agents.
In some embodiments, the chemotherapeutic agent can be selected from
the group consisting of Abiraterone Acetate, Abitrexate (Methotrexate), Abraxane (Paclitaxel
Albumin-stabilized Nanoparticle Formulation), ABVD, ABVE, ABVE-PC , AC, AC-T,
Adcetris (Brentuximab Vedotin), ADE, Ado-Trastuzumab Emtansine ,Adriamycin
(Doxorubicin Hydrochloride) , Afatinib Dimaleate, Afinitor (Everolimus), Akynzeo
(Netupitant and Palonosetron Hydrochloride), Aldara (Imiquimod), Aldesleukin, Alecensa
(Alectinib), Alectinib, Alemtuzumab, Alimta (Pemetrexed Disodium), Aloxi (Palonosetron
Hydrochloride), Ambochlorin (Chlorambucil), Amboclorin (Chlorambucil), Aminolevulinic
Acid, \ Anastrozole, Aprepitant, Aredia (Pamidronate Disodium), Arimidex (Anastrozole),
Aromasin (Exemestane), Arranon (Nelarabine), Arsenic Trioxide, Arzerra (Ofatumumab),
Asparaginase Erwinia chrysanthemi , Avastin (Bevacizumab), Axitinib, Azacitidine,
BEACOPP, Becenum (Carmustine), Beleodaq (Belinostat), Belinostat, Bendamustine
Hydrochloride, BEP, Bevacizumab, Bexarotene, Bexxar (Tositumomab and Iodine I 131
Tositumomab), Bicalutamide, BiCNU (Carmustine), Bleomycin, Blinatumomab, Blincyto
(Blinatumomab), Bortezomib, Bosulif (Bosutinib), Bosutinib, Brentuximab Vedotin,
Busulfan, Cabazitaxel, Cabozantinib-S-Malate, CAF, Campath (Alemtuzumab), Camptosar
(Irinotecan Hydrochloride), Capecitabine, CAPOX, Carac (Fluorouracil--Topical),
Carboplatin, CARBOPLATIN-TAXOL, Carfilzomib, Carmubris (Carmustine), Carmustine,
Carmustine Implant, Casodex (Bicalutamide), CeeNU (Lomustine), Ceritinib, Cerubidine
(Daunorubicin Hydrochloride), Cervarix (Recombinant HPV Bivalent Vaccine) , Cetuximab,
Chlorambucil, CHLORAMBUCIL-PREDNISONE, CHOP, Cisplatin, Clafen
(Cyclophosphamide), Clofarabine, Clofarex (Clofarabine), Clolar (Clofarabine), CMF,
Cobimetinib, Cometriq (Cabozantinib-S-Malate), COPDAC, COPP, COPP-ABV, Cosmegen
(Dactinomycin), Cotellic (Cobimetinib), Crizotinib, CVP, Cyclophosphamide, Cyfos
(Ifosfamide), Cyramza (Ramucirumab), Cytarabine, Cytarabine Liposome, Cytosar-U
(Cytarabine), Cytoxan (Cyclophosphamide), Dabrafenib, Dacarbazine, Dacogen (Decitabine),
Dactinomycin, Daratumumab, Darzalex (Daratumumab), Dasatinib, Daunorubicin
Hydrochloride, Decitabine, Degarelix, Denileukin Diftitox, Denosumab, DepoCyt
(Cytarabine Liposome), Dexamethasone, Dexrazoxane Hydrochloride, Dinutuximab,
Docetaxel, Doxil (Doxorubicin Hydrochloride Liposome), Doxorubicin Hydrochloride,
Doxorubicin Hydrochloride Liposome, Dox-SL (Doxorubicin Hydrochloride Liposome),
DTIC-Dome (Dacarbazine), Efudex (Fluorouracil--Topical), Elitek (Rasburicase), Ellence
(Epirubicin Hydrochloride), Elotuzumab, Eloxatin (Oxaliplatin), Eltrombopag Olamine,
Emend (Aprepitant), Empliciti (Elotuzumab), Enzalutamide, Epirubicin Hydrochloride,
EPOCH, Erbitux (Cetuximab), Eribulin Mesylate, Erivedge (Vismodegib), Erlotinib
Hydrochloride, Erwinaze (Asparaginase Erwinia chrysanthemi), Etopophos (Etoposide
Phosphate), Etoposide, Etoposide Phosphate, Evacet (Doxorubicin Hydrochloride Liposome),
Everolimus, Evista (Raloxifene Hydrochloride), Exemestane, 5-FU (Fluorouracil Injection),
-FU (Fluorouracil--Topical), Fareston (Toremifene), Farydak (Panobinostat), Faslodex
(Fulvestrant), FEC, Femara (Letrozole), Filgrastim, Fludara (Fludarabine Phosphate),
Fludarabine Phosphate, Fluoroplex (Fluorouracil--Topical), Fluorouracil Injection,
Fluorouracil—Topical, Flutamide, Folex (Methotrexate), Folex PFS (Methotrexate),
FOLFIRI, FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX,
Folotyn (Pralatrexate), FU-LV, Fulvestrant, Gardasil (Recombinant HPV Quadrivalent
Vaccine), Gardasil 9 (Recombinant HPV Nonavalent Vaccine), Gazyva (Obinutuzumab),
Gefitinib, Gemcitabine Hydrochloride, GEMCITABINE-CISPLATIN, GEMCITABINE-
OXALIPLATIN ,Gemtuzumab Ozogamicin, Gemzar (Gemcitabine Hydrochloride), Gilotrif
(Afatinib Dimaleate), Gleevec (Imatinib Mesylate), Gliadel (Carmustine Implant), Gliadel
wafer (Carmustine Implant), Glucarpidase, Goserelin Acetate, Halaven (Eribulin
Mesylate),Herceptin (Trastuzumab), HPV Bivalent Vaccine, Recombinant, HPV Nonavalent
Vaccine, Recombinant, HPV Quadrivalent Vaccine, Recombinant, Hycamtin (Topotecan
Hydrochloride), Hyper-CVAD, Ibrance (Palbociclib), Ibritumomab Tiuxetan, Ibrutinib, ICE,
Iclusig (Ponatinib Hydrochloride), Idamycin (Idarubicin Hydrochloride), Idelalisib, Ifex
(Ifosfamide), Ifosfamide, IL-2 (Aldesleukin), Imatinib Mesylate, Imbruvica (Ibrutinib),
Imiquimod, Imlygic (Talimogene Laherparepvec), Inlyta (Axitinib), Interferon Alfa-2b,
Recombinant, Interleukin-2 (Aldesleukin), Intron A (Recombinant Interferon Alfa-2b), Iodine
I 131 Tositumomab and Tositumomab, Ipilimumab, Iressa (Gefitinib), Irinotecan
Hydrochloride, Irinotecan Hydrochloride Liposome, Istodax (Romidepsin), Ixabepilone,
Ixazomib Citrate, Ixempra (Ixabepilone), Jakafi (Ruxolitinib Phosphate), Jevtana
(Cabazitaxel), Kadcyla (Ado-Trastuzumab Emtansine), Keoxifene (Raloxifene
Hydrochloride), Kepivance (Palifermin), Keytruda (Pembrolizumab), Kyprolis (Carfilzomib),
Lanreotide Acetate, Lapatinib Ditosylate, Lenalidomide, Lenvatinib Mesylate, Lenvima
(Lenvatinib Mesylate), Letrozole, Leucovorin Calcium, Leukeran (Chlorambucil), Leuprolide
Acetate, Levulan (Aminolevulinic Acid), Linfolizin (Chlorambucil), LipoDox (Doxorubicin
Hydrochloride Liposome), Lomustine, Lonsurf (Trifluridine and Tipiracil Hydrochloride),
Lupron (Leuprolide Acetate) ,Lupron Depot (Leuprolide Acetate), Lupron Depot-Ped
(Leuprolide Acetate), Lupron Depot-3 Month (Leuprolide Acetate), Lupron Depot-4 Month
(Leuprolide Acetate), Lynparza (Olaparib), Marqibo (Vincristine Sulfate Liposome),
Matulane (Procarbazine Hydrochloride), Mechlorethamine Hydrochloride, Megace
(Megestrol Acetate), Megestrol Acetate, Mekinist (Trametinib), Mercaptopurine, Mesna,
Mesnex (Mesna), Methazolastone (Temozolomide), Methotrexate, Methotrexate LPF
(Methotrexate), Mexate (Methotrexate), Mexate-AQ (Methotrexate), Mitomycin C,
Mitoxantrone Hydrochloride, Mitozytrex (Mitomycin C), MOPP,Mozobil (Plerixafor),
Mustargen (Mechlorethamine Hydrochloride),,Mutamycin (Mitomycin C), Myleran
(Busulfan), Mylosar (Azacitidine), Mylotarg (Gemtuzumab Ozogamicin), Nanoparticle
Paclitaxel (Paclitaxel Albumin-stabilized Nanoparticle Formulation), Navelbine (Vinorelbine
Tartrate), Necitumumab, Nelarabine, Neosar (Cyclophosphamide), Netupitant and
Palonosetron Hydrochloride, Neupogen (Filgrastim), Nexavar (Sorafenib Tosylate) ,
Nilotinib, Ninlaro (Ixazomib Citrate), Nivolumab, Nolvadex (Tamoxifen Citrate), Nplate
(Romiplostim), Obinutuzumab, Odomzo (Sonidegib), OEPA, Ofatumumab, OFF, Olaparib,
Omacetaxine Mepesuccinate, Oncaspar (Pegaspargase), Ondansetron Hydrochloride,
Onivyde (Irinotecan Hydrochloride Liposome), Ontak (Denileukin Diftitox), Opdivo
(Nivolumab), OPPA , Osimertinib, Oxaliplatin, Paclitaxel, Paclitaxel Albumin-stabilized
Nanoparticle Formulation, PAD, Palbociclib, Palifermin, Palonosetron Hydrochloride,
Palonosetron Hydrochloride and Netupitant, Pamidronate Disodium, Panitumumab,
Panobinostat, Paraplat (Carboplatin), Paraplatin (Carboplatin), Pazopanib Hydrochloride,
PCV , Pegaspargase, Peginterferon Alfa-2b, PEG-Intron (Peginterferon Alfa-2b),
Pembrolizumab, Pemetrexed Disodium Perjeta (Pertuzumab), Pertuzumab, Platinol
(Cisplatin), Platinol-AQ (Cisplatin), Plerixafor, Pomalidomide, Pomalyst (Pomalidomide),
Ponatinib Hydrochloride, Portrazza (Necitumumab), Pralatrexate, Prednisone, Procarbazine
Hydrochloride, Proleukin (Aldesleukin), Prolia (Denosumab), Promacta (Eltrombopag
Olamine), Provenge (Sipuleucel-T), Purinethol (Mercaptopurine), Purixan (Mercaptopurine),
Radium 223 Dichloride, Raloxifene Hydrochloride, Ramucirumab, Rasburicase, R-CHOP,
R-CVP, Recombinant Human Papillomavirus (HPV) Bivalent Vaccine, Recombinant
Human Papillomavirus (HPV) Nonavalent Vaccine, Recombinant Human Papillomavirus
(HPV) Quadrivalent Vaccine, Recombinant Interferon Alfa-2b, Regorafenib, R-EPOCH,
Revlimid (Lenalidomide) , Rheumatrex (Methotrexate), Rituximab, Rolapitant
Hydrochloride, Romidepsin , Romiplostim, Rubidomycin (Daunorubicin Hydrochloride),
Ruxolitinib Phosphate, Sclerosol Intrapleural Aerosol (Talc),Siltuximab, Sipuleucel-T,
Somatuline Depot (Lanreotide Acetate), Sonidegib, Sorafenib Tosylate, Sprycel (Dasatinib),
STANFORD V, Sterile Talc Powder (Talc), Steritalc (Talc), Stivarga (Regorafenib),
Sunitinib Malate, Sutent (Sunitinib Malate), Sylatron (Peginterferon Alfa-2b), Sylvant
(Siltuximab), Synovir (Thalidomide), Synribo (Omacetaxine Mepesuccinate), Tabloid
(Thioguanine), TAC, Tafinlar (Dabrafenib), Tagrisso (Osimertinib), Talc, Talimogene
Laherparepvec, Tamoxifen Citrate, Tarabine PFS (Cytarabine), Tarceva (Erlotinib
Hydrochloride), Targretin (Bexarotene), Tasigna (Nilotinib), Taxol (Paclitaxel), Taxotere
(Docetaxel), Temodar (Temozolomide), Temozolomide, Temsirolimus, Thalidomide,
Thioguanine, Thiotepa, Tolak (Fluorouracil--Topical), Toposar (Etoposide), Topotecan
Hydrochloride, Toremifene, Torisel (Temsirolimus), Tositumomab and Iodine I 131,
Tositumomab, Totect (Dexrazoxane Hydrochloride), TPF, Trabectedin, Trametinib,
Trastuzumab, Treanda (Bendamustine Hydrochloride) , Trifluridine and Tipiracil
Hydrochloride, Trisenox (Arsenic Trioxide), Tykerb (Lapatinib Ditosylate), Unituxin
(Dinutuximab), Uridine Triacetate, VAC, Vandetanib, VAMP, Varubi (Rolapitant
Hydrochloride), Vectibix (Panitumumab), VeIP, Velban (Vinblastine Sulfate), Velcade
(Bortezomib), Velsar (Vinblastine Sulfate), Vemurafenib, VePesid (Etoposide), Viadur
(Leuprolide Acetate), Vidaza (Azacitidine), Vinblastine Sulfate, Vincasar PFS (Vincristine
Sulfate), Vincristine Sulfate, Vincristine Sulfate Liposome, Vinorelbine Tartrate, VIP,
Vismodegib, Vistogard (Uridine Triacetate), Voraxaze (Glucarpidase), Vorinostat, Votrient
(Pazopanib Hydrochloride), Wellcovorin (Leucovorin Calcium), Xalkori (Crizotinib), Xeloda
(Capecitabine), XELIRI,XELOX, Xgeva (Denosumab), Xofigo (Radium 223 Dichloride),
Xtandi (Enzalutamide), Yervoy (Ipilimumab),Yondelis (Trabectedin), Zaltrap (Ziv-
Aflibercept), Zarxio (Filgrastim), Zelboraf (Vemurafenib), Zevalin (Ibritumomab Tiuxetan),
Zinecard (Dexrazoxane Hydrochloride), Ziv-Aflibercept, Zofran (Ondansetron
Hydrochloride), Zoladex (Goserelin Acetate), Zoledronic Acid, Zolinza (Vorinostat), Zometa
(Zoledronic Acid), Zydelig (Idelalisib), Zykadia (Ceritinib), and Zytiga (Abiraterone
Acetate).
To further illustrate this invention, the following examples are included.
The examples should not, of course, be construed as specifically limiting the invention.
Variations of these examples within the scope of the claims are within the purview of one
skilled in the art and are considered to fall within the scope of the invention as described, and
claimed herein. The reader will recognize that the skilled artisan, armed with the present
disclosure, and skill in the art is able to prepare and use the invention without exhaustive
examples.
EXAMPLES
Example 1. Plinabulin Effect on Dendritic Cell Maturation
Cell lines: The immature mouse DC cell line SP37A3 (provided by Merck
KGaA) was cultured in Iscove's Modified Dulbecco's Medium (IMDM; Sigma)
supplemented with 10% heat-inactivated and endotoxin-tested FBS (PAA), sodium pyruvate
(Gibco), penicillin/streptomycin L-glutamine mix (Gibco), Eagle's Minimum Essential
Medium (MEM) nonessential amino acids (Sigma), Ciproxin (Bayer), and 0.05 mmol/L 2-
mercaptoethanol (Gibco). IMDM complete medium was supplemented with 20 ng/mL
recombinant mouse GM-CSF and 20 ng/mL recombinant mouse M-CSF (both Peprotech).
The murine tumor cell lines EG7 and 3LL-OVA were obtained from ATCC or provided by
Douglas T. Fearon (Cancer Research UK Cambridge Institute, Li Ka Shing Centre,
University of Cambridge, Cambridge, UK), respectively. All cell lines were tested and
validated to be Mycoplasma-free. Expression of OVA in EG7 and 3LL-OVA, and of Thy1.1
in RMAThy1.1, respectively, was confirmed; no genomic authentication was performed.
SP37A3 DCs (murine DC line, Merck) were plated (8x10 cells/well, 96-
well flat bottom, tissue-culture treated) in 180 uL IMDM complete medium [IMDM medium
(Sigma) supplemented with 10% heat-inactivated and endotoxin-tested FBS (PAA), sodium
pyruvate (Gibco), penicillin/streptomycin L-glutamine mix (Gibco), MEM nonessential
amino acids (Sigma) and 0.05 mM 2-mercaptoethanol (Gibco)]. IMDM complete medium
was supplemented with 20 ng/mL recombinant mouse GM-CSF. DCs were allowed to
adhere for two hours before Plinabulin, medium, or LPS as controls were added 10x
concentrated in 20 uL. DCs were incubated with Plinabulin in various concentrations (0.001
µM, 0.01 µM, 0.1 µM, 1 µM, 10 µM), medium, and LPS respectively for 20 h. Supernatants
of these cultures were collected and used for detection of cytokine production by ELISA (kits
available from BD) and the cells were stained with the LD-IR viability dye (Invitrogen) as
well as with fluorochrom-labeled monoclonal antibodies against CD80, CD86, CD40 and
MHCII for flow cytometric analysis. Cells were analyzed using a BD Fortessa Cytometer
equipped with DIVA software. Mean fluorescence intensity (MFI) of the DC maturation
markers CD40, CD80, CD86 and MHCII in live cells was normalized to the MFI of those
markers detected in untreated (medium) DCs. As shown in , Plinabulin significantly
increased expression of all four DC maturation markers: CD40, CD80, CD86 and MHCII.
DC viability did not change significantly at any of the drug concentrations tested, as
determined using SytoxGreen staining, as shown in .
Example 2. Plinabulin in comparison with Paclitaxel and Etoposide on Dendritic Cell
Maturation
Two other cancer drugs, Paclitaxel and Etoposide, were also tested to
compare their effects on DC maturation with Plinabulin. SP37A3 DCs (murine DC line,
Merck) were plated (8x10 cells/well, 96-well flat bottom, tissue-culture treated) in 180 uL
IMDM complete medium [IMDM medium (Sigma) supplemented with 10% heat-inactivated
and endotoxin-tested FBS (PAA), sodium pyruvate (Gibco), penicillin/streptomycin L-
glutamine mix (Gibco), MEM nonessential amino acids (Sigma) and 0.05 mM 2-
mercaptoethanol (Gibco)]. IMDM complete medium was supplemented with 20 ng/mL
recombinant mouse GM-CSF. DCs were allowed to adhere for two hours before Plinabulin,
Paclitaxel, Etoposide, medium, or LPS (positive control) were added 10x concentrated in 20
uL. DCs were incubated with Plinabulin (0.001 µM, 0.01 µM, 0.1 µM, 1 µM, 10 µM),
Paclitaxel (0.001 µM, 0.01 µM, 0.1 µM, 1 µM, 10 µM), Etoposide (0.001 µM, 0.01 µM, 0.1
µM, 1 µM, 10 µM), medium, and LPS (positive control) respectively for 20h. Supernatants
of these cultures were collected and used for detection of cytokine production by ELISA (kits
available from BD) and the cells were stained with the LD-IR viability dye (Invitrogen) as
well as with fluorochrom-labeled monoclonal antibodies against CD80, CD86, CD40 and
MHCII for flow cytometric analysis. Cells were analyzed using a BD Fortessa Cytometer
equipped with DIVA software. Mean fluorescence intensity (MFI) of the DC maturation
markers CD40 (), CD80(), CD86 () and MHCII() in live
cells was normalized to the MFI of those markers detected in untreated (medium) DCs. The
production of the pro-inflammatory cytokines IL-1β(Fig. 3A), IL-6(Fig. 3B), and IL-
12p40(Fig. 3C) were also determined by ELISA. Supernatants from the DC cultures were
analyzed for these proinflammatory cytokines that have been demonstrated to play critical
roles in regulating T-cell function and antitumor immune responses.
It was noted that Plinabulin was the most potent inducer of DC maturation
among all three drugs. Plinabulin showed much greater expression of all four DC maturation
markers, CD 40, CD 80, MHCII, and CD 86 than Paclitaxel and Etoposide. Plinabulin also
showed significantly increased expression of all four markers when compared with the
positive control LPS. Plinabulin triggered increased production of IL1b, IL6, and IL12,
compared to in contrast to Paclitaxel, Etoposide, and LPS. Therefore, Plinabulin increased
up-regulation of maturation markers and production of pro-inflammatory cytokines, resulting
in an enhanced T cell stimulatory capacity.
Example 3. Synergy of Plinabulin and immune checkpoint inhibitors (PD-1 antibody)
The combined treatment with Plinabulin and a PD-1 checkpoint inhibitor
is tested in comparison with the treatment with Plinabulin alone and the treatment with PD-1
antibody alone. The tests are performed using seven to ten-week old mice that are injected
subcutaneously with MC-38 tumor cells. Five testing groups are prepared, and each group
includes 9 mice.
Group 1 is administered with saline; Group 2 is administered with the
Plinabulin diluent (in the absence of Plinabulin); Group 3 is administered with Plinabulin
dissolved in diluent at a concentration of 7.5 mg/kg; Group 4 is administered with PD-1
antibody; and Group 5 is administered with a Plinabulin/PD-1 antibody combined treatment.
For the Plinabulin/PD-1 antibody combined treatment (Group 5), the mice are administered
twice per week (Day 1 and Day 4 of each week) with Plinabulin (7.5 mg/kg) that is dissolved
in diluent, followed by administering PD-1 antibody one hour after each Plinabulin
administration. For the Plinabulin only treatment (Group 3) or the antibody only treatment
(Group 4), mice are administered Plinabulin (7.5 mg/kg dissolved in diluent) or antibody
alone twice per week (Day 1 and Day 4 of each week). For Groups 1 and 2, the mice are
administered with saline or the Plinabulin diluent alone twice per week.
Each treatment starts at tumor size of around 125 mm and continues until
tumor size of 1500 mm is reached. If the mean tumor size in any group has not reached 1500
mm by Experimental Day 45, treatment will be stopped and tumor size continued to be
assessed. To determine the efficacy of each treatment, the following data are collected:
mortality rate prior to tumor size reaching 1500 mm ; the body weight of the mice assessed
twice weekly both prior to treatments; the rate of tumor growth as determined by the tumor
size measurement (twice every week); the tumor growth index; overall survival rate; and the
time required to double tumor size. The test results of the combined treatment with
Plinabulin and PD-1 antibody show that Plinabulin acts in synergy with PD-1 antibody in
inhibiting tumor growth.
Example 4. In vivo stimulation of OVA specific OT-I and OT-II T cells
SP37A3 cells or day 7 BMDCs are pulsed for 1 hour with OVA full-length
protein (0.1 mg/mL) before activation with Plinabulin or with OVA257–264 peptide
(T4)/OVA323–339 peptide (500 ng/mL; after activation) and added at the indicated ratios to
+ + 5
CD8 /CD4 T cells purified from OT-I/OT-II transgenic mice (2x10 total cells/well, 96-well
round bottomed plate). CD4 T cells are loaded with the proliferation dye eFluor670 before
co-culture. Proliferation is assessed after 3 days using flow cytometry.
Example 5. In vivo stimulation of antigen specific CD4 and CD8 T cells
Langerhans cells (LC) and spleen cells from naive OT-I and OT-II
transgenic mice (Ly5.2) are labeled with eFluor670 and adoptively transferred into C57BL/6-
Ly5.1 mice. After 24 hours, mice are immunized via tail-base injection with OVA257–264
peptide (T4: SIINFEKL; low-affinity variant of SIINFEKL) or OVA323–339 peptide
together with Plinabulin or LPS. Proliferation of OT-I CD8 and OT-II CD4 T cells is
assessed 4 days after adoptive transfer by flow cytometry.
Example 6. Analysis of DC homing to tumor draining LNs
For detection of DC homing upon injection of Plinabulin, mice bearing
subcutaneous EG7 tumors are injected intratumorally with FITC-conjugated dextran (100
mg/mouse; Sigma) together with Plinabulin or PBS/carrier (mock control). Single-cell
suspensions from tumor draining and nondraining LNs are prepared 48 hours after injection
of Plinabulin and analyzed by flow cytometry.
Example 7. Synergy of Plinabulin and immune checkpoint inhibitors (PD-1 antibody and
CTLA-4 antibody)
The combined treatment with Plinabulin and a PD-1 checkpoint inhibitor
in combination with a CTLA-4 checkpoint inhibitor was tested in comparison with the
treatment with Plinabulin alone, the treatment with PD-1 antibody alone, or the treatment
with PD-1 antibody in combination with CTLA-4 antibody. The tests were performed using
seven to ten-week old mice that were injected subcutaneously with MC-38 tumor cells. Six
testing groups were prepared, and each group included 10 mice.
Group 1 was administered with IgG2a and plinabulin vehicle; Group 2
was administered with Plinabulin dissolved in diluent at a concentration of 7.5 mg/kg; Group
3 was administered with PD-1 antibody; Group 4 was administered with a Plinabulin/PD-1
antibody combined treatment; Group 5 was administered combined PD-1/CTLA-4
antibodies; and Group 6 was administered combined PD-1 antibody/CTLA-4
antibody/Plinabulin treatment. For the Plinabulin/PD-1 antibody combined treatment (Group
4) and the Plinabulin/PD-1/CTLA-4 antibody treatment (Group 6), the mice were
administered twice per week (Day 1 and Day 4 of each week) with Plinabulin (7.5 mg/kg)
that was dissolved in diluent, followed by administering antibody (ies) one hour after each
Plinabulin administration. For the Plinabulin only treatment (Group 2) or the antibody (ies)
only treatment (Groups 3 and 5), mice were administered Plinabulin (7.5 mg/kg dissolved in
diluent) or antibody (ies) alone twice per week (Day 1 and Day 4 of each week).
Each treatment started at tumor size of around 125 mm and continued
until tumor size of 3000 mm was reached. When the mean tumor size for Group 1 reached
3000 mm , the experiment ended. To determine the efficacy of each treatment, the
following data were collected: mortality rate prior to tumor size reaching 3000 mm ; the body
weight of the mice assessed twice weekly both prior to treatments; the rate of tumor growth
as determined by the tumor size measurement (twice every week); the tumor growth index;
overall survival rate; the tumor weight at necropsy; and the time required to increase tumor
size 10 fold. At necropsy the tissues were weighed and subjected to FACS analysis.
The test results of the combined treatment with Plinabulin and PD-
1antibody and CTLAantibody showed that Plinabulin acted in synergy with the antibodies
in inhibiting tumor growth and had the longest time to reach 10-fold increased tumor weight
among the six test groups. shows the effects of Groups 1, 5, and 6 on tumor growth.
As shown in , Group 6, the combined treatment with Plinabulin, PD-1 antibody and
CTLAantibody, had better inhibition of tumor growth than Group 5, the combination of
PD-1 antibody and CTLA-4 antibody treatment group, and both groups 5 and 6 showed
inhibition of tumor growth when compared with the control group 1. shows the
effects of the six treatment groups on the mean tumor weight at necropsy. As shown in , the combined treatment with Plinabulin, PD-1 antibody and CTLAantibody produced
the lowest mean tumor weight at necropsy, followed by the treatment group with Plinabulin
and PD-1 antibody. Fig 4C shows the time for tumors to reach 10 fold of their starting
volume in the six treatment groups. As shown in , the treatment group with
Plinabulin, PD-1 antibody and CTLAantibody combined had the longest time for the
tumors to reach 10 fold of their starting volume. Therefore, Plinabulin treatment either alone
or in combination with PD-1 antibody or PD-1 plus CTLA-4 antibodies, resulted in a
decreased tumor weight at necropsy. The combined treatment of Plinabulin, PD-1 antibody
and CTLAantibody had better tumor inhibitor effect than the treatment of Plinabulin and
PD-1 antibody, which showed had better tumor inhibitor effect than the treatment of
Plinabulin alone.
shows the results of FACS analysis of the tumors at necropsy,
including the percentage change of Treg cells, the ration of CD8+/Treg, and the percentage of
macrophages in CD45+ lymphocytes, in the MC-38 CRC tumor model described above.
shows the effects of the six treatment groups on the percentage of Treg cells. As
shown in , the treatment of Plinabulin, PD-1 antibody and CTLAantibody , the
treatment of Plinabulin and PD-1 antibody and the treatment of Plinabulin alone all showed a
reduction in % Treg cells as compared to the comparator group without plinabulin.. FIG 5B
shows the ratio of CD8+ cells to Treg cells. As shown in , the treatment of
Plinabulin, PD-1 antibody and CTLAantibody showed the highest ratio of CD8+/Treg
cells. FIG 5C shows the effects of the six treatment groups on macrophages. As shown in
, the treatment group of Plinabulin, PD-1 antibody and CTLAantibody, the
treatment group of Plinabulin, and the treatment group of PD-1 antibody and CTLA
antibody all showed decreased percentage of macrophage when compared with the respective
comparator groups.
Therefore, the FACS analysis of the tumor tissue demonstrated that
treatments of Plinabulin alone, Plinabulin and the immune checkpoint inhibitors (e.g.,
plinabulin with PD-1 antibody, Plinabulin with PD-1 antibody and CTLAantibody) were
associated with a decreased percentage of Regulatory T cells (Treg cells), a decreased
percentage of macrophage stained cells, and a concomitant increase in the ratio of CD8+/Treg
cells. The decrease of the Treg cells percentage and macrophage stained cells and the increase
in the ratio of CD8+/Treg cells were more significant in the treatment groups with plinabulin
and immune checkpoint inhibitors than the group with plinabulin alone or
antibody(antibodies) alone. These data has demonstrated the synergistic immuno-oncology
properties of the combined treatment using Plinabulin and the immune checkpoint inhibitors
(e.g., PD-1 antibody and CTLAantibody).
Claims (24)
1. A pharmaceutical composition, comprising Plinabulin and one or more immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is an inhibitor of PD-L2, PD-L3, PD-L4, LAG3, B7-H3, B7-H4, KIR or TIM3.
2. The composition of claim 2, wherein the immune checkpoint inhibitor is a PD-L2 inhibitor.
3. The composition of claim 1, comprising a first immune checkpoint inhibitor and a second immune checkpoint inhibitor, wherein the first immune checkpoint inhibitor is different from the second immune checkpoint inhibitor.
4. The composition of claim 3, wherein the first and the second immune checkpoint inhibitor is independently an inhibitor of PD-L2, PD-L3, PD-L4, LAG3, B7-H3, B7-H4, KIR or TIM3.
5. The composition of claim 4, wherein the first immune checkpoint inhibitor is a PD- L2 inhibitor.
6. The composition of any one of claims 1 to 5, wherein the immune checkpoint inhibitor is an antibody.
7. The composition of claim 6, wherein the immune checkpoint inhibitor is a PD-L2 antibody.
8. The composition of claim 6, wherein the antibody is selected from α-CD3-APC, α- CD3-APC-H7, α-CD4-ECD, α-CD4-PB, α-CD8-PE-Cy7, α-CDPerCP-Cy5.5, α-CD11c-APC, α-CD11b-PE-Cy7, α-CD11b-AF700, α-CD14-FITC, α-CD16-PB, α-CD19-AF780, α-CD19- AF700, α-CD20-PO, α-CD25-PE-Cy7, α-CD40-APC, α-CD45-Biotin, Streptavidin-BV605, α- CD62L-ECD, α-CD69-APC-Cy7, α-CD80-FITC, α-CD83-Biotin, Streptavidin-PE-Cy7, α-CD86- PE-Cy7, α-CD86-PE, α-CD123-PE, α-CD154-PE, α-CD161-PE, α-FoxP3-AF488 (clone 259D), IgG1-isotype-AF488, α-ICOS (CD278)-PE, α-HLA-A2-PE, α-HLA-DR-PB, α-HLA-DR- PerCPCy5.5, VISTA, co-stimulatory molecule OX40, and CD137.
9. The composition of anyone of claims 1 to 8, further comprising one or more pharmaceutically acceptable excipients.
10. The composition of anyone of claims 1 to 9, further comprising one or more additional chemotherapeutic agent.
11. Use of the pharmaceutical composition of any one of claims 1 to 10 for the manufacture of a medicament in treating cancer.
12. Use of Plinabulin for the manufacture of a medicament in treating cancer, wherein Plinabulin is used in combination with one or more immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is an inhibitor of PD-L2, PD-L3, PD-L4, LAG3, B7-H3, B7-H4, KIR or TIM3.
13. The use of any one of claims 11 or 12, wherein the cancer comprises cancer cells expressing a binding ligand of PD-L2.
14. The use of claim 13, wherein the cancer is head and neck cancer, lung cancer, stomach cancer, colon cancer, pancreatic cancer, prostate cancer, breast cancer, kidney cancer, bladder cancer, ovary cancer, cervical cancer, melanoma, glioblastoma, myeloma, lymphoma, or leukemia.
15. The use of claim 13, wherein the cancer is renal cell carcinoma, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, Hodgkin’s lymphoma or squamous cell carcinoma.
16. The use of claim 11, wherein the immune checkpoint inhibitor is a PD-L2 inhibitor.
17. The use of claim any one of claims 12 to 16, comprising a first immune checkpoint inhibitor and a second immune checkpoint inhibitor, wherein the first immune checkpoint inhibitor is different from the second immune checkpoint inhibitor.
18. The use of claim 17, wherein the first and the second immune checkpoint inhibitor is independently an inhibitor of PD-L2, PD-L3, PD-L4, LAG3, B7-H3, B7-H4, KIR or TIM3.
19. The use of claim 18, wherein the first immune checkpoint inhibitor is a PD-L2 inhibitor.
20. The use of claim 12, wherein the immune checkpoint inhibitor is an antibody.
21. The use of claim 20, wherein the immune checkpoint inhibitor is a PD-L2 antibody.
22. The use of claim 20, wherein the antibody is selected from α-CD3-APC, α-CD3- APC-H7, α-CD4-ECD, α-CD4-PB, α-CD8-PE-Cy7, α-CDPerCP-Cy5.5, α-CD11c-APC, α- CD11b-PE-Cy7, α-CD11b-AF700, α-CD14-FITC, α-CD16-PB, α-CD19-AF780, α-CD19-AF700, α-CD20-PO, α-CD25-PE-Cy7, α-CD40-APC, α-CD45-Biotin, Streptavidin-BV605, α-CD62L- ECD, α-CD69-APC-Cy7, α-CD80-FITC, α-CD83-Biotin, Streptavidin-PE-Cy7, α-CD86-PE-Cy7, α-CD86-PE, α-CD123-PE, α-CD154-PE, α-CD161-PE, α-FoxP3-AF488 (clone 259D), IgG1- isotype-AF488, α-ICOS (CD278)-PE, α-HLA-A2-PE, α-HLA-DR-PB, α-HLA-DR-PerCPCy5.5, VISTA, co-stimulatory molecule OX40, and CD137.
23. The use of 11 or 12, wherein the cancer is selected from breast cancer, colon cancer, rectal cancer, lung cancer, prostate cancer, melanoma, leukemia, ovarian cancer, gastric cancer, renal cell carcinoma, liver cancer, pancreatic cancer, lymphomas and myeloma.
24. The use of 11 or 12, wherein the cancer is a solid tumor or hematological cancer.
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US201562115468P | 2015-02-12 | 2015-02-12 | |
US62/115,468 | 2015-02-12 | ||
US201562255259P | 2015-11-13 | 2015-11-13 | |
US62/255,259 | 2015-11-13 | ||
NZ734256A NZ734256A (en) | 2015-02-12 | 2016-02-11 | Use of plinabulin in combination with immune checkpoint inhibitors |
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NZ750444B2 true NZ750444B2 (en) | 2021-06-29 |
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