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WO2025188909A1 - Conjugués inhibiteurs de shp-1 avec des composés pro-inflammatoires - Google Patents

Conjugués inhibiteurs de shp-1 avec des composés pro-inflammatoires

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Publication number
WO2025188909A1
WO2025188909A1 PCT/US2025/018593 US2025018593W WO2025188909A1 WO 2025188909 A1 WO2025188909 A1 WO 2025188909A1 US 2025018593 W US2025018593 W US 2025018593W WO 2025188909 A1 WO2025188909 A1 WO 2025188909A1
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Prior art keywords
conjugate
salt
pia
shp1i
shp
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Pending
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WO2025188909A8 (fr
Inventor
Yuan Liu
Lei Shi
Harry Stylli
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Mdx Management LLC
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Mdx Management LLC
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Publication of WO2025188909A1 publication Critical patent/WO2025188909A1/fr
Publication of WO2025188909A8 publication Critical patent/WO2025188909A8/fr
Pending legal-status Critical Current
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    • C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
    • C07C65/38—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups having unsaturation outside the aromatic rings
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07K16/241—Tumor Necrosis Factors
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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    • C07K16/244—Interleukins [IL]
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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    • C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
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    • C07—ORGANIC CHEMISTRY
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    • A61K2039/572—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 cytotoxic response
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    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific

Definitions

  • the present invention relates to compositions and methods for treating cancer involving administering a SHP-1 inhibitor conjugated to a pro-inflammatory agent.
  • a SHP-1 inhibitor conjugated to a pro-inflammatory agent BACKGROUND OF THE INVENTION
  • intratumoral myeloid leukocytes including macrophages (i.e., tumor-associated macrophage or TAM) and myeloid-derived suppressive cells (MDSC)
  • TAM tumor-associated macrophage
  • MDSC myeloid-derived suppressive cells
  • ITIMs cell surface inhibitory receptors
  • essential cell surface iRs such as SIRP ⁇ , Siglecs, LilRBs, PirB, LAIR1, lectin receptors, SLAM family receptors, etc. (1, 2), which also show increased expression in the TME with tumor progression to advanced stages, lead their regulations via activation of SHP-1, which then mediate downstream inhibition.
  • 1 sf-6604130 Attorney Docket No.245162001040 [0004] Given these inhibitory mechanisms elucidated within previous years, pipelines of therapeutic developments aiming to blockade iRs (e.g., anti-LilRB1/2 and anti-SIRP ⁇ ) and their ligands (e.g., anti-CD47) are being undertaken (3-5).
  • SHP-1 inhibitors which are covalently conjugated to pro-inflammatory agents, referred to herein as “SHP1I-PIA conjugates.”
  • SHP1I-PIA conjugates can be directly bonded to the pro-inflammatory agent.
  • SHP-1 inhibitor of the conjugate can be bonded to the pro-inflammatory agent via an optional covalent linker.
  • the present application in one aspect provides a method of treating a cancer in an individual, comprising administering to the individual a SHP1I-PIA conjugate.
  • the method comprises systemically administering the SHP1I-PIA conjugate.
  • the method comprises locally (e.g., intratumorally) administering the SHP1I-PIA conjugate.
  • the method can comprise administering the SHP1I-PIA conjugate to the individual intermittently.
  • the pro-inflammatory agent comprises or is selected from the group consisting of a TLR agonist, a STING activator, a PAMP/DAMP molecule, a checkpoint inhibitor, a pro- inflammatory cytokine, a chemotherapeutic agent, or a bacterial component.
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate comprises or is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), and a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1), or a protein agent that contains a SH2 domain (by competing for binding to ITIM motif so to inhibit SHP-1 activation), or an agent that inhibits a tyrosine kinase or SHP-1 signaling (“TK/SHP-1 inhibitor”), such as a tyrosine kinase inhibitor that inhibits ITIM phosphorylation, thereby inhibiting SHP-1 activation.
  • a nucleic acid e.g., a siRNA, a shRNA, an antisense RNA, a microRNA
  • a protein agent e.g., an antibody agent that targets SHP-1 or activated SHP-1
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate is selected from the group consisting of TPI-1 or an analog or a derivative thereof, vitamin E derivative, phomoxanthone A (PXA), and a PKC-theta activator.
  • the SHP-1 inhibitor comprises TPI-1. 2 sf-6604130 Attorney Docket No.245162001040 [0007]
  • the present application in another aspect provides a method of treating a cancer in an individual, comprising administering to the individual a SHP1I-PIA conjugate, wherein the individual is having an inflammation reaction or has an ongoing infection.
  • the method comprises administering the SHP1I-PIA conjugate to the individual intermittently.
  • the method comprises systemically administering the SHP1I-PIA conjugate. In some embodiments, the method comprises locally (e.g., intratumorally) administering the SHP1I-PIA conjugate. [0008] In some embodiments according to any one of the methods described above, the method comprises administering the SHP1I-PIA conjugate to the individual at an interval of no more than once every three days for at least two administrations. [0009] In some embodiments according to any one of the methods described above, the method comprises administering the SHP1I-PIA conjugate to the individual for at least two cycles, wherein each cycle is about three to about twenty days long.
  • the SHP1I-PIA conjugate has a half-life of no more than about 5 days, optionally the SHP1I-PIA conjugate has a half-life of no more than about 3 days. [0011] In some embodiments according to any of the methods described above, the SHP1I-PIA conjugate is effective in inhibiting more than 50% of the SHP-1 activity for no more than about 5 days, optionally wherein the SHP1I-PIA conjugate is effective in inhibiting more than 50% of the SHP-1 activity for no more than about 3 days. [0012] In some embodiments according to any of the methods described above, the SHP1I-PIA conjugate is administered at least three times.
  • the method comprises administering the SHP1I-PIA conjugate to a site that is different from the site of the cancer to be treated.
  • the pro- inflammatory agent comprises a TLR agonist.
  • the TLR agonist activates a TLR on a macrophage.
  • the TLR comprises TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, and/or TLR9.
  • the TLR agonist comprises CpG, polyI:C, R837, and/or R848, flagellin (TLR5), zymosan (TLR2/4), radiation therapy produced DAMP such as HMGB1 (TLR2/4), DNA and RNA molecules (TLR3/7/8/9), etc.
  • the pro- inflammatory agent comprises a bacterial component; optionally the bacterial component comprises lipopolysaccharide (LPS).
  • the pro- inflammatory agent comprises a STING activator.
  • the STING activator comprises 2’3’-cGAMP.
  • the pro- inflammatory agent comprises a chemotherapeutic agent.
  • the chemotherapeutic agent comprises azathioprine (AZA).
  • the pro- inflammatory agent comprises a pro-inflammatory cytokine.
  • the pro- inflammatory cytokine comprises IL-1 family cytokines (e.g., IL-1b, IL-18), IL-6, IL-17, TNF family cytokines (e.g., TNF ⁇ ), and their combination with type I and type II interferons (IFN ⁇ , IFN ⁇ and IFN ⁇ ).
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate comprises or is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), and a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1), or a protein agent that contains a SH2 domain (by competing for binding to ITIM motif so to inhibit SHP-1 activation), or an agent that inhibits a tyrosine kinase or SHP-1 signaling (“TK/SHP-1 inhibitor”), such as a tyrosine kinase inhibitor that inhibits ITIM phosphorylation, thereby inhibiting SHP-1 activation.
  • a nucleic acid e.g., a siRNA, a shRNA, an antisense RNA, a microRNA
  • a protein agent e.g., an antibody agent that targets SHP-1 or activated SHP-1
  • the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm, including, but not limited to, an anti-TNF ⁇ antibody and an anti-IL6 antibody.
  • the agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm is administered simultaneously with the SHP1I-PIA conjugate.
  • the agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm is administered sequentially (e.g., prior to or after) with the SHP1I-PIA conjugate.
  • the administration of the agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm follows the same dosing schedule as the SHP1I-PIA conjugate.
  • the cancer is a solid tumor.
  • the cancer is a hematological cancer.
  • the cancer is a late stage cancer.
  • the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and/or a checkpoint inhibitor.
  • the individual is a human.
  • the present application in another aspect provides a composition comprising a SHP1I-PIA conjugate and a pharmaceutically acceptable excipient, optionally wherein the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a PAMP/DAMP activator, a checkpoint inhibitor, a pro- inflammatory cytokine, a chemotherapeutic agent, or a bacterial component.
  • the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a PAMP/DAMP activator, a checkpoint inhibitor, a pro- inflammatory cytokine, a chemotherapeutic agent, or a bacterial component.
  • FIG. 1A shows the study system of human monocyte-derived macrophages surrounded with cancer cells (OVCAR5) were treated with either monomers of R848 ⁇ TPI-1 or Ester or Amide conjugated R848-TPI-1 compounds.
  • FIG. 1B shows schematics of R848 and TPI-1 monomers and ester conjugate and amide conjugated R848-TPI-1 compounds.
  • FIG. 1C shows the results of ELISAs assaying macrophage proinflammatory (TNF ⁇ and IL- 6) or anti-inflammatory (IL-10) response stimulated by R848 ⁇ TPI-1, or Ester and Amide conjugated R848-TPI-1 compounds, in the absence and the presence of cancer cells.
  • FIG. 1A shows the study system of human monocyte-derived macrophages surrounded with cancer cells (OVCAR5) were treated with either monomers of R848 ⁇ TPI-1 or Ester or Amide conjugated R848-TPI-1 compounds.
  • FIG. 1B shows schematics of R848 and
  • FIG. 1D shows the results of flow cytometry measuring macrophage expression of cell surface antigen presentation machinery following stimulation with R848 ⁇ TPI-1, or Ester and Amide conjugated R848-TPI-1 compounds, in the absence and the presence of cancer cells. All monomer and conjugate compounds in FIGS. 1C-1D were used at 1 ⁇ M.
  • FIG. 1E shows the dose-dependent effects of Ester and Amide conjugated R848-TPI-1 compounds on activation of macrophage production of TNF ⁇ , as measured by ELISA. In FIG. 1E, the amide curve is the upper curve and the ester curve is the lower curve [0033] FIGS.
  • FIG. 2A-2D show dose-dependent efficacies of R848-TPI-1 Ester and Amide conjugated compounds treating KPC pancreatic cancer.
  • FIG. 2A shows the experimental design. KPC cells were engrafted (5 ⁇ 10 5 , s.c.) into the right flank of C57BL6 mice. After 6 sf-6604130 Attorney Docket No.245162001040 tumors reached 200 mm 3 , mice were treated daily with escalated doses of R848-TPI-1 Ester and Amide conjugated compounds.
  • FIG. 2B shows KPC tumor volume changes over time (in days) following treatments.
  • FIG. 3A-3D show the results of dTPI-1 treatment in a murine lung cancer model (LLC).
  • LLC lung cancer were engrafted (5 ⁇ 10 5 , s.c.) into the right flank of C57BL6 mice. After tumor stably formed (>200 mm 3 ), the mice were treated with anti-PD-1 ( ⁇ PD-1, 100ug, i.p.
  • FIG. 3B shows bioluminescence images of LLC tumor burden changes post treatments.
  • FIG. 3C shows the tumor volume over time post-treatment (in days) for LLC treated with the control, ester- conjugated R848-TPI-1, or amide-conjugated R848-TPI-1.
  • FIG. 3D shows tumor microenvironment (TME) analyses by flow cytometry of cell populations post-treatment with ⁇ PD-1, ester-conjugated R848-TPI-1 + ⁇ PD-1, and amide-conjugated R848-TPI-1 + ⁇ PD-1.
  • TEE tumor microenvironment
  • FIG. 4A-FIG. 4E show the results of in vitro assays of perdeuterated TPI-1 (dTPI-1) for inhibition of SHP-1 activity in macrophages.
  • FIG.4A shows the study system. Human monocyte-derived macrophages without or with cancer cells surrounding were stimulated with TLR agonist (aTLR) R848 and IFN ⁇ ⁇ dTPI-1. The presence of cancer cells was to ligate macrophage surface inhibitory receptors (iRs), of which cytoplasmic domain phosphorylation in ITIMs led to SHP-1 activation.
  • FIG. 4B shows the results of protein tyrosine phosphatase (PTP) activity assays.
  • FIG. 4C shows the results of flow cytometric assay, demonstrating inhibition of SHP-1 by dTPI-1 unleashed macrophage antigen presentation inhibited by the cancer environment.
  • FIG. 4D shows cytokine profiling by ELISA of IL-6, TNF ⁇ , and IL-10 of human monocyte-derived macrophages with or without cancer cells, with or without R848/IFN ⁇ , and with or without dTPI-1 treatment.
  • FIG. 4E shows cytokine profiling by ELISA of TNF ⁇ as a function of dTPI concentration.
  • FIGS. 5A-5B show the results of R848 or dTPI-1 treatment, alone or in combination, in a murine metastatic melanoma model.
  • FIG. 5A-5B show the results of R848 or dTPI-1 treatment, alone or in combination, in a murine metastatic melanoma model.
  • FIG. 5A shows the experimental scheme.
  • FIG. 5B shows lung images of melanoma prior to treatment (d12) and after different treatments.
  • FIG. 6A-6D show the results of dTPI-1 treatment in a murine lung cancer model.
  • FIG. 6A shows the experimental design. Controls (ctl.) were mice treated with topical non- 7 sf-6604130 Attorney Docket No.245162001040 drug lotion; anti-PD-1 ( ⁇ PD-1) was given to mice with topical non-drug lotion treatment.
  • Topical drugs were TLR agonists (aTLR: PolyI;C, R848 and LPS) + dTPI-1, mixed in lotion, or Sting activator (aSting: MSA-2, ADU-S100, cGAMP) + dTPI-1, together mixed in lotion.
  • FIG. 6B shows that LLC tumor burden changes post treatments recorded as bioluminescence images.
  • FIG. 6C shows tumor microenvironment (TME) analyses of MHC-I, MHC-II, CD80, and CD86 expression by flow cytometry.
  • FIG. 6D shows flow cytometric analysis of cell populations in the TME.
  • the present application is based upon the finding that combining an inhibitor of SHP-1 with a pro-inflammatory treatment stimulates proinflammatory signal transduction in the tumor environment. This alters the tumor microenvironment (TME), changes the behavior of tumor infiltrating macrophages, and activates innate and adaptive immune cells, causing an anti-cancer effect.
  • TME tumor microenvironment
  • SHP-1 has an inhibitory effect on the immune response to tumors, which serves to protect the tumor from the immune system, and also promotes a wound healing response that facilitates tumor progression.
  • Inhibiting SHP-1 reduces the inhibitory effect on the immune system, and in combination with a pro-inflammatory treatment, enhances the effect of the pro-inflammatory treatment.
  • Conjugates of a SHP-1 inhibitor e.g., TPI-1 with a pro-inflammatory agent (such as TLR agonists, pro- inflammatory cytokines, or checkpoint inhibitors) can transform an immunosuppressive TME into an inflammatory TME, activate various types of immune cells (such as macrophages, T cells, and B cells), and deplete tumors.
  • a pro-inflammatory agent such as TLR agonists, pro- inflammatory cytokines, or checkpoint inhibitors
  • the present application in one aspect provides conjugates comprising a SHP-1 inhibitor covalently linked to a pro-inflammatory agent (“SHP1I-PIA conjugates”).
  • the SHP-1 inhibitor can be directly linked covalently to the pro-inflammatory agent.
  • the SHP-1 inhibitor can be covalently linked to the pro-inflammatory agent via a linker.
  • the present application in one aspect provides methods of treating a cancer in an individual, comprising administering to the individual a SHP1I-PIA conjugate.
  • the individual is having an inflammatory reaction.
  • the individual has an ongoing infection.
  • the SHP1I-PIA conjugate is administered systemically.
  • the SHP1I-PIA conjugate is administered intratumorally. In some embodiments, the SHP1I-PIA conjugate is administered systemically and intratumorally. In some embodiments, the method comprises administering the SHP1I-PIA conjugate to the individual at an interval of no more than once every three days for at least two administrations. In some embodiments, the method comprises administering the SHP1I-PIA conjugate to the individual for at least two cycles, wherein the SHP1I-PIA conjugate is administered for at least once in each cycle and wherein each cycle is about three to about twenty days long.
  • the pro-inflammatory agent comprises an agent selected from the group consisting of a TLR agonist, a STING activator, a PAMP/DAMP activator, a checkpoint inhibitor, a pro-inflammatory cytokine, a chemotherapeutic agent, or a bacterial component.
  • the SHP1I-PIA conjugate can be administered with an agent that reduces systemic inflammation (e.g., an anti-TNF ⁇ mAb) in order to reduce toxicity of the treatment, while not impairing the inflammatory effect within the tumor microenvironment.
  • an agent that reduces systemic inflammation e.g., an anti-TNF ⁇ mAb
  • the term “individual,” “subject,” or “patient” is used synonymously herein to describe a mammal, including humans.
  • An individual includes, but is not limited to, human, bovine, horse, feline, canine, rodent, or primate.
  • the individual is human.
  • an individual suffers from a disease, such as cancer.
  • the individual is in need of treatment.
  • a “reference” as used herein refers to any sample, standard, or level that is used for comparison purposes. A reference may be obtained from a healthy and/or non-diseased sample.
  • a reference may be obtained from an untreated sample. In some examples, a reference is obtained from a non-diseased or non-treated sample of an individual. 9 sf-6604130 Attorney Docket No.245162001040 In some examples, a reference is obtained from one or more healthy individuals who are not the individual or individual. [0046] As used herein, the term “intermittent” or “intermittently” in the context of dosing refers to a non-continuous dosing regimen.
  • “intermittent” dosing refers to a dosing where a) the SHP1I-PIA conjugate is administered less than 12 consecutive days (e.g., less than 11, 10, 9, 8, 7, 6, 5, 4 and 3 days), and b) the SHP1I-PIA conjugate is administered at least two times, and the two administrations are separated by at least one day (i.e., Day 1 and Day 3). In some embodiments, the SHP1I-PIA conjugate is administered daily for no more than three consecutive days, and at least twice that is separated by at least one day.
  • the term “cycle” in the context of dosing refers to a time period during which there is at least one administration of a SHP1I-PIA conjugate.
  • Day 1 of a cycle is defined as the day when the first administration of a SHP1I-PIA conjugate happens during that time period.
  • Day 1 of the cycle is defined as the day of the first administration of the multiple daily consecutive administrations.
  • the last day of the cycle is defined as the day before the next non-consecutive administration of the SHP1I-PIA conjugate happens.
  • the cycles do not have to have the same length of time. For example, the first cycle can have five days, and the second cycle can have seven days.
  • Each cycle may have different numbers of administrations of the SHP1I-PIA conjugate.
  • the first cycle which may have five days, may have one administration of the SHP1I-PIA conjugate
  • the second cycle which may have seven days, may have two administrations of the SHP1I-PIA conjugate.
  • immunogenic is the ability to elicit an immune response, e.g., via T-cells, B cells, or both.
  • treatment or “treating” is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired clinical results include, but are not limited to, one or more of the following: decreasing one or more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread (e.g., metastasis) of the disease, preventing or delaying the occurrence or recurrence of the disease, delay or slowing the progression of the disease, ameliorating the disease state, providing a remission (whether partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, delaying the progression 10 sf-6604130 Attorney Docket No.245162001040 of the disease, increasing the quality of life, and/or prolonging survival.
  • treatment is a reduction of pathological consequence of the disease.
  • the methods of the invention contemplate any one or more of these aspects of treatment.
  • “delaying” the development of cancer means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease.
  • a method that “delays” development of cancer is a method that reduces probability of disease development in a given time frame and/or reduces the extent of the disease in a given time frame, when compared to not using the method.
  • cancer development can be detectable using standard methods, including, but not limited to, computerized axial tomography (CAT Scan), Magnetic Resonance Imaging (MRI), abdominal ultrasound, clotting tests, arteriography, or biopsy. Development may also refer to cancer progression that may be initially undetectable and includes occurrence, recurrence, and onset.
  • CAT Scan computerized axial tomography
  • MRI Magnetic Resonance Imaging
  • abdominal ultrasound clotting tests
  • clotting tests arteriography
  • biopsy arteriography
  • development may also refer to cancer progression that may be initially undetectable and includes occurrence, recurrence, and onset.
  • the term “simultaneous administration,” as used herein, means that a first therapy and second therapy in a combination therapy are administered with a time separation of no more than about 15 minutes, such as no more than about any of 10, 5, or 1 minutes.
  • the first and second therapies may be contained in the same composition (e.g., a composition comprising both a first and second therapy) or in separate compositions (e.g., a first therapy in one composition and a second therapy is contained in another composition).
  • the term “sequential administration” means that the first therapy and second therapy in a combination therapy are administered with a time separation of more than about 15 minutes, such as more than about any of 20, 30, 40, 50, 60, or more minutes. Either the first therapy or the second therapy may be administered first.
  • the first and second therapies are contained in separate compositions, which may be contained in the same or different packages or kits.
  • the term “concurrent administration” means that the administration of the first therapy and that of a second therapy in a combination therapy overlap with each other.
  • 11 sf-6604130 Attorney Docket No.245162001040
  • pharmaceutically acceptable or “pharmacologically compatible” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to an individual without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • a “small molecule” refers to a molecule with a molecular weight less than about 900 Dalton.
  • a “small organic molecule” refers to an organic molecule with a molecular weight less than about 900 Dalton.
  • embodiments of the application described herein include “consisting” and/or “consisting essentially of” embodiments.
  • Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se.
  • description referring to “about X” includes description of “X”.
  • reference to “not” a value or parameter generally means and describes “other than” a value or parameter.
  • the method is not used to treat cancer of type X means the method is used to treat cancer of types other than X.
  • the term “about X-Y” used herein has the same meaning as “about X to about Y.”
  • the singular forms “a,” “an,” and “the” as used herein include plural referents unless the context clearly dictates otherwise.
  • Alkyl refers to and includes, unless otherwise stated, a saturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbon atoms).
  • Particular alkyl groups are those having 1 to 20 carbon atoms (a “C1-C20 alkyl”), having 1 to 10 carbon atoms (a “C 1 -C 10 alkyl”), having 6 to 10 carbon atoms (a “C 6 -C 10 alkyl”), having 1 to 6 carbon atoms (a “C1-C6 alkyl”), having 2 to 6 carbon atoms (a “C2-C6 alkyl”), or having 1 to 4 carbon atoms (a “C1-C4 alkyl”).
  • alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n- pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. 12 sf-6604130 Attorney Docket No.245162001040 [0062] “Alkylene” as used herein refers to the same residues as alkyl, but having bivalency.
  • Particular alkylene groups are those having 1 to 20 carbon atoms (a “C1-C20 alkylene”), having 1 to 10 carbon atoms (a “C1-C10 alkylene”), having 6 to 10 carbon atoms (a “C6-C10 alkylene”), having 1 to 6 carbon atoms (a “C 1 -C 6 alkylene”), 1 to 5 carbon atoms (a “C 1 -C 5 alkylene”), 1 to 4 carbon atoms (a “C1-C4 alkylene”) or 1 to 3 carbon atoms (a “C1-C3 alkylene”).
  • An alkenyl group may have “cis” or “trans” configurations, or alternatively have “E” or “Z” configurations.
  • alkenyl group examples include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2- methylbuta-1,3-dienyl, pent-1-enyl, pent-2-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, and the like.
  • Alkenylene refers to the same residues as alkenyl, but having bivalency.
  • Particular alkynyl groups are those having 2 to 20 carbon atoms (a “C2- C20 alkynyl”), having 6 to 10 carbon atoms (a “C6-C10 alkynyl”), having 2 to 8 carbon atoms (a “C 2 -C 8 alkynyl”), having 2 to 6 carbon atoms (a “C 2 -C 6 alkynyl”), or having 2 to 4 carbon atoms (a “C2-C4 alkynyl”).
  • alkynyl group examples include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2- ynyl, but-3-ynyl, and the like.
  • Alkynylene refers to the same residues as alkynyl, but having bivalency.
  • Particular alkynylene groups are those having 2 to 20 carbon atoms (a “C2-C20 alkynylene”), having 2 to 10 carbon atoms (a “C2-C10 alkynylene”), having 6 to 10 carbon atoms (a “C 6 -C 10 alkynylene”), having 2 to 6 carbon atoms (a “C 2 -C 6 alkynylene”), 2 to 4 carbon atoms (a “C2-C4 alkynylene”) or 2 to 3 carbon atoms (a “C2-C3 alkynylene”).
  • alkynylene examples include, but are not limited to, groups such as ethynylene (or acetylenylene) (-C ⁇ C-), propynylene (-C ⁇ CCH 2 -), and the like.
  • Cycloalkyl refers to and includes, unless otherwise stated, saturated cyclic univalent hydrocarbon structures, having the number of carbon atoms designated (i.e., C 3 -C 10 means three to ten carbon atoms). Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl.
  • a cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof.
  • Particular cycloalkyl groups are those having from 3 to 12 annular carbon atoms.
  • a preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C 3 -C 8 cycloalkyl"), having 3 to 6 annular carbon atoms (a “C3-C6 cycloalkyl”), or having from 3 to 4 annular carbon atoms (a "C3-C4 cycloalkyl").
  • Cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.
  • Cycloalkylene refers to the same residues as cycloalkyl, but having bivalency. Cycloalkylene can consist of one ring or multiple rings which may be fused, spiro or bridged, or combinations thereof. Particular cycloalkylene groups are those having from 3 to 12 annular carbon atoms.
  • a preferred cycloalkylene is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C3-C8 cycloalkylene”), having 3 to 6 carbon atoms (a “C3-C6 cycloalkylene”), or having from 3 to 4 annular carbon atoms (a "C3-C4 cycloalkylene”).
  • C3-C8 cycloalkylene having 3 to 6 carbon atoms
  • C3-C4 cycloalkylene or having from 3 to 4 annular carbon atoms
  • 14 sf-6604130 Attorney Docket No.245162001040
  • Examples of cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, norbornylene, and the like.
  • a cycloalkylene may attach to the remaining structures via the same ring carbon atom or different ring carbon atoms.
  • the connecting bonds may be cis- or trans- to each other.
  • cyclopropylene may include 1,1-cyclopropylene and 1,2-cyclopropylene (e.g., cis-1,2- cyclopropylene or trans-1,2-cyclopropylene), or a mixture thereof.
  • cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, and the like.
  • Cycloalkenylene refers to the same residues as cycloalkenyl, but having bivalency.
  • Aryl or “Ar” as used herein refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic.
  • Particular aryl groups are those having from 6 to 14 annular carbon atoms (a “C 6 -C 14 aryl”).
  • An aryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position.
  • an aryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.
  • “Arylene” as used herein refers to the same residues as aryl, but having bivalency.
  • Particular arylene groups are those having from 6 to 14 annular carbon atoms (a “C 6 -C 14 arylene”).
  • Heteroaryl refers to an unsaturated aromatic cyclic group having from 1 to 14 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur.
  • a heteroaryl group may have a single ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl) 15 sf-6604130 Attorney Docket No.245162001040 which condensed rings may or may not be aromatic.
  • Particular heteroaryl groups are 5 to 14- membered rings having 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 5 to 10-membered rings having 1 to 8 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 5, 6 or 7-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • particular heteroaryl groups are monocyclic aromatic 5-, 6- or 7-membered rings having from 1 to 6 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • particular heteroaryl groups are polycyclic aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • a heteroaryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position.
  • a heteroaryl group having more than one ring where at least one ring is non- aromatic is connected to the parent structure at an aromatic ring position.
  • a heteroaryl group may be connected to the parent structure at a ring carbon atom or a ring heteroatom.
  • Heteroarylene refers to the same residues as heteroaryl, but having bivalency.
  • Heterocycle refers to a saturated or an unsaturated non-aromatic cyclic group having a single ring or multiple condensed rings, and having from 1 to 14 annular carbon atoms and from 1 to 6 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like.
  • a heterocycle comprising more than one ring may be fused, bridged or spiro, or any combination thereof, but excludes heteroaryl groups.
  • the heterocyclyl group may be optionally substituted independently with one or more substituents described herein.
  • Particular heterocyclyl groups are 3 to 14-membered rings having 1 to 13 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 12-membered rings having 1 to 11 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 10- membered rings having 1 to 9 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 8-membered rings having 1 to 7 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 3 to 6-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • heterocyclyl includes monocyclic 3-, 4-, 5-, 6- or 7-membered rings having from 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 annular carbon atoms and 1 to 2, 1 to 3, or 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • heterocyclyl includes polycyclic non-aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • “Heterocyclylene” as used herein refers to the same residues as heterocyclyl, but having bivalency.
  • Halo refers to elements of the Group 17 series having atomic number 9 to 85.
  • Preferred halo groups include the radicals of fluorine, chlorine, bromine and iodine. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-3- fluorophenyl is within the scope of dihaloaryl.
  • perhaloalkyl An alkyl group in which each hydrogen is replaced with a halo group is referred to as a “perhaloalkyl.”
  • a preferred perhaloalkyl group is trifluoromethyl (-CF 3 ).
  • perhaloalkoxy refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group.
  • An example of a perhaloalkoxy group is trifluoromethoxy (–OCF3).
  • D refers to deuterium ( 2 H).
  • T refers to tritium ( 3 H).
  • a group in which each hydrogen is replaced with deuterium is referred to as “perdeuterated.”
  • a group in which each hydrogen is replaced with tritium is referred to as “pertritiated.”
  • the disclosure includes all isotopologues of the compounds disclosed herein, such as, for example, deuterated derivatives of the compounds.
  • Isotopologues can have isotopic replacements at 17 sf-6604130 Attorney Docket No.245162001040 any or at all locations in a structure, or can have atoms present in natural abundance at any or all locations in a structure.
  • “Optionally substituted” unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents listed for that group in which the substituents may be the same of different.
  • an optionally substituted group has one substituent.
  • an optionally substituted group has two substituents.
  • an optionally substituted group has three substituents.
  • an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. In one embodiment, an optionally substituted group is unsubstituted. [0086] It is understood that an optionally substituted moiety can be substituted with more than five substituents, if permitted by the number of valences available for substitution on the moiety. For example, a propyl group can be substituted with seven halogen atoms to provide a perhalopropyl group. The substituents may be the same or different.
  • pharmaceutically acceptable or “pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
  • “Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like
  • organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like
  • Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and 18 sf-6604130 Attorney Docket No.245162001040 the like.
  • Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound of the invention in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification.
  • excipient means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the invention as an active ingredient.
  • a drug or pharmaceutical such as a tablet containing a compound of the invention as an active ingredient.
  • Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent.
  • substantially pure intends a composition that contains no more than 10% impurity, such as a composition comprising less than 9%, 7%, 5%, 3%, 1%, 0.5% impurity.
  • aspects and embodiments described herein as “comprising” include “consisting of” and “consisting essentially of” embodiments. 19 sf-6604130 Attorney Docket No.245162001040 [0092] Any terms not directly defined herein shall be understood to have the meanings commonly associated with them as understood within the art of the invention.
  • a SHP1I-PIA conjugate is a SHP-1 inhibitor which is covalently conjugated to a pro-inflammatory agent, (e.g., TPI-1 conjugated to R848).
  • a pro-inflammatory agent e.g., TPI-1 conjugated to R848.
  • the SHP1I-PIA conjugate is administered intermittently.
  • the SHP1I-PIA conjugate is administered daily for no more than two or three consecutive days, and optionally for at least two administrations which are separated by at least one day.
  • the SHP1I-PIA conjugate is administered at least three, four, or five times.
  • At least two SHP1I-PIA conjugate administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each SHP1I-PIA conjugate administration is separated by at least one day from the preceding or following SHP1I-PIA conjugate administration. In some embodiments, the method comprises systemically administering the SHP1I-PIA conjugate. In some embodiments, the method comprises locally administering (e.g., intratumorally administering) the SHP1I-PIA conjugate.
  • a method of treating a cancer comprising administering to the individual a SHP1I-PIA conjugate, and wherein the SHP1I-PIA 20 sf-6604130 Attorney Docket No.245162001040 conjugate is administered systemically (e.g., intravenously or subcutaneously).
  • the SHP1I-PIA conjugate is administered intratumorally.
  • the SHP1I-PIA conjugate is administered systemically and intratumorally.
  • the SHP1I-PIA conjugate is administered intermittently. In some embodiments, the SHP1I-PIA conjugate is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the SHP1I-PIA conjugate is administered at least three, four, or five times. In some embodiments, at least two SHP1I-PIA conjugate administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the SHP1I-PIA conjugate administration is separated by at least one day from the preceding or following SHP1I-PIA conjugate administration.
  • the SHP1I-PIA conjugate is administered at an interval of no more than once every two days. In some embodiments, the SHP1I-PIA conjugate is administered no less than two times and no more than 5 times within ten consecutive days (e.g., twice in ten days, three times in ten days, four times in ten days, or five times in ten days). In some embodiments, the SHP1I-PIA conjugate has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days).
  • the SHP1I-PIA conjugate is effective in inhibiting more than 50% of the SHP-1 activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days).
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate is selected from the group consisting of TPI-1 or an analog or a derivative thereof, vitamin E derivative, phomoxanthone A (PXA), and a PKC-theta activator.
  • the method further comprises locally (e.g., intratumorally) administering SHP1I-PIA conjugate into the individual.
  • the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody).
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the SHP1I-PIA conjugate.
  • the pro-inflammatory agent of the SHP1I-PIA conjugate comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine and Vesatolimod.
  • the pro-inflammatory agent of the SHP1I-PIA conjugate comprises a TLR agonist (e.g., R848) and a pro-inflammatory cytokine 21 sf-6604130 Attorney Docket No.245162001040 (e.g., IFN-gamma).
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate comprises TPI-1.
  • a method of treating a cancer comprising administering to the individual a SHP1I-PIA conjugate (e.g., where the SHP-1 inhibitor of the SHP1I-PIA conjugate is TPI-1 or an analog or a derivative thereof, and the pro-inflammatory agent of the SHP1I-PIA conjugate is a TLR agonist, e.g., R848), and wherein the method comprises intravenous or subcutaneous administration of the SHP1I-PIA conjugate, optionally wherein the SHP1I-PIA conjugate is administered intermittently.
  • a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • the SHP1I-PIA conjugate is administered daily for no more than three or two consecutive days, and optionally at least twice where the administrations are separated by at least one day. In some embodiments, the SHP1I-PIA conjugate is administered at least three, four, or five times. In some embodiments, at least two SHP1I-PIA conjugate administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the SHP1I-PIA conjugate administrations is separated by at least one day from the preceding or following SHP1I-PIA conjugate administration.
  • the method comprises administering the SHP1I-PIA conjugate to the individual at an interval of no more than once every three days for at least twice.
  • the SHP1I-PIA conjugate is administered twice (e.g., two consecutive days) every seven to twenty days.
  • the SHP1I-PIA conjugate is administered three times (e.g., three consecutive days) every ten to twenty days.
  • the SHP1I-PIA conjugate is administered at an interval of no more than once every two days.
  • the SHP1I-PIA conjugate is administered no less than two times and no more than 5 times within ten consecutive days (e.g., twice in ten days, three times in ten days, four times in ten days, or five times in ten days). In some embodiments, the SHP1I-PIA conjugate has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days).
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), a nucleic acid editing system (e.g., a CRISPR system), and a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1).
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate is selected from the group consisting of TPI-1 or an analog or a derivative thereof, vitamin E derivative, phomoxanthone A (PXA), and a PKC-theta activator.
  • the method 22 sf-6604130 Attorney Docket No.245162001040 further comprises locally (e.g., intratumorally) administering the SHP1I-PIA conjugate to the individual.
  • the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody).
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the SHP1I-PIA conjugate.
  • the pro-inflammatory agent of the SHP1I-PIA conjugate comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine and Vesatolimod.
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate comprises TPI-1 or an analog or derivative thereof.
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate comprises TPI-1.
  • a method of treating a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • administering to the individual a SHP1I-PIA conjugate
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate is, e.g., TPI-1 or an analog or a derivative thereof
  • the pro- inflammatory agent of the SHP1I-PIA conjugate is e.g., a TLR agonist, e.g., R848
  • the method comprises intravenous or subcutaneous administration of the SHP1I-PIA conjugate, optionally wherein the SHP1I-PIA conjugate is administered intermittently.
  • the SHP1I-PIA conjugate is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the SHP1I-PIA conjugate is administered at least three, four, or five times. In some embodiments, at least two SHP1I-PIA conjugate administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the SHP1I-PIA conjugate administrations are separated by at least one day from the preceding or following SHP1I-PIA conjugate administration.
  • the method comprises administering the SHP1I-PIA conjugate to the individual for at least two cycles, further optionally wherein the SHP1I-PIA conjugate is administered for at least once in each cycle and wherein each cycle is about three to about twenty days long.
  • the SHP1I-PIA conjugate is administered for at least twice (e.g., at least two consecutive days) in each cycle.
  • the SHP1I-PIA conjugate is administered for at least three times (e.g., at least three consecutive days) in each cycle.
  • the SHP1I-PIA conjugate has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days).
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), a nucleic acid editing system (e.g., a CRISPR system), and a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1).
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate is selected from the group consisting of TPI-1 or an analog or a derivative thereof, vitamin E derivative, phomoxanthone A (PXA), and a PKC-theta activator.
  • the method further comprises locally (e.g., intratumorally) administering the SHP1I-PIA conjugate into the individual.
  • the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti- TNF ⁇ antibody or an anti-IL6 antibody).
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the SHP1I-PIA conjugate.
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate is TPI-1 or an analog or derivative thereof.
  • the pro-inflammatory agent of the SHP1I-PIA conjugate comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine and Vesatolimod.
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate comprises TPI-1.
  • a method of treating a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • intravenously, subcutaneously and/or intratumorally administering to the individual a SHP1I-PIA conjugate where the SHP-1 inhibitor of the SHP1I-PIA conjugate can be, e.g., TPI-1 or an analog or a derivative thereof, and the pro-inflammatory agent of the SHP1I-PIA conjugate can be, e.g., a TLR agonist, e.g., R848), optionally wherein the SHP1I-PIA conjugate is effective in inhibiting more than 50% of the SHP-1 activity for no more than about
  • the SHP1I-PIA conjugate is administered intermittently. In some embodiments, the SHP1I-PIA conjugate is administered 24 sf-6604130 Attorney Docket No.245162001040 daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the SHP1I-PIA conjugate is administered at least three, four, or five times. In some embodiments, at least two SHP1I-PIA conjugate administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days.
  • each of the SHP1I-PIA conjugate administrations is separated by at least one day from the preceding or following SHP1I-PIA conjugate administration.
  • the SHP1I-PIA conjugate is administered at an interval of no more than twice every seven to twenty days. In some embodiments, the SHP1I-PIA conjugate is administered at an interval of no more than three times every seven to twenty days. In some embodiments, the SHP1I-PIA conjugate is administered for a period of at least fourteen to twenty days at an interval of about 1-3 times every seven to twenty days.
  • the SHP1I-PIA conjugate is administered at least about 2, 3, 4, 5, or 6 times in a period of about fourteen to about forty days (e.g., about fourteen to about twenty days).
  • the SHP1I-PIA conjugate has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days).
  • the SHP1I-PIA conjugate is effective in inhibiting more than 50% of the SHP-1 activity for no more than about 7 days (e.g., about 5 days, 4 days, or 3 days).
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), and a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1).
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate is selected from the group consisting of TPI-1 or an analog or a derivative thereof, vitamin E derivative, phomoxanthone A (PXA), and a PKC-theta activator.
  • the method further comprises locally (e.g., intratumorally) administering the SHP1I-PIA conjugate into the individual.
  • the SHP1I-PIA conjugate is administered systemically.
  • the SHP1I-PIA conjugate is administered intratumorally.
  • the SHP1I-PIA conjugate is administered systemically and intratumorally.
  • the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody).
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the SHP1I-PIA conjugate, 25 sf-6604130 Attorney Docket No.245162001040 where the SHP-1 inhibitor of the SHP1I-PIA conjugate can be, e.g., TPI-1 or an analog or derivative thereof and the pro-inflammatory agent of the SHP1I-PIA conjugate can comprise an agent or can be selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine and Vesatolimod.
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate comprises TPI-1.
  • a method of treating a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • intravenously, subcutaneously and/or intratumorally administering to the individual a SHP1I-PIA conjugate where the SHP-1 inhibitor of the SHP1I-PIA conjugate can be, e.g., TPI-1 or an analog or a derivative thereof, and the pro-inflammatory agent of the SHP1I-PIA conjugate can be, e.g., a TLR agonist, e.g., R848), wherein the SHP1I-PIA conjugate is effective in inhibiting more than 50% of the SHP-1 activity for no more than about 5 days
  • the SHP1I-PIA conjugate is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the SHP1I-PIA conjugate is administered at least three, four, or five times. In some embodiments, at least two SHP1I-PIA conjugate administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the SHP1I-PIA conjugate administrations is separated by at least one day from the preceding or following SHP1I-PIA conjugate administration.
  • the method comprises administering the SHP1I-PIA conjugate to the individual for at least two cycles, wherein the SHP1I-PIA conjugate is administered for at least once in each cycle and wherein each cycle has about three to about twenty days.
  • the SHP1I-PIA conjugate is administered for at least twice (e.g., at least two consecutive days) in each cycle.
  • the SHP1I-PIA conjugate is administered for at least three times (e.g., at least three consecutive days) in each cycle.
  • the SHP1I-PIA conjugate has a half-life of no more than about 10 days (e.g., no more than about 7 days, 5 days, 4 days, or 3 days).
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), and a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1).
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate is selected from the group consisting of TPI-1 or an analog or a derivative thereof, vitamin E derivative, 26 sf-6604130 Attorney Docket No.245162001040 phomoxanthone A (PXA), and a PKC-theta activator.
  • the method further comprises locally (e.g., intratumorally) administering the SHP1I-PIA conjugate into the individual.
  • the SHP1I-PIA conjugate is administered systemically.
  • the SHP1I-PIA conjugate is administered intratumorally.
  • the SHP1I-PIA conjugate is administered systemically and intratumorally.
  • the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody).
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the SHP1I-PIA conjugate (where the SHP-1 inhibitor of the SHP1I-PIA conjugate can be, e.g., TPI-1 or an analog or derivative thereof and the pro-inflammatory agent can comprise or be selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine and Vesatolimod).
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate comprises TPI-1.
  • a method of treating a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • administering e.g., intravenously, subcutaneously and/or intratumorally
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate can be, e.g., TPI-1 or an analog or a derivative thereof
  • the pro-inflammatory agent of the SHP1I-PIA conjugate can be, e.g., a TLR agonist, e.g., R848) and immune cells (such as any of the immune cells described herein).
  • a method of treating a cancer comprising administering (e.g., intravenously, subcutaneously and/or intratumorally) to the individual a SHP1I-PIA conjugate (where the SHP-1 inhibitor of the SHP1I-PIA conjugate can be, e.g., TPI-1 or an analog or a derivative thereof, and the pro- inflammatory agent of the SHP1I-PIA conjugate can be, e.g., a TLR agonist, e.g., R848), and immune cells.
  • a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • administering e.g., intravenously, subcutaneously and/or intratumorally
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate can be, e.g., TPI-1 or an analog or a derivative thereof
  • the immune cells are derived from the same individual.
  • the immune cells comprise monocytes or macrophages.
  • the immune cells comprise T cells (e.g., CAR-T cells).
  • the immune cells comprise NK cells (e.g., CAR-NK cells).
  • the immune cells comprise neutrophils (e.g., CAR-expressing neutrophils cells).
  • the immune cells comprise antigen presenting cells (APCs).
  • the immune cells are engineered to express a chimeric receptor that specifically binds to a tumor antigen.
  • the SHP1I-PIA conjugate is administered intermittently. In some embodiments, the SHP1I-PIA conjugate is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the SHP1I-PIA conjugate is administered at least three, four, or five times. In some embodiments, at least two SHP1I-PIA conjugate administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the SHP1I-PIA conjugate administrations is separated by at least one day from the preceding or following SHP1I-PIA conjugate administration.
  • the SHP1I-PIA conjugate and the immune cells are administered within 7, 6, 5, 4, 3, 2 or 1 day. In some embodiments, the SHP1I-PIA conjugate and the immune cells are administered within 24 hours (e.g., within 12, 8, 4, 2, or 1 hour, or within 30 minutes) of each other. In some embodiments, the SHP1I-PIA conjugate and the immune cells are administered simultaneously. In some embodiments, the SHP1I-PIA conjugate and the immune cells are administered concurrently. In some embodiments, the SHP1I-PIA conjugate and the immune cells are administered sequentially. In some embodiments, the SHP1I-PIA conjugate is administered systemically.
  • the SHP1I-PIA conjugate is administered intratumorally. In some embodiments, the SHP1I-PIA conjugate is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody).
  • an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody.
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the SHP1I-PIA conjugate (where the SHP-1 inhibitor of the SHP1I-PIA conjugate can be, e.g., TPI-1 or an analog or derivative thereof, and the pro-inflammatory agent of the SHP1I-PIA conjugate can comprise or be selected from the group consisting of R848, 3M- 852A, Motolimod, Bropirimine and Vesatolimod).
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate comprises TPI-1.
  • a method of treating a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • 28 sf-6604130 Attorney Docket No.245162001040 administering to the individual a SHP1I-PIA conjugate
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate can be, e.g., TPI-1 or an analog or a derivative thereof
  • the pro- inflammatory compound of the SHP1I-PIA conjugate can be a TLR agonist, e.g., R848)
  • the SHP1I-PIA conjugate is administered at least twice (e.g., at least 3, 4, or 5 times).
  • the SHP1I-PIA conjugate is administered intermittently. In some embodiments, the SHP1I-PIA conjugate is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the SHP1I-PIA conjugate is administered at least three, four, or five times. In some embodiments, at least two SHP1I-PIA conjugate administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the SHP1I-PIA conjugate administrations is separated by at least one day from the preceding or following SHP1I-PIA conjugate administration.
  • the method comprises administering the SHP1I-PIA conjugate to the individual at an interval of no more than once every three days for at least twice. In some embodiments, the method comprises administering the SHP1I-PIA conjugate to the individual for at least two cycles, wherein the SHP1I-PIA conjugate is administered for at least once (e.g., at least twice or three time) in each cycle and wherein each cycle has about three to about twenty days. In some embodiments, the SHP1I-PIA conjugate is administered systemically (e.g., intravenously or subcutaneously) and/or locally (e.g., intratumorally).
  • the pro- inflammatory agent of the SHP1I-PIA conjugate is a TLR agonist
  • the TLR agonist activates TLR1 or TLR2, optionally wherein the TLR agonist comprises a triacylated lipoprotein, a peptidoglycan, zymosan, and/or Pam3CSK4.
  • the TLR agonist activates any one of TLR2, TLR3, TLR4, TLR5, and TLR6, optionally wherein the TLR agonist comprises a diacylated lipopeptide, a hot shock protein, HMGB1, uric acid, fibronectin, and/or ECM protein.
  • the TLR agonist activates TLR2, optionally wherein the TLR agonist comprises Pam3Cys, SMP-105, and/or CBLB612. In some embodiments, the TLR agonist activates TLR3, optionally wherein the TLR agonist comprises dsRNA, Poly I:C, PolyICIC, Poly-IC12U, IPH302, ARNAX, and/or MPLA (Monophosphoryl Lipid A).
  • the TLR agonist activates TLR4, optionally wherein the TLR agonist comprises LPS, lipoteichoic acid beta-defensin 2, fibronectin EDA, HMGB1, snapin, tenascin C, OK-432, AS04, FP20, G100, and/or GLA-SE.
  • the TLR agonist activates TLR5, optionally wherein the TLR agonist comprises flagellin, CBLB502, and/or M-VM3.
  • the TLR agonist activates TLR6.
  • the TLR agonist activates TLR7 or TLR8, optionally 29 sf-6604130 Attorney Docket No.245162001040 wherein the TLR agonist comprises ssRNA, CpG-A, poly G10, poly G3, and/or 324 BDB001.
  • the TLR agonist activates TLR7, optionally wherein the TLR agonist comprises bistriazolyl and/or R848.
  • the TLR agonist activates TLR8, optionally wherein the TLR agonist comprises VTX1463, VTX2337 (motolimod), and/or R848.
  • the TLR agonist activates TLR9, optionally wherein the TLR agonist comprises unmethylated CpG DNA, CpG (e.g., CpG- 7909, KSK-CpG, CpG-1826), MGN1703, dsSLIM, IMO2055, SD101, and/or ODN M362.
  • the TLR agonist activates TLR10, optionally wherein the TLR agonist comprises Pam3CSK4.
  • the TLR agonist activates TLR11, optionally wherein the TLR agonist comprises toxoplasma gondii profilin.
  • the TLR agonist activates TLR12.
  • the TLR agonist activates TLR13, optionally wherein the TLR agonist comprises VSV. In some embodiments, the TLR agonist activates TLR1, TLR2, TLR3, TLR4, TLR7, TLR8, and/or TLR9. In some embodiments, the TLR agonist activates TLR1. In some embodiments, the TLR agonist activates TLR2. In some embodiments, the TLR agonist activates TLR3. In some embodiments, the TLR agonist activates TLR4. In some embodiments, the TLR agonist activates TLR7. In some embodiments, the TLR agonist activates TLR8. In some embodiments, the TLR agonist activates TLR9.
  • the TLR agonist activates TLR9, TLR4 and TLR7/8.
  • the TLR agonist comprises CpG, polyI:C and/or R848.
  • the pro-inflammatory agent comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine and Vesatolimod.
  • the SHP1I-PIA conjugate is administered systemically. In some embodiments, the SHP1I-PIA conjugate is administered intratumorally. In some embodiments, the SHP1I-PIA conjugate is administered systemically and intratumorally.
  • the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti- TNF ⁇ antibody or an anti-IL6 antibody).
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the SHP1I-PIA conjugate (where the SHP-1 inhibitor of the SHP1I-PIA conjugate can comprise, e.g., TPI-1 or an analog or derivative thereof, or can be TPI-1).
  • a method of treating a cancer comprising administering a SHP1I-PIA conjugate, where the SHP-1 inhibitor of the SHP1I-PIA conjugate comprises TPI-1 or an analog or a derivative thereof, and the pro-inflammatory agent of the SHP1I-PIA conjugate comprises a TLR agonist (e.g., R848), optionally wherein the TLR agonist activates one or more TLRs selected from the group consisting of TLR9, TLR4, TLR7 and TLR8.
  • a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • the pro-inflammatory agent of the SHP1I-PIA conjugate comprises a TLR agonist (e.g., R848), optionally wherein the TLR agonist activates one or more TLRs selected from the group consisting of TLR9, TLR4, TLR7 and TLR8.
  • the SHP1I-PIA conjugate is administered intermittently. In some embodiments, the SHP1I-PIA conjugate is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the SHP1I-PIA conjugate is administered at least three, four, or five times. In some embodiments, at least two SHP1I-PIA conjugate administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the SHP1I-PIA conjugate administrations is separated by at least one day from the preceding or following SHP1I-PIA conjugate administration.
  • the SHP1I-PIA conjugate is administered at least twice (e.g., at least three, four, five or six times). In some embodiments, the SHP1I-PIA conjugate is administered for at least two cycles (e.g., at least three cycles). In some embodiments, each cycle has about seven to about twenty days.
  • the TLR agonist of the SHP1I-PIA conjugate activates a TLR on a macrophage, optionally wherein the TLR comprises TLR9. In some embodiments, the TLR agonist activates at least two TLRs (e.g., TLR4, TLR7, TLR8, or TLR9).
  • the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody).
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the SHP1I-PIA 31 sf-6604130 Attorney Docket No.245162001040 conjugate (where the SHP-1 inhibitor of the SHP1I-PIA conjugate can be, e.g., TPI-1 or an analog or derivative thereof, e.g., TPI-1).
  • a method of treating a cancer comprising administering to the individual a SHP1I-PIA conjugate, where the SHP-1 inhibitor of the SHP1I-PIA conjugate can be, e.g., TPI-1 or an analog or a derivative thereof, and where the pro-inflammatory agent of the SHP1I-PIA conjugate can be a STING activator (e.g., cGAMP, e.g., MSA-2), optionally wherein the SHP1I-PIA conjugate is administered at least twice (at least three, four, five, or six times).
  • a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate can be, e.g., TPI-1 or an analog or a derivative thereof
  • the pro-inflammatory agent of the SHP1I-PIA conjugate can be a STING activator (e.g.
  • the SHP1I-PIA conjugate is administered intermittently. In some embodiments, the SHP1I-PIA conjugate is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the SHP1I-PIA conjugate is administered at least three, four, or five times. In some embodiments, at least two SHP1I-PIA conjugate administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the SHP1I-PIA conjugate administrations is separated by at least one day from the preceding or following SHP1I-PIA conjugate administration.
  • the method comprises administering the SHP1I-PIA conjugate to the individual at an interval of no more than once every three days for at least twice. In some embodiments, the method comprises administering the SHP1I-PIA conjugate to the individual for at least two cycles, wherein the SHP1I-PIA conjugate is administered for at least once in each cycle and wherein each cycle has about three to about twenty days. In some embodiments, the SHP1I-PIA conjugate is administered systemically (e.g., intravenously, e.g., subcutaneously) and/or locally (e.g., intratumorally).
  • systemically e.g., intravenously, e.g., subcutaneously
  • locally e.g., intratumorally
  • the STING activator of the SHP1I-PIA conjugate is a cyclic-guanosine monophosphate-adenosine monophosphate (cGAMP, e.g., 3’3’ cGAMP, e.g., 2’3’ cGAMP), a bacterial vector (e.g., SYNB1891, STACT-TREX-1), a CDN compound (e.g., ADU-S100, BI-STING, BMS-986301, GSK532, JNJ-4412, MK-1454, SB11285, 3’3’-cyclic AIMP), a non-CDN small molecule (e.g., ALG-031048, E7755, JNJ-‘6196, MK-2118, MSA-1, MSA- 2, SNX281, SR-717, TAK676, TTI-10001), a nanovaccine (e.g., PC7A NP, cCAMP-NP, ONM-500)
  • the SHP1I-PIA conjugate is administered systemically. In some embodiments, the SHP1I-PIA conjugate is administered intratumorally. In some embodiments, the SHP1I-PIA conjugate is administered systemically and intratumorally. In some embodiments, 32 sf-6604130 Attorney Docket No.245162001040 the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti- TNF ⁇ antibody or an anti-IL6 antibody).
  • an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm e.g., an anti- TNF ⁇ antibody or an anti-IL6 antibody.
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the SHP1I-PIA conjugate (where the SHP-1 inhibitor of the SHP1I-PIA conjugate can be, e.g., TPI-1 or an analog or derivative thereof, e.g., TPI- 1).
  • a method of treating a cancer comprising administering to the individual a SHP1I-PIA conjugate (where the SHP-1 inhibitor of the SHP1I-PIA conjugate can be, e.g., TPI-1 or an analog or a derivative thereof, and the pro- inflammatory agent of the SHP1I-PIA conjugate can be a PAMP/DAMP activator), optionally wherein the SHP1I-PIA conjugate is administered at least twice (at least three, four, five, or six times).
  • a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • the SHP1I-PIA conjugate can be, e.g., TPI-1 or an analog or a derivative thereof, and the pro- inflammatory agent of the SHP1I-PIA conjugate can be a PAMP/DAMP activator
  • the SHP1I-PIA conjugate is administered intermittently. In some embodiments, the SHP1I-PIA conjugate is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the SHP1I-PIA conjugate is administered at least three, four, or five times. In some embodiments, at least two SHP1I-PIA conjugate administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the SHP1I-PIA conjugate administrations is separated by at least one day from the preceding or following SHP1I-PIA conjugate administration.
  • the method comprises administering the SHP1I-PIA conjugate to the individual at an interval of no more than once every three days for at least twice. In some embodiments, the method comprises administering the SHP1I-PIA conjugate to the individual for at least two cycles, wherein the SHP1I-PIA conjugate is administered for at least once in each cycle and wherein each cycle has about three to about twenty days. In some embodiments, the SHP1I-PIA conjugate is administered systemically (e.g., intravenously, e.g., subcutaneously) and/or locally (e.g., intratumorally). In some embodiments, the pro- inflammatory agent is a PAMP activator.
  • the PAMP activator is triacyl lipopeptides, LPS, lipoprotein, peptidoglycan, zymosan, lipoteichoic acid, trypanosomal phospholipids, Pam3Cys porins, lipoarabinomannan, double-stranded RNA, 33 sf-6604130 Attorney Docket No.245162001040 poly(I:C), trypanosomal lipids, taxol, Pseudomonas exoenzyme S, RSV F protein, MMTV envelope protein, flagellin, diacyl lipopeptides, single-stranded RNA, imiquimod, single- stranded RNA, resiquimod, bacterial/viral DNA, CpG DNA, ureobacteria, or toxoplasma LPS.
  • the pro-inflammatory agent is a DAMP activator.
  • the DAMP activator is defensins, HSP60, HSP70, messenger RNA, low- molecular-weight hyaluronic acid, fibrinogen, fibronectin, fx1-defensin, heparan sulfate, HSP60, HSP70, HSP90, HMGB1, or unmethylated CpG DNA.
  • the SHP1I-PIA conjugate is administered systemically.
  • the SHP1I-PIA conjugate is administered intratumorally.
  • the SHP1I-PIA conjugate is administered systemically and intratumorally.
  • the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody).
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the SHP1I-PIA conjugate, where the SHP-1 inhibitor of the SHP1I-PIA conjugate can comprise, e.g., TPI-1 or an analog or derivative thereof, e.g., TPI-1.
  • a method of treating a cancer comprising administering to the individual a SHP1I-PIA conjugate, where the SHP-1 inhibitor of the SHP1I-PIA conjugate can be, e.g., TPI-1 or an analog or a derivative thereof, and the pro- inflammatory compound of the SHP1I-PIA conjugate can comprise a checkpoint inhibitor (e.g., an anti-PD-1 agent, an anti-PD-L1 agent, or an anti-CTLA-4 agent), optionally wherein the SHP1I-PIA conjugate is administered at least twice (at least three, four, five, or six times).
  • a checkpoint inhibitor e.g., an anti-PD-1 agent, an anti-PD-L1 agent, or an anti-CTLA-4 agent
  • the SHP1I-PIA conjugate is administered intermittently. In some embodiments, the SHP1I-PIA conjugate is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the SHP1I-PIA conjugate is administered at least three, four, or five times. In some embodiments, at least two SHP1I-PIA conjugate administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the SHP1I-PIA conjugate administrations is separated by at least one day from the preceding or following SHP1I-PIA conjugate administration.
  • the method 34 sf-6604130 Attorney Docket No.245162001040 comprises administering the SHP1I-PIA conjugate to the individual at an interval of no more than once every three days for at least twice. In some embodiments, the method comprises administering the SHP1I-PIA conjugate to the individual for at least two cycles, wherein the SHP1I-PIA conjugate is administered for at least once in each cycle and wherein each cycle has about three to about twenty days. In some embodiments, the SHP1I-PIA conjugate is administered systemically (e.g., intravenously, e.g., subcutaneously) and/or locally (e.g., intratumorally).
  • systemically e.g., intravenously, e.g., subcutaneously
  • locally e.g., intratumorally
  • the checkpoint inhibitor targets LAG-3, TIM-3, B7- H3, B7-H4, A2aR, CD73, NKG2A, PVRIG/PVRL2, CEACAM1, CEACAM 5/6, FAK, CCL2/CCR2, LIF, CD47/SIRP ⁇ , CSF-1(M-CSF)/CSF-1R, IL-1/IL-1R3 (IL-1RAP), IL-8, SEMA4D, Ang-2, CLEVER-1, Axl, or phosphatidylserine.
  • the checkpoint inhibitor comprises or is lipilimumab, Cemiplimab, Nivolumab, Pembrolizumab, Atezolizumab, Avelumab, Durvalumab, LAG525 (IMP701), REGN3767, BI 754,091, tebotelimab (MGD013), eftilagimod alpha (IMP321), FS118, MBG453, Sym023, TSR-022, MGC018, FPA150, EOS100850, AB928, CPI-006, Monalizumab, COM701, CM24, NEO- 201, Defactinib, PF-04136309, MSC-1, Hu5F9-G4 (5F9), ALX148, TTI-662, RRx-001, Lanotuzumab (MCS110), LY3022855, SNDX-6352, Emactuzumab (RG7155), Pexidartinib (PLX3397
  • the SHP1I-PIA conjugate is administered systemically. In some embodiments, the SHP1I-PIA conjugate is administered intratumorally. In some embodiments, the SHP1I-PIA conjugate is administered systemically and intratumorally. In some embodiments, the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti- TNF ⁇ antibody or an anti-IL6 antibody).
  • an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm e.g., an anti- TNF ⁇ antibody or an anti-IL6 antibody.
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the SHP1I-PIA conjugate (where the SHP-1 inhibitor of the SHP1I-PIA conjugate can comprise, e.g., TPI-1 or an analog or derivative thereof, e.g., TPI-1).
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate can comprise, e.g., TPI-1 or an analog or derivative thereof, e.g., TPI-1).
  • a method of treating a cancer comprising administering to the individual a SHP1I-PIA conjugate, where the SHP-1 inhibitor of the 35 sf-6604130 Attorney Docket No.245162001040
  • SHP1I-PIA conjugate can comprise, e.g., TPI-1 or an analog or a derivative thereof, and the pro-inflammatory agent of the SHP1I-PIA conjugate can comprise a pro-inflammatory cytokine (e.g., IL-1b, IL-18, IL-6, and/or TNF ⁇ ), optionally wherein the SHP1I-PIA conjugate is administered at least twice (at least three, four, five, or six times).
  • the SHP1I-PIA conjugate is administered intermittently. In some embodiments, the SHP1I-PIA conjugate is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the SHP1I-PIA conjugate is administered at least three, four, or five times. In some embodiments, at least two SHP1I-PIA conjugate administration is separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the SHP1I-PIA conjugate administrations are separated by at least one day from the preceding or following SHP1I-PIA conjugate administration.
  • the method comprises administering the SHP1I-PIA conjugate to the individual at an interval of no more than once every three days for at least twice. In some embodiments, the method comprises administering the SHP1I-PIA conjugate to the individual for at least two cycles, wherein the SHP1I-PIA conjugate is administered for at least once in each cycle and wherein each cycle has about three to about twenty days. In some embodiments, the SHP1I-PIA conjugate is administered systemically (e.g., intravenously, e.g., subcutaneously) and/or locally (e.g., intratumorally). In some embodiments, the pro-inflammatory cytokine of the SHP1I-PIA conjugate promotes the M1 macrophages.
  • the pro-inflammatory cytokine comprises or is TNF, IFN ⁇ , and/or GM-CSF. In some embodiments, the pro-inflammatory cytokine comprises IFN ⁇ . In some embodiments, the pro-inflammatory cytokine comprises IL-1. In some embodiments, the pro-inflammatory cytokine comprises TNF-a. In some embodiments, the pro-inflammatory cytokine comprises IL-6.
  • the SHP1I-PIA conjugate is administered systemically. In some embodiments, the SHP1I-PIA conjugate is administered intratumorally. In some embodiments, the SHP1I-PIA conjugate is administered systemically and intratumorally.
  • the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti- TNF ⁇ antibody or an anti-IL6 antibody).
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the SHP1I-PIA conjugate, where the SHP-1 inhibitor 36 sf-6604130 Attorney Docket No.245162001040 of the SHP1I-PIA conjugate can comprise, e.g., TPI-1 or an analog or derivative thereof, e.g.
  • a method of treating a cancer comprising administering to the individual a SHP1I-PIA conjugate, where the SHP-1 inhibitor of the SHP1I-PIA conjugate can comprise, e.g., TPI-1 or an analog or a derivative thereof, and the pro-inflammatory agent of the SHP1I-PIA conjugate can comprise a chemotherapeutic agent (e.g., azathioprine), optionally wherein the SHP1I-PIA conjugate is administered at least twice (at least three, four, five, or six times).
  • a cancer e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer
  • the SHP1I-PIA conjugate is administered intermittently. In some embodiments, the SHP1I-PIA conjugate is administered daily for no more than three or two consecutive days, and optionally at least twice which are separated by at least one day. In some embodiments, the SHP1I-PIA conjugate is administered at least three, four, or five times. In some embodiments, at least two SHP1I-PIA conjugate administrations are separated by two, three, four, five, six, seven, eight, nine, or ten days. In some embodiments, each of the SHP1I-PIA conjugate administrations is separated by at least one day from the preceding or following SHP1I-PIA conjugate administration.
  • the method comprises administering the SHP1I-PIA conjugate to the individual at an interval of no more than once every three days for at least twice. In some embodiments, the method comprises administering the SHP1I-PIA conjugate to the individual for at least two cycles, wherein the SHP1I-PIA conjugate is administered for at least once in each cycle and wherein each cycle has about three to about twenty days. In some embodiments, the SHP1I-PIA conjugate is administered systemically (e.g., intravenously, e.g., subcutaneously) and/or locally (e.g., intratumorally). In some embodiments, the chemotherapeutic agent of the SHP1I-PIA conjugate is an alkylating agent.
  • the alkylating agent is selected from the group consisting of nitrogen mustard (e.g., endamustine, cyclophosphamide, ifosfamide), nitrosoureas (e.g., carmustine, lomustine), platinum analogs (e.g., carboplatin, cisplatin, oxaliplatin), triazenes (e.g., dacarbazine, procarbazine, temozolamide), alkyl sulfonate (e.g., busulfan), and ethyleneimine (e.g., thiotepa).
  • nitrogen mustard e.g., endamustine, cyclophosphamide, ifosfamide
  • nitrosoureas e.g., carmustine, lomustine
  • platinum analogs e.g., carboplatin, cisplatin, oxaliplatin
  • triazenes e.g., dacar
  • the chemotherapeutic agent of the SHP1I-PIA conjugate is an antimetabolite.
  • the antimetabolite is selected from the group consisting of icytidine analogs (e.g., azacitidine, decitabine, cytarabine, gemcitabine), folate antagonists (e.g., methotrexate, pemetrexed), purine analogs (e.g., cladribine, clofarabine, nelarabine), pyrimidine analogs (e.g., fluorouracil (5-FU), capecitabine (prodrug 37 sf-6604130 Attorney Docket No.245162001040 of 5-FU)).
  • icytidine analogs e.g., azacitidine, decitabine, cytarabine, gemcitabine
  • folate antagonists e.g., methotrexate, pemetrexed
  • purine analogs e.g., cladribine,
  • the chemotherapeutic agent of the SHP1I-PIA conjugate is an antimicrotubular agent.
  • the antimicrotubular agent is selected from the group consisting of topoisomerase II inhibitors (e.g., anthracyclines, doxorubicin, daunorubicin, idarubicin, mitoxantrone), topoisomerase I inhibitors (e.g., irinotecan, topotecan), taxanes (e.g., paclitaxel, docetaxel, cabazitaxel), vinca alkaloids (e.g., vinblastine, vincristine, vinorelbine), antibiotics (e.g., actinomycin D, bleomycin, daunomycin).
  • topoisomerase II inhibitors e.g., anthracyclines, doxorubicin, daunorubicin, idarubicin, mitoxantrone
  • the chemotherapeutic agent of the SHP1I-PIA conjugate is hydroxyurea, tretinoin, arsenic trioxide, or a proteasome inhibitor (e.g., bortezomib).
  • the SHP1I-PIA conjugate is administered systemically. In some embodiments, the SHP1I-PIA conjugate is administered intratumorally. In some embodiments, the SHP1I-PIA conjugate is administered systemically and intratumorally.
  • the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti- TNF ⁇ antibody or an anti-IL6 antibody).
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the SHP1I-PIA conjugate (where the SHP-1 inhibitor of the SHP1I-PIA conjugate can comprise, e.g., TPI-1 or an analog or derivative thereof, e.g., TPI-1).
  • the present application also provides a method of modulating monocytes or macrophages derived from an individual having a cancer, comprising contacting the monocytes or macrophages with a SHP1I-PIA conjugate as described herein.
  • the monocytes or macrophages are derived from the same individual.
  • the method further comprises administering to the individual an agent that reduces systemic inflammation and/or reduces inflammatory cytokine cascade or cytokine storm (e.g., an anti-TNF ⁇ antibody or an anti-IL6 antibody).
  • the method further comprises administering to the individual an anti-TNF ⁇ antibody, optionally wherein the anti-TNF ⁇ antibody is administered prior to (e.g., within two weeks, ten days, a week, 48 hours, or 24 hours), concurrently with or simultaneously with, or immediately after (within 3, 2, 1, or 0.5 hour) the administration of the SHP1I-PIA conjugate (where the SHP-1 inhibitor of the SHP1I-PIA conjugate can comprise, e.g., TPI-1 or an analog or derivative thereof, e.g., TPI-1).
  • the SHP-1 inhibitor of the SHP1I-PIA conjugate can comprise, e.g., TPI-1 or an analog or derivative thereof, e.g., TPI-1).
  • the SHP1I-PIA conjugate (e.g., comprising TPI-1 or an analog or a derivative thereof) is administered at least two times (such as at least 3, 4, 5, or 6 times).
  • the method comprises administering the SHP1I-PIA conjugate (e.g., comprising TPI-1 or an analog or a derivative thereof) at an interval of no more than once every two days for at least twice (such as at least three times, four times, five times, or six times).
  • the method comprises administering the SHP1I-PIA conjugate (e.g., comprising TPI-1 or an analog or a derivative thereof) at an interval of no more than once every three days for at least twice (such as at least three times, four times, five times, or six times).
  • the method comprises administering the SHP1I-PIA conjugate (e.g., TPI-1 or an analog or a derivative thereof) for at least two cycles.
  • the SHP1I-PIA conjugate e.g., comprising TPI-1 or an analog or a derivative thereof
  • each cycle has about three to about 50 days (e.g., about 3-40 days, about 3-30 days, about 3-20 days, about 3-15 days, about 3-10 days, or about 2-10 days).
  • the SHP1I-PIA conjugate is administered systemically (e.g., orally, intravenously, subcutaneously, intraperitoneally). In some embodiments, the SHP1I-PIA conjugate is administered locally (e.g., intratumorally). In some embodiments, the SHP1I-PIA conjugate is administered both systemically and locally (e.g., intratumorally).
  • Local administration of the SHP1I-PIA conjugate can comprise topical administration.
  • Topical administration can include, but is not limited to, the application of a cream, a lotion, a paste, a patch, an ointment, a spray, a gel, an isotonic aqueous solution (e.g., an eyedrop), or a microneedle.
  • the SHP1I-PIA conjugate is comprised in: a) a nanoparticle (e.g., lipid nanoparticle), a microparticle, and/or a liposome, and/or b) a slow-release formulation.
  • Topical dosage forms available to treat mammals include solids (dusting powders), semisolids (creams, ointments, pastes, and gels), and liquids (solutions, suspension concentrates, suspoemulsions, emulsifiable concentrates, paints, and tinctures).
  • Suitable routes of administration may, for example, include oral, rectal, transmucosal, topical, intestinal, intranasal, or intraocular administration.
  • the compounds can also be 39 sf-6604130 Attorney Docket No.245162001040 administered in sustained or controlled release dosage forms, including transdermal (e.g., electrotransport) patches, creams, lotions, pastes, patches, ointments, sprays, gels, isotonic aqueous solutions (e.g., eyedrops), or microneedles and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.
  • the SHP1I-PIA conjugate formulation is sterile.
  • the SHP1I-PIA conjugate is complexed with a delivery vehicle before being administered into the individual.
  • the delivery vehicle promotes the delivery into the tumor.
  • the SHP1I-PIA conjugate modulates a monocyte or macrophage (e.g., a monocyte or macrophage derived from the individual to be treated) in vitro.
  • TME Tumor microenvironment
  • SHP-1 Src homology region 2 (SH-2) domain-containing phosphatase 1 (SHP-1) is a non- receptor tyrosine phosphatase.
  • SHP-1 is encoded by the PTPN6 gene (on chromosome 12p13).
  • SHP-1 As there are two promoter regions, one on exon 1 (active in cells of non- hematopoietic lineage) and one on exon 2 (active in cells of hematopoietic lineage), there are two forms of SHP-1 which have different N-terminal sequences, but which both have phosphatase activity. Both promoters may be active in epithelial cancer cells, giving rise to alternative SHP-1 transcripts. Form I of SHP-1 is primarily found in the nucleus, while form II is primarily found in the cytoplasm, and presumably they have different substrates. [0120] SHP-1 is a 595 amino acid protein.
  • N- SH2 and C-SH2 have two tandem N-terminal SH2 domains (N- SH2 and C-SH2), and a classic catalytic protein tyrosine phosphatase (PTP) domain.
  • the C- terminal tail has multiple sites for phosphorylation.
  • Structural analysis of SHP-1 indicates that its N-SH2 is bound to and auto-inhibits the catalytic site in its inactive state.
  • phosphotyrosine residues bind to the SH2 domains, the electrostatic interactions between N- SH2 and the catalytic site is disrupted, allowing the enzyme to become active.
  • substrate interaction plays a role in regulating the activity of SHP-1.
  • Phosphorylation of amino acids Tyr536, Tyr564 and Ser591 also increase SHP-1 activity.
  • Ser591 may also play a role in down-regulating SHP-1 activity, via phosphorylation by protein kinase C (PKC) or mitogen-activated protein kinases (MAPKs).
  • PLC protein kinase C
  • MAPKs mitogen-activated protein kinases
  • 40 sf-6604130 Attorney Docket No.245162001040
  • SHP-1 activity in solid cancers and blood cancers is altered, and this alteration may be due to mutations or changes in epigenetic regulation.
  • SHP-1 is involved in multiple signal transduction pathways related to development and progression of cancer. Presumably, disruption of the normal, highly regulated phosphorylation patterns involved in SHP-1 regulation is a factor in SHP-1’s role in cancer.
  • Inhibition of SHP-1 can also cause deleterious effects.
  • Motheaten mice (me/me or me v /me v ) which are genetically deficient in SHP-1 show abnormal immune function, including hyperactivation of immune cells, and such mice have shortened life spans. Depletion of SHP-1 in adult wild-type mice also caused pathology, including enlarged spleens and inflammation of the lungs. Thus, approaches to treatment of cancer by inhibition of SHP-1 require careful balancing of the need for normal SHP-1 activity versus preventing abnormal SHP-1 activity.
  • Inhibitors of SHP-1 phosphatase activity include TPI-1, suramine, NSC-87877, and sodium stibogluconate. Sodium stibogluconate entered Phase I clinical trials for malignant melanoma, but showed severe side effects.
  • CRS cytokine release syndrome
  • the methods described herein can further comprises administration of an agent that reduces systemic inflammation (including, for example, an agent that reduces inflammatory cytokine cascade or cytokine storm), in order to curb down systemic inflammation and reduce adverse toxicity.
  • agents that reduce systemic inflammation include, but are not limited to, inhibitors of TNF ⁇ , IL6, IL10, and IFN ⁇ .
  • the agent that reduces systemic inflammation is administered simultaneously with the SHP1I-PIA conjugate.
  • the agent that reduces systemic inflammation is administered sequentially (e.g., prior to or after) with the SHP1I-PIA conjugate. In some embodiments, the administration of the agent that reduces systemic inflammation follows the same dosing schedule as the SHP1I-PIA conjugate. In some embodiments, the agent that reduces systemic inflammation is administered at a sub-therapeutic dose, namely, at a dose that is lower than an effective amount for treating a disease when administered alone.
  • the administration of the agent that reduces systemic inflammation allows more frequent administration of the SHP1I-PIA conjugate (e.g., daily, once every two days, once every three days, etc.).
  • the agent that reduces systemic inflammation can include any anti-inflammatory agent known in the art, including inhibitors of or antagonists to pro-inflammatory agents.
  • the agent can be an inhibitor or antagonist, including but not limited to, a small molecule inhibitor, a neutralizing antibody, a receptor blockade antibody, a soluble receptor, a targeting short interfering RNA (siRNA), a chemical inhibitor of mRNA stability, derivatives thereof, and any combination thereof, including combinations of agents targeting one or more molecules (e.g., targeting via the inhibition of TNF ⁇ alone, IL6 alone, TNF ⁇ and IL6 in combination).
  • Anti-TNF ⁇ antagonist [0127] TNF ⁇ , a major proinflammatory cytokine, is secreted by activated macrophages, monocytes and lymphocytes.
  • Administration of an anti-TNF ⁇ antibody to an individual who has been administered with a SHP1I-PIA conjugate may alleviate toxicity caused by systemic inflammation without compromising the efficacy of the therapeutic agent.
  • the methods of the present application therefore in some embodiments comprises administration of TNF ⁇ inhibitor, e.g., an anti-TNF ⁇ antagonist (e.g., in the context where the proinflammatory agent is not TNF ⁇ ) in addition to the SHP1I-PIA conjugate.
  • the TNF ⁇ inhibitor is selected from the group consisting of a small molecule inhibitor, a neutralizing antibody, a TNF ⁇ receptor blockade antibody, a soluble TNF ⁇ receptor, a TNF ⁇ -targeting short interfering RNA (siRNA), a chemical inhibitor of TNF ⁇ mRNA stability, an inhibitor of TNF ⁇ converting enzyme (TACE), and derivatives thereof.
  • the TNF ⁇ inhibitor is an anti-TNF ⁇ neutralizing antibody.
  • the TNF ⁇ inhibitor is an anti-TNF ⁇ receptor blockade antibody.
  • the anti-TNF ⁇ antibody is a monoclonal antibody.
  • anti- TNF ⁇ antibody is a chimeric, humanized, and/or fully human antibody.
  • Suitable antibodies for use in the methods provided herein include, but are not limited to, Remicade® (Infliximab (Centocor)), and those antibodies described, for example, in U.S. Patent No. 6,835,823; 6,790,444; 6,284,471; 6,277,969; 5,919,452; 5,698,195; 5,656,272; and 5,223,395 and in EP Patent No. 0610201, the contents of each of which are hereby incorporated by reference in their entirety, or antibodies that bind to the same epitope as Remicade®.
  • anti-TNF ⁇ antibodies for use in the methods provided herein are, by way of non-limiting example, Humira (Adalimumab (Abbott Laboratories, Esai)) as described in U.S. Patent No. 6,090,382; 6,258,562; or 6,509,015 and related patents and applications, the contents of which are hereby incorporated by reference in their entirety; SimponiTM (Golimimab, CNTO 148 (Centocor)) as described in PCT Publication No.
  • Humira Adalimumab (Abbott Laboratories, Esai)
  • SimponiTM Golimimab, CNTO 148 (Centocor)
  • the TNF ⁇ inhibitor e.g., anti-TNF ⁇ antagonist
  • the TNF ⁇ inhibitor is a fusion protein.
  • Suitable fusion proteins for use in the methods provided herein include, but are not limited to, Enbrel (Etanercept (Amgen)) and other fusion proteins or fragments thereof described in U.S. Patent No. 5,712,155, PCT Publication No.
  • the TNF ⁇ inhibitor e.g., anti-TNF ⁇ antagonist
  • the TNF ⁇ inhibitor is a modified antibody antagonist or a non-antibody-based antagonist.
  • Such antagonists include advanced antibody therapeutics, such as antibody fragments including, but not limited to, CimziaTM (Certolizumab pegol, CDP870 (Enzon)), bispecific antibodies, Nanobodies® such as ABX 0402 (Ablynx), immunotoxins, and radiolabeled therapeutics; peptide therapeutics; gene therapies, particularly intrabodies; oligonucleotide therapeutics such as aptamer therapeutics, antisense therapeutics, interfering RNA therapeutics; and small molecules such as LMP-420 (LeukoMed) as described in EP Patent No. 0767793, and related patents and applications, the contents of which are hereby incorporated by reference in their entirety.
  • advanced antibody therapeutics such as antibody fragments including, but not limited to, CimziaTM (Certolizumab pegol, CDP870 (Enzon)), bispecific antibodies, Nanobodies® such as ABX 0402 (Ablynx), immunotoxins, and radiolabeled therapeutics; peptide therapeutics;
  • the TNF ⁇ inhibitor (e.g., an anti-TNF ⁇ antibody) is administered within two weeks, 10 days, or one week prior to the administration of a 43 sf-6604130 Attorney Docket No.245162001040 SHP1I-PIA conjugate described herein.
  • Exemplary TNF ⁇ inhibitors such an anti-TNF ⁇ antibody is usually stable for at least one or two weeks.
  • the TNF ⁇ inhibitor (e.g., an anti-TNF ⁇ antibody) is administered concurrently or simultaneously with the SHP1I-PIA conjugate.
  • the TNF ⁇ inhibitor (e.g., an anti-TNF ⁇ antibody) is administered immediately after (e.g., within 1 hour or 30 minutes) the administration of the SHP1I-PIA conjugate.
  • the TNF ⁇ inhibitor is administered systemically.
  • the TNF ⁇ inhibitor is administered at least once a week, once every five days, once every three days, or daily.
  • the TNF ⁇ inhibitor is administered intermittently.
  • the TNF ⁇ inhibitor is administered to the individual for at least two cycles, wherein each cycle has about three to about seven days. In some embodiments, the individual does not develop cytokine release syndrome or pro- inflammatory organ damage.
  • an “anti-IL6 antagonist” or “IL6 inhibitor” refers to an agent that inhibits or blocks IL6 biological activity via binding to IL6 or IL6 receptor.
  • the anti-IL6 antagonist is an antibody.
  • the anti-IL6 antagonist is an antibody that binds IL6 receptor.
  • Antibodies that bind IL-6 receptor include tocilizumab (including intravenous, i.v., and subcutaneous, s.c., formulations thereof) (Chugai, Roche, Genentech), satralizumab (Chugai, Roche, Genentech), sarilumab (Sanofi, Regeneron), NI-1201 (Novimmune and Tiziana), and vobarilizumab (Ablynx).
  • the anti-IL6 antagonist is a monoclonal antibody that binds IL6.
  • Antibodies that bind IL-6 include sirukumab (Centecor, Janssen), olokizumab (UCB), clazakizumab (BMS and Alder), siltuximab (Janssen), and EBI-031 (Eleven Biotherapeutics and Roche).
  • the IL6 antagonist is olamkicept.
  • the IL6 inhibitor is administered systemically. In some embodiments, the IL6 inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the IL6 inhibitor is administered intermittently.
  • the IL6 inhibitor is administered to the individual for at least two cycles, wherein each cycle has about three to about seven days.
  • 44 sf-6604130 Attorney Docket No.245162001040 Structure of SHP1I-PIA Conjugates [0136]
  • the present application provides SHP1I-PIA conjugates, which comprise a SHP-1 inhibitor which is covalently conjugated to a pro-inflammatory agent.
  • a SHP-1 inhibitor can be covalently conjugated directly to a pro-inflammatory agent.
  • a SHP-1 inhibitor can be covalently conjugated to a pro-inflammatory agent via a linker.
  • the SHP1I-PIA conjugates are of the following formula: PIA-L A -R 1 wherein PIA is a pro-inflammatory agent, L A is an optional linker, and R 1 is a SHP-1 inhibitor.
  • Pro-inflammatory agents used in the SHP1I-PIA conjugates [0137] Infection and tissue injury are the two classic instigators of inflammation. See e.g., Medzhitov, Nature. 2008 Jul 24;454(7203):428-35.
  • the pro-inflammatory agents that can be used in the SHP1I-PIA conjugates described herein include at least two overlapping categories: 1) an agent or therapy of any kind or sort that can promote an inflammation (e.g., by promoting one or more pro-inflammatory cytokines or chemokines, inhibiting one or more anti-inflammatory cytokines or chemokines, recruiting macrophages, NK cells, neutrophils, effector T cells, or B cells to the tissue or activating any of these cells, or suppressing regulatory/suppressive immune cells such as regulatory T cells or MDSC), and 2) an agent or therapy that can cause damage of cancer cells (e.g., necrosis of cancer cells).
  • an agent or therapy of any kind or sort that can promote an inflammation (e.g., by promoting one or more pro-inflammatory cytokines or chemokines, inhibiting one or more anti-inflammatory cytokines or chemokines, recruiting macrophages, NK cells, neutrophils, effector T cells, or B cells to the tissue or activating
  • the pro-inflammatory agent triggers a pro-inflammatory signal on macrophages.
  • the pro-inflammatory agent activates a TLR, a TNFR, or ITAM-R. See Lionel et al., Eur J Immunol. 2011 Sep; 41(9): 2477–2481.
  • the pro- inflammatory can activate a pro-inflammatory signal on macrophages via a direct manner or indirect manner.
  • a TLR agonist which directly activates TLR on macrophages
  • a radiotherapy which indirectly activates a pro-inflammatory signal on macrophages, when used with a SHP-1 inhibitor both demonstrated remarkable anti-tumor effects.
  • the pro-inflammatory agent comprises an agent selected from the group consisting of TLR agonists, STING activators, PAMP/DAMP activators, checkpoint inhibitors, pro-inflammatory cytokines or chemokines, chemotherapeutic agents, and bacterial components.
  • the pro-inflammatory agent comprises an agent selected from the group consisting of TLR agonists, STING activators, PAMP/DAMP activators, pro- inflammatory cytokines or chemokines, and bacterial components.
  • the pro-inflammatory agent comprises a TLR agonist (e.g., R848) and a cytokine (e.g., IFN-gamma).
  • TLR agonists e.g., R848
  • cytokine e.g., IFN-gamma
  • TLR agonists e.g., R848
  • the pro-inflammatory agent comprises or is a TLR agonist.
  • TLRs play a vital role in activating immune responses. TLRs recognize conserved pathogen-associated molecular patterns (PAMPs) expressed on a wide array of microbes, as well as endogenous DAMPs released from stressed or dying cells.
  • PAMPs pathogen-associated molecular patterns
  • TLR1, -2, -4, -5, -6, and - 10 are expressed on the cell surface, whereas TLR3, -7, -8, and -9 are situated on endosomal membranes within the cell.
  • TLR1 and TLR2 can heterodimerize to recognize a variety of bacterial lipid structures and cell wall components, such as triacylated lipoproteins, lipoteichoic acid, and ⁇ -glucans. TLR2 also heterodimerizes with TLR6 to bind diacylated lipopeptides. Additionally, TLR2 can bind various endogenous DAMPs, such as HSPs, HMGB1, uric acid, fibronectin, and other extracellular matrix proteins.
  • TLR1 and TLR6 can heterodimerize with TLR10; however, the TLR agonist recognized by this dimer remains to be identified.
  • TLR3 recognizes viral dsRNA, as well as synthetic analogs of dsRNA, such as ligand Poly I:C.
  • TLR4 binds LPS in complex with lipid A binding protein, CD14, and myeloid differentiation protein 2, MD2 as well as recognizing various DAMPs. Endogenous TLR4 ligands, which have been described, include ⁇ -defensin 2, fibronectin extra domain A EDA, HMGB1, Snapin, and tenascin C.
  • TLR5 recognizes bacterial flagellin
  • TLR7 and TLR8 bind viral ssRNA
  • TLR9 interacts with unmethylated CpG DNA from bacteria and some viruses. Additional TLRs have been identified more recently in mice based on sequence homology of the highly conserved TIR domain.
  • TLR10 is a surface receptor whose natural ligand remains unknown.
  • TLR11, -12, and -13 are present in mice but not in humans.
  • TLR11 was shown to bind a T. gondii profilin and uropathogenic Escherichia coli.
  • the ligand for TLR12 has not yet been identified, whereas TLR13 is an endosomal receptor that recognizes VSV.
  • TLR signaling can act as a double-edged sword in cancer. It was found that TLR stimulation of cancer cells can lead to either tumor progression or inhibition. For example, 46 sf-6604130 Attorney Docket No.245162001040 Stimulation of TLR 2, 4, and 7/8 was found to lead to tumor progression via production of immunosuppressive cytokines, increased cell proliferation and resistance to apoptosis. R848- stimulation of TLR7/8 overexpressing pancreatic cancer cell line resulted in increased cell proliferation and reduced chemosensitivity.
  • the TLR agonist activates any of the TLRs.
  • the TLR agonist activates TLR1 or TLR2, optionally wherein the TLR agonist comprises a triacylated lipoprotein, a peptidoglycan, zymosan, and/or Pam 3 CSK 4 .
  • the TLR agonist activates any one of TLR2, TLR3, TLR4, TLR5, and TLR6, optionally wherein the TLR agonist comprises a diacylated lipopeptide, a hot shock protein, HMGB1, uric acid, fibronectin, and/or ECM protein.
  • the TLR agonist activates TLR2, optionally wherein the TLR agonist comprises Pam3Cys, SMP-105, and/or CBLB612.
  • the TLR agonist activates TLR3, optionally wherein the TLR agonist comprises dsRNA, Poly I:C, PolyICIC, Poly-IC12U, IPH302, ARNAX, and/or MPLA.
  • the TLR agonist activates TLR4, optionally wherein the TLR agonist comprises LPS, lipoteichoic acid beta-defensin 2, fibronectin EDA, HMGB1, snapin, tenascin C, OK-432, AS04, FP20, G100, and/or GLA-SE.
  • the TLR agonist activates TLR5, optionally wherein the TLR agonist comprises flagellin, CBLB502, and/or M-VM3. [0152] In some embodiments, the TLR agonist activates TLR6. [0153] In some embodiments, the TLR agonist activates TLR7 or TLR8, optionally wherein the TLR agonist comprises ssRNA, CpG-A, poly G10, poly G3, and/or 324 BDB001. [0154] In some embodiments, the TLR agonist activates TLR7, optionally wherein the TLR agonist comprises bistriazolyl and/or R848.
  • the TLR agonist activates TLR8, optionally wherein the TLR agonist comprises VTX1463, VTX2337 (motolimod), and/or R848.
  • the TLR agonist activates TLR9, optionally wherein the TLR agonist comprises unmethylated CpG DNA, CpG (e.g., CpG-7909, KSK-CpG, CpG-1826), MGN1703, dsSLIM, IMO2055, SD101, and/or ODN M362.
  • the TLR agonist activates TLR10, optionally wherein the TLR agonist comprises Pam 3 CSK 4 .
  • the TLR agonist activates TLR11, optionally wherein the TLR agonist comprises toxoplasma gondii profilin.
  • the TLR agonist activates TLR12.
  • the TLR agonist activates TLR13, optionally wherein the TLR agonist comprises VSV.
  • the TLR agonist activates a TLR on a macrophage.
  • the TLR agonist activates TLR1, TLR2, TLR3, TLR4, TLR7, TLR8, and/or TLR9. [0163] In some embodiments, the TLR comprises TLR1, TLR4, and/or TLR9. In some embodiments, the TLR comprises TLR9. [0164] In some embodiments, the TLR comprises TLR2, TLR4, TLR7, and/or TLR8. [0165] In some embodiments, the TLR agonist comprises CpG. In some embodiments, the TLR agonist comprises polyI:C. In some embodiments, the TLR agonist comprises CpG and/or polyI:C. In some embodiments, the TLR agonist comprises CpG, polyI:C and/or R848.
  • the TLR agonist is R848, 3M-852A, Motolimod, Bropirimine or Vesatolimod. In some embodiments, the TLR agonist is R848. [0167] In some embodiments where the TLR agonist is R848, the SHP1I-PIA conjugate is of the form: 48 sf-6604130 Attorney Docket No.245162001040 or a salt thereof, wherein L A is an optional linker and R 1 is a SHP-1 inhibitor. Radiopharmaceuticals [0168] In some embodiments, the pro-inflammatory agent is a radiopharmaceutical. Examples of radiopharmaceuticals that can be used are disclosed in, e.g., Sgouros et al.
  • the pro-inflammatory agent comprises or is a STING activator.
  • Stimulator of IFN genes (STING, also known as TMEM173, MITA, MPYS or ERIS) is a pattern recognition receptor (PRR) that recognizes cytosolic DNA in the form of cyclic dinucleotides (CDNs), such as the bacterial product cyclic-guanosine monophosphate- adenosine monophosphate (3’3’ cGAMP).
  • CDNs cyclic dinucleotides
  • cGAMP c-GMP-AMP
  • cGAS converts ATP and GTP into the metazoan-specific CDN 2’3’-cGAMP for STING recognition and activation.
  • STING is a transmembrane protein that exists as dimers anchored within the endoplasmic reticulum membrane and forms a V-shaped pocket that enables cytosolic CDN binding. Ligand binding results in significant conformational changes in the C-terminal domain of STING, mediating its transport to Golgi compartments.
  • STING recruits TANK-binding kinase 1 (TBK1), which facilitates IRF3 phosphorylation, nuclear translocation and the strong induction of transcription of type I IFNs (e.g., IFN- ⁇ ).
  • STING 49 sf-6604130 Attorney Docket No.245162001040 also triggers a robust pro-inflammatory cytokine response [e.g., tumor necrosis factor (TNF)] by activating Nuclear Factor-kappa B (NF- ⁇ B) and this part of the pathway can be mediated independent of TBK1 via a closely related homologue protein, IKK ⁇ . See e.g., Peng et al., Front Immunol.
  • TNF- ⁇ B Nuclear Factor-kappa B
  • the STING activator is a cyclic-guanosine monophosphate- adenosine monophosphate (cGAMP, e.g., 3’3’ cGAMP, e.g., 2’3’ cGAMP).
  • the STING activator is a bacterial vector (e.g., SYNB1891, STACT-TREX-1).
  • the STING activator is a CDN compound (e.g., ADU-S100, BI-STING, BMS-986301, GSK532, JNJ-4412, MK-1454, SB11285, 3’3’-cyclic AIMP).
  • the STING activator is a non-CDN small molecule (e.g., ALG- 031048, E7755, JNJ-‘6196, MK-2118, MSA-1, MSA-2, SNX281, SR-717, TAK676, TTI- 10001).
  • the STING activator is a nanovaccine (e.g., PC7A NP, cCAMP-NP, ONM-500).
  • the STING activator is an antibody-drug conjugate (e.g., XMT-2056, CRD-5500).
  • the STING activator is the compound SR-717 of the formula: . 50 sf-6604130 Attorney Docket No.245162001040
  • the STING activator is the compound MSA-2 of the formula: .
  • the STING activator is the compound SNX-281 of the formula: .
  • the STING activator is the compound alpha-mangostin of the formula: . 51 sf-6604130 Attorney Docket No.245162001040 Any of the three hydroxy groups of alpha-mangostin can be used as the attachment point to the SHP-1 inhibitor, or to the optional linker L A connecting alpha-mangostin and the SHP-1 inhibitor.
  • the STING activator is the compound DMXAA of the formula: .
  • Other exemplary STING activators can be found in Amougezar et al., Cancers (Basel). 2021 May 30;13(11):2695, which is incorporated by reference here by its entirety.
  • the pro-inflammatory agent comprises or is a PAMP/DAMP activator.
  • the organism senses microbial infection through innate receptors encoded in the genome, called pattern-recognition receptors, including the Toll-like receptors (TLRs), the nucleotide-binding and oligomerization domain (NOD)-like receptors, and retinoic acid– inducible gene I (RIG-I)-like receptors. These receptors recognize pathogen-associated molecular patterns (PAMPs) expressed by bacteria, fungi, and viruses, but also bind damage- associated molecular patterns (DAMPs), which are molecules released by sterile injury.
  • TLRs Toll-like receptors
  • NOD nucleotide-binding and oligomerization domain
  • RIG-I retinoic acid– inducible gene I
  • the pro-inflammatory agent is a PAMP activator.
  • Exemplary PAMP activators include triacyl lipopeptides, LPS, lipoprotein, peptidoglycan, zymosan, lipoteichoic acid, trypanosomal phospholipids, Pam3Cys porins, lipoarabinomannan, double- stranded RNA, poly(I:C), trepanosomal lipids, taxol, Pseudomonas exoenzyme S, RSV F protein, MMTV envelope protein, flagellin, diacyl lipopeptides, single-stranded RNA, imiquimod, single-stranded RNA, resquimod, bacterial/viral DNA, CpG DNA, ureobacteria, and toxoplasma LPS.
  • the pro-inflammatory agent is a DAMP activator.
  • DAMP activators include defensins, HSP60, HSP70, messenger RNA, low-molecular-weight hyaluronic acid, fibrinogen, fibronectin, fx1-defensin, heparan sulfate, HSP60, HSP70, HSP90, HMGB1, and unmethylated CpG DNA.
  • Chemotherapeutic agent [0187]
  • the pro-inflammatory agent comprises or is a chemotherapeutic agent.
  • the chemotherapeutic agent is an alkylating agent.
  • alkylating agents include nitrogen mustard (e.g., endamustine, cyclophosphamide, ifosfamide), nitrosoureas (e.g., carmustine, lomustine), platinum analogs (e.g., carboplatin, cisplatin, oxaliplatin), triazenes (e.g., dacarbazine, procarbazine, temozolamide), alkyl sulfonate (e.g., busulfan), and ethyleneimine (e.g., thiotepa).
  • the chemotherapeutic agent is an antimetabolite.
  • Exemplary antimetabolites include cytidine analogs (e.g., azacitidine, decitabine, cytarabine, gemcitabine), folate antagonists (e.g., methotrexate, pemetrexed), purine analogs (e.g., cladribine, clofarabine, nelarabine), pyrimidine analogs (e.g., fluorouracil (5-FU), capecitabine (prodrug of 5-FU)).
  • the chemotherapeutic agent is an antimicrotubular agent.
  • antimmicrotubular agents include topoisomerase II inhibitors (e.g., anthracyclines, doxorubicin, daunorubicin, idarubicin, mitoxantrone), topoisomerase I inhibitors (e.g., irinotecan, topotecan), taxanes (e.g., paclitaxel, docetaxel, cabazitaxel), vinca alkaloids (e.g., vinblastine, vincristine, vinorelbine), antibiotics (e.g., actinomycin D, bleomycin, daunomycin).
  • topoisomerase II inhibitors e.g., anthracyclines, doxorubicin, daunorubicin, idarubicin, mitoxantrone
  • topoisomerase I inhibitors e.g., irinotecan, topotecan
  • taxanes e.g., paclitaxel,
  • chemotherapeutic agents include hydroxyurea, tretinoin, arsenic trioxide, and proteasome inhibitors (e.g., bortezomib). 53 sf-6604130 Attorney Docket No.245162001040 Pro-inflammatory cytokines [0192]
  • the pro-inflammatory agent is a pro-inflammatory cytokine.
  • the pro-inflammatory cytokine promotes the M1 macrophages. See e.g., Duque et al., Front Immunol. 2014; 5: 491.
  • the pro- inflammatory cytokine comprises or is TNF, IFN ⁇ , and/or GM-CSF.
  • the pro-inflammatory cytokine comprises IL-6, TNF ⁇ , a cytokine from IL-1 family (e.g., IL-1 ⁇ , IL-1 ⁇ , IL-18, IL-33 and IL-36), and/or IFN ⁇ .
  • the pro-inflammatory cytokine comprises a cytokine from IL-1 family.
  • the pro-inflammatory cytokine comprises any one or more of IL-1 ⁇ , IL-1 ⁇ , IL-18, IL-33, and IL-36. See e.g., Sims, J., Smith, D. The IL-1 family: regulators of immunity. Nat Rev Immunol 10, 89–102 (2010).
  • the pro-inflammatory agent is a checkpoint inhibitor.
  • Immune checkpoints are pathways with inhibitory or stimulatory features that maintain self-tolerance and assist with immune response. The most well-described checkpoints are inhibitory in nature and include the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1). See e.g., Marin-Acevedo et al., J Hematol Oncol 14, 45 (2021).
  • the checkpoint inhibitor targets CLTA-4, PD-1 or PD-L1 (e.g., an antibody targeting CTLA-4, PD-1 or PD-L1).
  • the checkpoint inhibitor targets LAG-3, TIM-3, B7-H3, B7- H4, A2aR, CD73, NKG2A, PVRIG/PVRL2, CEACAM1, CEACAM 5/6, FAK, CCL2/CCR2, LIF, CD47/SIRP ⁇ , CSF-1(M-CSF)/CSF-1R, IL-1/IL-1R3 (IL-1RAP), IL-8, SEMA4D, Ang-2, CLEVER-1, Axl, or phosphatidylserine.
  • the checkpoint inhibitor comprises or is lipilimumab, Cemiplimab, Nivolumab, Pembrolizumab, Atezolizumab, Avelumab, Durvalumab, LAG525 (IMP701), REGN3767, BI 754,091, tebotelimab (MGD013), eftilagimod alpha (IMP321), FS118, MBG453, Sym023, TSR-022, MGC018, FPA150, EOS100850, AB928, CPI-006, Monalizumab, COM701, CM24, NEO-201, Defactinib, PF-04136309, MSC-1, Hu5F9-G4 (5F9), ALX148, TTI-662, RRx-001, Lanotuzumab (MCS110), LY3022855, SNDX-6352, Emactuzumab (RG7155), Pexidartinib (PL
  • a tyrosine kinase inhibitor can be used as, or in place of, the pro-inflammatory agent of the SHP1I-PIA conjugates.
  • the tyrosine kinase inhibitors referred to herein are agents of any kind or sort that inhibits the expression or activation of tyrosine kinase.
  • the tyrosine kinase inhibitor is capable of inhibiting at least about 20% (e.g., at least 20%, 30%, 40%, or 50%) of the tyrosine kinase activity.
  • the tyrosine kinase inhibitor is capable of inhibiting at least about 20% (e.g., at least 20%, 30%, 40%, or 50%) of the tyrosine kinase expression.
  • the tyrosine kinase inhibitor specifically inhibits SHP-1 signaling.
  • Optional Linkers of the SHP1I-PIA conjugates [0204] A SHP-1 inhibitor can be directly conjugated to the pro-inflammatory agent through functional groups on the SHP-1 inhibitor and the pro-inflammatory agent. However, an optional linker can also be used to covalently link a SHP-1 inhibitor and a pro-inflammatory agent.
  • the optional linker when present, can link the pro-inflammatory agent and the SHP-1 inhibitor by attachment to a functional group on the pro-inflammatory agent at one end of the linker and attachment to a functional group on the SHP-1 inhibitor at the other end of the linker.
  • Typical functional groups for attachment include amino, hydroxy, sulfhydryl, or carboxyl groups.
  • the linker may be attached to either the pro-inflammatory agent, the SHP-1 inhibitor, or both, at a valence opened on the pro-inflammatory agent, the SHP-1 inhibitor, or both by replacement of a hydrogen, halogen, or methyl group with a bond to the linker.
  • the optional linker L A When the optional linker L A is present in the conjugate of form PIA-L A -R 1 , where PIA is a pro-inflammatory agent and R 1 is a SHP-1 inhibitor, the optional linker L A can be between 1 and 25 atoms in length. The length is 55 sf-6604130 Attorney Docket No.245162001040 defined by the chain that connects the PIA moiety to the R 1 moiety. ; there may be other substituents that define shorter chains.
  • linker where the bonds crossed by a wavy line indicate where the linker attached to the PIA moiety on one end and the R 1 moiety on the other end, has a length of 9, from the first carbon marked with asterisk * to the second carbon marked with asterisks **.
  • the linker can comprise any number of carbon atoms and heteroatoms, such as N, O, or S.
  • PEG linkers such as –(CH 2 CH 2 O) n - or –(OCH 2 CH 2 ) n - , where n is between 1 and 8 inclusive, are useful linkers.
  • PEG compounds terminated with functional groups such as hydroxy groups, amino groups, and carboxy groups are commercially available and can be readily used in synthesis.
  • L A is –(CH 2 CH 2 O) n - or –(OCH 2 CH 2 ) n -, where n is an integer between 1 and 8 inclusive
  • a PEG compound of the form OH–(CH2CH2O)n-H or HO 2 C–(OCH 2 CH 2 ) n -NH 2 can be used to connect to appropriate functional groups on the pro-inflammatory agent or SHP-1 inhibitor.
  • L A can be C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, or heteroalkyl containing between two to twelve chain atoms total and one, two, or three chain atoms selected from the group consisting of N, O, and S, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl are optionally substituted with one, two, or three R A groups, where R A is C1-C4 alkyl, -OH, -O-C1-C6, oxo, F, Cl, Br, I, -CN, or -NO2.
  • R A wide variety of functional groups may be present on the reagent used to form the LA group.
  • sebacic acid HO 2 C-(CH 2 ) 8 -CO 2 H
  • L A can be composed of multiple regions, such as when L A is L 1 -L 2 -L 3 , where: L 1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or heteroalkyl containing between two to eight chain atoms total and one, two, or three chain atoms selected from the group consisting 56 sf-6604130 Attorney Docket No.245162001040 of N, O, and S, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl are optionally substituted with one, two, or three R A groups; L 2 is C3-C8 cycloalkyl, C6-C10 aryl, three-to-twelve-membered heterocyclyl, or five-to- twelve-membered heteroaryl, wherein the cycloalkyl or heterocyclyl are optionally substituted with one, two, or three R A groups, and the aryl or hetero
  • L A linkers include: , wherein the wavy bonds indicate the bonds attaching L A to the remainder of the molecule.
  • Additional examples of chemistry that can be used to form linkers between various functional groups on different molecules can be found in publications such as “Chemistry of Protein and Nucleic Acid Cross-Linking and Conjugation” by Shan S. Wong and David M. Jameson (CRC Press: Boca Raton, Florida, USA, 2012), and Bargh et al., Chem. Sci., 2020, 11, 2375–2380.
  • SHP-1 inhibitors of the SHP1I-PIA conjugates are agents of any kind or sort that inhibit the expression or activation of SHP-1.
  • the SHP-1 inhibitor directly targets SHP-1.
  • the SHP-1 inhibitor targets a molecule involved in SHP-1 signaling pathway in macrophages that is distinct from SHP-1.
  • the SHP-1 inhibitor is capable of inhibiting at least about 20% (e.g., at least 20%, 30%, 40%, or 50%) of the SHP-1 activity.
  • the SHP-1 inhibitor is capable of inhibiting at least about 20% (e.g., at least 20%, 30%, 40%, or 50%) of the SHP-1 expression.
  • the SHP-1 inhibitor is selected from the group consisting of a small molecule, a nucleic acid (e.g., a siRNA, a shRNA, an antisense RNA, a microRNA), a protein agent (e.g., an antibody agent that targets SHP-1 or activated SHP-1, e.g., a dominant negative SHP-1 or a constitutively active SHP-1 mutant), a protein agent that contains a SH2 domain (by competing for binding to ITIM motif so to inhibit SHP-1 activation), and an agent that inhibits a tyrosine kinase or SHP-1 signaling (“TK/SHP-1 inhibitor”), such as a tyrosine kinase inhibitor that inhibits ITIM phosphorylation.
  • TK/SHP-1 inhibitor an agent that inhibits a tyrosine kina
  • the SHP-1 inhibitor does not significantly inhibit SHP-2 (e.g., does not inhibit the SHP-2 activity more than 50%, 40%, 30%, or 20%). [0221] In some embodiments, the SHP-1 inhibitor also inhibits SHP-2. [0222] In some embodiments, the SHP-1 inhibitor has a half-life of no more than about 10, 9, 8, or 7 days (e.g., a half-life of no more than about 7, 6, 5, 4, 3, 2 or 1 day). [0223] In some embodiments, the SHP-1 inhibitor is effective in inhibiting more than 50% of the SHP-1 activity for no more than about 10, 9, 8, 7, 6, or 5 days.
  • the SHP-1 inhibitor is effective in inhibiting more than 50% of the SHP-1 activity for no more than 4, 3, 2 or 1 day.
  • the SHP-1 inhibitor is a covalent inhibitor.
  • the SHP-1 inhibitor is a noncovalent inhibitor.
  • the SHP-1 inhibitor is a competitive inhibitor.
  • the SHP-1 inhibitor is Phomoxanthone A (PXA) or Phomoxanthone B (PXB). See e.g., Yang et al., ACS Omega.
  • the SHP-1 inhibitor targets the catalytic site.
  • the SHP-1 inhibitor binds to the catalytic site (e.g., covalently or competitively binds to the catalytic site).
  • Exemplary catalytic site inhibitors include TPI-1 or TPI analogs such as those shown in Kundu et al. (e.g., TPI-1a1-10). See J Immunol. 2010 Jun 1; 184(11): 6529–6536.
  • SHP-1 inhibitors e.g., SHP-1 inhibitors targeting the catalytic site
  • recombinant protein of SHP- 1 catalytic domain can be used to screen and identify SHP-1 inhibitors that target the catalytic site.
  • SHP-1 inhibition activities can be evaluated with various methods such as rapid SHP-1 PTP assay. See “materials and methods” in Kundu et al. [0227]
  • the SHP-1 inhibitor targets the allosteric or regulatory site. See e.g., Wang et al. J Cell Biochem. 2011 Aug; 112(8): 2062–2071 for the structure of SHP-1.
  • the SHP-1 inhibitor is TPI-1, a derivative thereof or an analog thereof.
  • Exemplary analogs include those disclosed in Kundu et al. (J Immunol. 2010 Jun 1; 184(11): 6529–6536.) See, e.g., FIG. 6 of Kundu et al.
  • the SHP-1 inhibitor comprises TPI-1.
  • the SHP-1 inhibitor is PTP-I.
  • the SHP-1 inhibitor is vitamin E.
  • the SHP-1 inhibitor is tocofersolan (TPGS).
  • the SHP-1 inhibitor is ⁇ - tocopherol acetate ( ⁇ TA).
  • the SHP-1 inhibitor is ⁇ -tocopheryl succinate ( ⁇ TOS). In some embodiments, the SHP-1 inhibitor is a tocopherol. In some embodiments, the SHP-1 inhibitor is alpha-tocopherol. In some embodiments, the SHP-1 inhibitor is beta-tocopherol. In some embodiments, the SHP-1 inhibitor is gamma- tocopherol. In some embodiments, the SHP-1 inhibitor is delta-tocopherol. In some embodiments, the SHP-1 inhibitor is a tocotrienol. In some embodiments, the SHP-1 inhibitor is alpha-tocotrienol. In some embodiments, the SHP-1 inhibitor is beta-tocotrienol.
  • ⁇ TOS ⁇ -tocopheryl succinate
  • the SHP-1 inhibitor is gamma-tocotrienol. In some embodiments, the SHP-1 inhibitor is delta-tocotrienol. [0232] In some embodiments, the SHP-1 inhibitor is phomoxanthone A (PXA). [0233] In some embodiments, the SHP-1 inhibitor is PKC-theta activator (such as PMA). [0234] In some embodiments, the SHP-1 inhibitor is a siRNA or a shRNA that inhibits or knocks down the amount of endogenous SHP-1 protein. See e.g., WO2009/023333.
  • the SHP-1 inhibitor is a dominant negative SHP-1 or a constitutively active SHP-1 mutant. See e.g., WO2009/023333.
  • the SHP-1 inhibitor is a chemical inducer of dimerization. See e.g., Buck et al., ACS Omega. 2022 Apr 11;7(16):14180-14188.
  • the SHP-1 inhibitor is SB8091. See, e.g., Kim et al., Cancer Res (2024) 84 (6_Supplement): 1183.
  • a useful SHP-1 inhibitor is 2-(2,5-dichlorophenyl)benzoquinone: which is also referred to as 2-(2,5-dichlorophenyl)cyclohexa-2,5-diene-1,4-dione, Tyrosine Phosphatase Inhibitor 1 or TPI-1; CAS Registry No. 79756-69-7.
  • TPI-1 can be derivatized with a functional group for facile attachment to a pro- inflammatory compound, or to a linker to a pro-inflammatory compound.
  • a carboxyl group can be introduced at the 3-position of the dichlorophenyl ring to provide: 61 sf-6604130 Attorney Docket No.245162001040 which can be readily coupled to an amino or hydroxy group on a linker or on a pro- inflammatory compound.
  • Derivatives and analogs of TPI-1 include compounds of the following structure: where R C is R CA or -C1-C4 alkyl-R CA , where R CA is -COOH, -NH2, or -OH; or a pharmaceutically acceptable salt thereof. [0240]
  • Various methods for preparing TPI-1 analogs are available.
  • an R C -substituted 2,5-dichloroaniline is suitably protected on its R C group (the protected R C group is indicated as R CP in the scheme below). Then the amino group is converted to the corresponding diazonium ion and coupled with quinone to give the TPI-1 scaffold.
  • R C group is indicated as R CP in the scheme below.
  • the amino group is converted to the corresponding diazonium ion and coupled with quinone to give the TPI-1 scaffold.
  • An example of the experimental conditions that can be adapted for this reaction is shown in the synthesis in Jones et al., Journal of Organic Chemistry 58(8):2035 (1993) for 2-(4- carboxyphenyl)-3,6-dichloro-2,5-cyclohexadiene-1,4-dione. The Jones et al.
  • reaction can be adapted to preparation of carboxylic acid-functionalized TPI-1 derivatives by replacing the 2,5-dichloro-2,5-cyclohexadiene-1,4-dione reagent with 1,4-benzoquinone, and replacing the 4-aminobenzoic acid reagent with 2-amino-3,6-dichlorobenzoic acid, 3-amino-3,6- dichlorobenzoic acid, or 4-amino-3,6-dichlorobenzoic acid, to yield 2-(2-carboxy-3,6- dichlorophenyl)-2,5-cyclohexadiene-1,4-dione, 2-(5-carboxy-3,6-dichlorophenyl)-2,5- cyclohexadiene-1,4-dione, or 2-(4-carboxy-3,6-dichlorophenyl)-2,5-cyclohexadiene-1,4- dione, respectively.
  • 2-amino-3,6-dichlorobenzoic acid can be replaced by 2-(2-amino-3,6-dichlorophenyl)acetic acid, 3-(2-amino-3,6- dichlorophenyl)propanoic acid, etc., and similarly for the other positional isomers.
  • Deprotection affords the TPI-1 analog ready for conjugation to a linker or PIA.
  • the amino group is converted to a halide through a diazonium intermediate using t-butyl nitrite and copper halide (CuX 2 , e.g., CuBr 2 ) (Sandmeyer reaction).
  • CuX 2 t-butyl nitrite and copper halide
  • Pd-catalyst and 2,5-dimethoxyphenyl boronic acid provides the biaryl structure of TPI-1.
  • Oxidative conditions, such as ceric ammonium nitrate, give the quinone. Deprotection affords the TPI-1 analog ready for conjugation to a linker or PIA.
  • 63 sf-6604130 Attorney Docket No.245162001040 .
  • 64 sf-6604130 Attorney Docket No.245162001040 [0242]
  • TPI-1 can also be used in perdeuterated form.
  • the compound can be conjugated to a pro-inflammatory agent, either directly or through a linker.
  • Perdeuterated TPI-1 derivatives can be prepared by using appropriately deuterated compounds in the synthetic preparations of the TPI-1 derivatives disclosed herein.
  • the individual has a solid tumor. In some embodiments, the individual has a hematologic cancer. [0244] In some embodiments, the individual has an advanced cancer. In some embodiments, the individual has a late stage cancer. In some embodiments, the individual has a malignant cancer. In some embodiments, the individual has a cancer that is in stage II, III or IV. In some embodiments, the individual has an inoperable tumor and/or metastases. In some embodiments, the individual is a terminally ill individual.
  • the individual has been subjected (e.g., within 1, 2, 4, 8, 12, 16, 20, or 24 hours, e.g., within 1, 2, 3, 4, 5, 6 or 7 days before the administration of the SHP1I-PIA conjugate) to a therapy that induces an inflammation reaction or an immunogenic 65 sf-6604130 Attorney Docket No.245162001040 cell death (e.g., radiotherapy).
  • a therapy that induces an inflammation reaction or an immunogenic 65 sf-6604130 Attorney Docket No.245162001040 cell death (e.g., radiotherapy).
  • the individual is to be subjected to (e.g., within 1, 2, 4, 8, 12, 16, 20, or 24 hours, e.g., within 1, 2, 3, 4, 5, 6 or 7 days after the administration of the SHP1I-PIA conjugate) a therapy that induces an inflammation reaction or an immunogenic cell death (e.g., radiotherapy).
  • a therapy that induces an inflammation reaction or an immunogenic cell death e.g., radiotherapy.
  • the individual has been subjected (e.g., within 1, 2, 4, 8, 12, 16, 20, or 24 hours, e.g., within 1, 2, 3, 4, 5, 6 or 7 days before the administration of the SHP1I-PIA conjugate) to a pro-inflammatory agent (such as any of the pro-inflammatory agents described herein).
  • a pro-inflammatory agent such as any of the pro-inflammatory agents described herein.
  • the individual is to be subjected to (e.g., within 1, 2, 4, 8, 12, 16, 20, or 24 hours, e.g., within 1, 2, 3, 4, 5, 6 or 7 days after the administration of the SHP1I-PIA conjugate) a pro-inflammatory agent (such as any of the pro-inflammatory agents described herein).
  • a pro-inflammatory agent such as any of the pro-inflammatory agents described herein.
  • the individual does not have an autoimmune disease.
  • the individual is a female.
  • the individual is a male.
  • the individual is a human.
  • the individual is at least about 50, 55, 60, 65, 70 or 75 years old.
  • the individual is selected for treatment based upon a high expression level and/or a high activation level of SHP-1 in the tumor tissue.
  • the individual has a high expression level and/or a high activation level of SHP-1 when the expression level and/or the activation level is at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, or 200% more than a reference expression level and/or a reference activation level of SHP-1.
  • the individual has a high expression level and/or a high activation level of SHP-1 when the expression level and/or the activation level is at least about 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 500-fold, or 1000-fold more than a reference expression level and/or a reference activation level of SHP-1.
  • the reference expression level or the reference activation level of SHP-1 is the corresponding expression or activation level of SHP-1 in a reference state, wherein the individual is not treated with a pro-inflammatory agent (or any immune therapy).
  • the individual is at risk of developing systemic inflammation and/or CRS.
  • the individual develops systemic inflammation and/or 66 sf-6604130 Attorney Docket No.245162001040 CRS prior to the administration of an agent that reduces systemic inflammation.
  • Cytokine release syndrome can damage or cause organ failure in most organ systems.
  • organs that can become damaged due to CRS may include, but are not limited to, the lungs, the kidneys, the liver, the brain, the heart, the spleen, or any combination thereof, for example multi-organ failure.
  • the individual is administered an agent that reduces systemic inflammation.
  • the administration occurs prior to the development of systemic inflammation in the individual.
  • the individual develops mild cytokine release syndrome.
  • the individual develops CRS of grade 1.
  • Mild symptoms of CRS can include fever, fatigue, headache, rash, arthralgia, and myalgia.
  • Mild CRS can be treated by treating the symptoms or by administration of anti-inflammatory drugs such as corticosteroids. Mild CRS can often be resolved within one to two weeks and does not require or necessitate hospitalization.
  • the individual does not develop severe cytokine release syndrome.
  • the individual does not develop CRS of grade 2.
  • the individual does not develop CRS of grade 3.
  • the individual does not develop CRS of grade 4. More severe cases are characterized by hypotension and high fever, and severe CRS can progress to an uncontrolled systemic inflammatory response with vasopressor-requiring circulatory shock, vascular leakage, disseminated intravascular coagulation, and multi-organ system failure. More severe cases of CRS often require hospitalization of symptoms. Laboratory abnormalities that are common in patients with CRS include cytopenias, elevated creatinine and liver enzymes, deranged coagulation parameters, and a high CRP. There are four grading systems currently used for cytokine release syndrome, as shown in Table 1 below. See, e.g., Liu, D. and Zhao, J., J Hematol Oncol.
  • the individual has developed CRS prior to administration of an agent that reduces systemic inflammation.
  • the individual has developed CRS of grade 1.
  • the individual has developed CRS of grade 2.
  • the individual has developed CRS of grade 3.
  • the individual has developed CRS of grade 4.
  • the individual who has developed CRS is administered an agent that reduces systemic inflammation.
  • the agent that reduces systemic inflammation 67 sf-6604130 Attorney Docket No.245162001040 ameliorates, eliminates, or reverses the CRS, including organ damage, for example pro- inflammatory organ damage (e.g., nephritis, hepatitis, pneumonitis, myocarditis, appendicitis).
  • organ damage for example pro- inflammatory organ damage (e.g., nephritis, hepatitis, pneumonitis, myocarditis, appendicitis).
  • Table 1 Cytokine release syndrome medical grading systems.
  • Cancer as described herein can be any type or kind.
  • the cancer is a solid tumor.
  • the cancer is a hematologic cancer.
  • the cancer is an advanced cancer.
  • the cancer is a late stage cancer.
  • the cancer is a terminal cancer.
  • the cancer is in stage II, III or IV. In some embodiments, the cancer is an inoperable tumor and/or is malignant. [0258] In some embodiments, the tumor is at least 0.2cm, 0.4cm, 0.6cm, 0.8cm, 1cm, 2 cm, 3cm, 4cm or 5cm in its longest length.
  • cancers described herein include, but are not limited to, adrenocortical carcinoma, agnogenic myeloid metaplasia, AIDS-related cancers (e.g., AIDS-related lymphoma), anal cancer, appendix cancer, astrocytoma (e.g., cerebellar and cerebral), basal 69 sf-6604130 Attorney Docket No.245162001040 cell carcinoma, bile duct cancer (e.g., extrahepatic), bladder cancer, bone cancer, (osteosarcoma and malignant fibrous histiocytoma), brain tumor (e.g., glioma, brain stem glioma, cerebellar or cerebral astrocytoma (e.g., pilocytic astrocytoma, diffuse astrocytoma, anaplastic (malignant) astrocytoma), malignant glioma, ependymoma, oligodenglio
  • the cancer is a virus-infection-related cancer.
  • the cancer is a human papillomavirus (HPV)-related cancer (e.g., HPV-related cervical cancer, e.g., HPV-related head and neck cancer, e.g., HPV related squamous cell carcinoma).
  • HPV human papillomavirus
  • the cancer is human herpes virus 8 (HHV8) related cancer (e.g., Kaposi sarcoma).
  • the cancer is human T-lymphotrophic virus (HTLV-1)-related cancer (e.g., adult T cell leukemia or lymphoma).
  • the cancer is Epstein-Barr virus (EBV) related cancer (e.g., Burkitt lymphoma, Hodgkin’s and non-Hodgkin’s lymphoma, stomach cancer).
  • EBV Epstein-Barr virus
  • the cancer is hepatitis B virus (HBV) related cancer (e.g., liver cancer).
  • HBV hepatitis B virus
  • the cancer is hepatitis C virus) related cancer (e.g., liver cancer, non-Hodgkin’s lymphoma).
  • the cancer is a liver cancer, a kidney cancer, an endometrial cancer, a thymic epithelial neoplasma, lung cancer, spindle cell sarcoma, chondrosarcoma, uterine smooth muscle, colon cancer, or pancreatic cancer.
  • the cancer has been subjected to and/or failed one or more prior therapy (e.g., an immune checkpoint blockage therapy (e.g., a PD-1 antibody), a chemotherapy, a surgery, a cell therapy (e.g., an allogenic NK cell infusion therapy)).
  • the cancer is a recurrent or refractory cancer.
  • the cancer is refractory to one or more of irradiation therapy, chemotherapy, or immunotherapy (e.g., checkpoint blockade).
  • irradiation therapy e.g., chemotherapy
  • immunotherapy e.g., checkpoint blockade
  • Dosing, Method of Administration, and Delivery Vehicles [0265] The SHP1I-PIA conjugates described herein can be administered at any desired dosage.
  • the size of the dose of the SHP1I-PIA conjugate is determined based on one or more criteria such as disease burden in the subject, such as tumor load, bulk, size, or degree, extent, or type of metastasis, stage, and/or likelihood or incidence of the subject developing toxic outcomes, e.g., CRS, macrophage activation syndrome, tumor lysis syndrome, neurotoxicity, and/or a host immune response against the activated immune cells being administered.
  • the amount of SHP1I-PIA conjugate 71 sf-6604130 Attorney Docket No.245162001040 administered in the dose is determined based on the tumor burden that is present in the subject immediately prior to administration of the SHP1I-PIA conjugate.
  • the SHP1I-PIA conjugate can be administered by any suitable means, for example, by bolus infusion, by injection, e.g., intravenous or subcutaneous injections.
  • the SHP1I-PIA conjugate is administered systemically (e.g., intravenously, subcutaneously, or intraperitoneally).
  • the SHP1I-PIA conjugate is administered locally (e.g., intratumorally).
  • the SHP1I-PIA conjugate is administered by parenteral, intrapulmonary, and intranasal, and, if desired for local treatment, intralesional, intratumoral, or topical administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, topical, or subcutaneous administration.
  • the SHP1I-PIA conjugate is administered orally.
  • the SHP1I-PIA conjugates described herein can be delivered via any proper vehicles or methods.
  • the SHP1I-PIA conjugate is directly delivered into the tumor tissue. Different carrier systems can be utilized for this purpose. See e.g., Manzari et al. Targeted drug delivery strategies for precision medicines. Nat Rev Mater 6, 351–370 (2021); Tewabe et al., J Multidiscip Healthc. 2021; 14: 1711–1724.
  • the SHP1I-PIA conjugate is delivered via a nanoparticle. In some embodiments, the SHP1I-PIA conjugate is delivered via a controlled release system. In some embodiments, the SHP1I-PIA conjugate is delivered via a biomaterial implant scaffold. In some embodiments, the SHP1I-PIA conjugate is delivered via an injectable biomaterial scaffold. In some embodiments, the SHP1I-PIA conjugate is delivered via a transdermal delivery system. See e.g., Riley et al., Nat Rev Drug Discov. 2019 Mar; 18(3): 175–196. [0269] In some embodiments, the SHP1I-PIA conjugate is associated with an antibody construct.
  • the SHP1I-PIA conjugate is connected with an antibody construct with via a linker (e.g., a cleavable linker).
  • the antibody construct specifically recognizes a tumor associated antigen.
  • the antibody construct comprises an antibody recognizing a tumor antigen.
  • the antibody construct is an antibody drug conjugate (ADC).
  • ADC antibody drug conjugate
  • the SHP1I-PIA conjugate is delivered via a method or device that promotes delivery into a particular organ (e.g., the organ that has a tumor).
  • the SHP1I-PIA conjugate is delivered via a controlled drug delivery system (e.g., a slow release system or vehicle, e.g., a sustained release system or vehicle). Examples of such systems can be found in e.g., Adepu et al., Molecules.
  • a controlled drug delivery system e.g., a slow release system or vehicle, e.g., a sustained release system or vehicle. Examples of such systems can be found in e.g., Adepu et al., Molecules.
  • compositions comprising the SHP1I-PIA conjugate
  • compositions comprising the SHP1I-PIA conjugate for treatment as described above.
  • a composition comprising a SHP1I-PIA conjugate (e.g., where the SHP-1 inhibitor of the conjugate is TPI-1 or an analog or a derivative thereof, and the pro-inflammatory agent of the conjugate is any of the pro-inflammatory agents described herein).
  • the composition further comprises a pharmaceutically acceptable carrier.
  • a composition e.g., a pharmaceutical composition
  • a SHP1I-PIA conjugate e.g., where the SHP-1 inhibitor of the conjugate is TPI-1 or an analog or a derivative thereof, and the pro-inflammatory agent of the conjugate is a TLR agonist (e.g., CpG, polyI:C and/or R848).
  • the composition further comprises a pharmaceutically acceptable carrier.
  • composition comprising a SHP1I-PIA conjugate (e.g., where the SHP-1 inhibitor of the conjugate is TPI-1 or an analog or a derivative thereof, and the pro-inflammatory agent of the conjugate is a STING activator (e.g., cGAMP, e.g., 2’3’-cGAMP, e.g., 3’3’-cGAMP)).
  • STING activator e.g., cGAMP, e.g., 2’3’-cGAMP, e.g., 3’3’-cGAMP
  • the composition further comprises a pharmaceutically acceptable carrier.
  • a composition comprising a SHP1I-PIA conjugate (e.g., where the SHP-1 inhibitor of the conjugate is TPI-1 or an analog or a derivative thereof, and the pro-inflammatory agent of the conjugate is a chemotherapeutic agent (e.g., azathioprine (AZA), e.g., gemcitabine)).
  • the composition further comprises a pharmaceutically acceptable carrier.
  • a composition comprising a SHP1I-PIA conjugate (e.g., where the SHP-1 inhibitor of the conjugate is TPI-1 or an analog or a derivative thereof, and the pro-inflammatory agent of the conjugate is a pro-inflammatory cytokine (e.g., IL-1b, IL-18, IL-6, and/or TNF ⁇ )).
  • the composition further comprises a pharmaceutically acceptable carrier.
  • compositions comprising a SHP1I-PIA conjugate (e.g., where the SHP-1 inhibitor of the conjugate is TPI-1 or an analog or a derivative thereof, and the pro-inflammatory agent of the conjugate is a checkpoint inhibitor (e.g., an anti-PD-L1 antibody, an anti-PD-1 antibody or an anti-CLTA4 antibody)).
  • the composition further comprises a pharmaceutically acceptable carrier.
  • composition comprising a SHP1I-PIA conjugate (e.g., where the SHP-1 inhibitor of the conjugate is TPI-1 or an analog or a derivative thereof, and the pro-inflammatory agent of the conjugate is a bacterial component (e.g., LPS)).
  • the composition further comprises a pharmaceutically acceptable carrier.
  • the composition further comprises a pharmaceutically acceptable carrier.
  • composition comprising a SHP1I-PIA conjugate (e.g., where the SHP-1 inhibitor of the conjugate is TPI-1 or an analog or a derivative thereof, and the pro-inflammatory agent of the conjugate is an agent that promotes immunogenic cell death (ICD)).
  • the composition further comprises a pharmaceutically acceptable carrier.
  • a composition comprising a SHP1I-PIA conjugate (e.g., where the SHP-1 inhibitor of the conjugate is TPI-1 or an analog or a derivative thereof, and the pro-inflammatory agent of the conjugate is a PAMP/DAMP activator (such as any of the PAMP/DAMP activators described herein)).
  • the composition further comprises a pharmaceutically acceptable carrier.
  • 74 sf-6604130 Attorney Docket No.245162001040
  • the SHP1I-PIA conjugates described herein can be prepared by a variety of synthetic methods.
  • PG is a protecting group (such as t-butyl)
  • Coupling reagents such as O-(7-azabenzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC or DIC), or benzotriazol-1- 76 sf-6604130 Attorney Docket No.245162001040 yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) can be used as coupling agents, in conjunction with the hindered bases
  • intermediate S1-3 which can then be deprotected to form intermediate S1-4 with a free carboxyl group.
  • carboxyl group of intermediate S1-4 can then be reacted with a nucleophile, such as the resiquimod derivative 1-[2-(2-aminoethoxy)-2-methylpropyl]-2-(ethoxymethyl)imidazo[4,5-c]quinolin-4-amine S1-5, for example by using the previously mentioned coupling reagents, to give the SHP1I- PIA conjugate S1-6.
  • a nucleophile such as the resiquimod derivative 1-[2-(2-aminoethoxy)-2-methylpropyl]-2-(ethoxymethyl)imidazo[4,5-c]quinolin-4-amine S1-5, for example by using the previously mentioned coupling reagents, to give the SHP1I- PIA conjugate S1-6.
  • Coupling reagents such as O-(7-azabenzotriazol-1-yl)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)- N,N,N’,N’- tetramethyluronium tetrafluoroborate (TBTU), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC or DIC), or benzotriazol-1- 78 sf-6604130 Attorney Docket No.245162001040 yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) can be used as coupling agents, in conjunction with the hinder
  • intermediate S1-3 which can then be deprotected to form intermediate S1-4 with a free carboxyl group.
  • carboxyl group of intermediate S1-4 can then be reacted with a nucleophile, such as the resiquimod derivative 1-[2-(2- aminoethoxy)-2-methylpropyl]-2-(ethoxymethyl)imidazo[4,5-c]quinolin-4-amine S1-5, for example by using the previously mentioned coupling reagents, to give the SHP1I-PIA conjugate S1-6.
  • a nucleophile such as the resiquimod derivative 1-[2-(2- aminoethoxy)-2-methylpropyl]-2-(ethoxymethyl)imidazo[4,5-c]quinolin-4-amine S1-5, for example by using the previously mentioned coupling reagents, to give the SHP1I-PIA conjugate S1-6.
  • HATU hexafluorophosphate azabenzotriazole tetramethyl uronium
  • DIPEA diisopropylethylamine
  • DMF dimethylformamide
  • 1-2 the alcohol t-butyl 4-hydroxybutanoate (1-2) is added.
  • the reaction proceeds for 30 minutes to form 4-(t-butoxy)-4-oxobutyl 2,5-dichloro-2',5'-dioxo-2',5'-dihydro-[1,1'-biphenyl]-3- carboxylate (1-3).
  • Compound (2-4) is then activated using 1.25 eq. HATU and 2.4 eq. DIPEA in DMF at room temperature for 15 minutes, followed by addition of 81 sf-6604130 Attorney Docket No.245162001040 nucleophile (2-5) (1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5- c]quinolin-4-amine) (1.05 eq).
  • Example S-4 Alternative procedure for preparation of Perdeuterated 2-(2,5-Dichlorophenyl)-1,4- Benzoquinone [0292] An alternative procedure for preparing 2-(2,5-dichlorophenyl)-1,4-benzoquinone-d6 is adapted from Termentzi A. et al., European Journal of Medicinal Chemistry 45 (2010) 5833- 5847.
  • This procedure utilizes a diazotized intermediate.
  • the starting materials for the reaction are 2,5-dichloroaniline-3,4,6-d3 (CAS Registry No. 783321-80-2, available from Clearsynth) and 1-4 benzoquinone-d4.
  • 83 sf-6604130 Attorney Docket No.245162001040 [0293]
  • a solution of NaNO 2 in water is added to a solution of 2,5-dichloroaniline-3,4,6-d3 in 9% aqueous hydrochloric acid solution and is stirred at 0°C to 5°C for 90 minutes to form the diazonium salt.
  • Examples B1 and B2 describe experiments using R848-TPI-1 Ester and Amide conjugates chemically formed by linking the TLR7/8 agonist R848 with TPI-1 through an Ester or Amide bond.
  • Examples B3-B5 describe perdeuterated TPI-1 (dTPI-1) assayed in vitro for the capability to inhibit SHP-1 in macrophages within a tumor environment, and the ability to unleash proinflammatory responses in vivo in the TME when combined with TLR agonists (e.g. R848, LPS, PolyI:C, etc.), Sting activators (e.g. MSA-2, ADU-S100, cGAMP), as well as other inflammatory factors or means, thereby inducing intratumoral antigen presentation and activation of T cell immunity against cancer.
  • TLR agonists e.g. R848, LPS, PolyI:C, etc.
  • Sting activators e.g. MSA-2, ADU-S100, cGAMP
  • other inflammatory factors or means thereby inducing intratumoral antigen presentation and activation of T cell immunity against cancer.
  • Example B-1 In vitro testing R848-TPI-1 Ester and Amide conjugates for proinflammatory activation of macrophages in a cancer environment [0295] Human monocytes-derived macrophages were treated with R848-TPI-1 Ester and Amide conjugates (1 ⁇ M each), in the absence or presence of ovarian cancer cells (OVCAR5). Parallel treatments were performed using non-conjugated compounds R848 and TPI-1 (1 ⁇ M each) to compare their effects to Ester Conjugate (Compound 1-6 of Example S-1) and Amide Conjugate (Compound 2-6 of Example S-2). The presence of cancer cells (OVCAR5) serves to ligate macrophage iRs and activate SHP-1, which drives negative regulation to suppress proinflammatory response.
  • FIG. 5 Human monocytes-derived macrophages were treated with R848-TPI-1 Ester and Amide conjugates (1 ⁇ M each), in the absence or presence of ovarian cancer cells (OVCAR5). Parallel treatments were performed using non-conjugated compounds R
  • FIG. 1A shows the study system: human monocyte- derived macrophages surrounded with cancer cells (OVCAR5) were treated with either monomers of R848 ⁇ TPI-1 or Ester (Compound 1-6) or Amide (Compound 2-6) conjugated R848-TPI-1 compounds.
  • FIG. 1B shows schematics of R848 and TPI-1 monomers and ester conjugate and amide conjugated R848-TPI-1 compounds. [0296] Results are in FIGS. 1C-1E.
  • FIG. 1A shows the study system: human monocyte- derived macrophages surrounded with cancer cells (OVCAR5) were treated with either monomers of R848 ⁇ TPI-1 or Ester (Compound 1-6) or Amide (Compound 2-6) conjugated R848-TPI-1 compounds.
  • FIG. 1B shows schematics of R848 and TPI-1 monomers and ester conjugate and amide conjugated R848-TPI-1 compounds.
  • FIG. 1C shows the results of assaying macrophage proinflammatory (TNF ⁇ and IL-6) or anti-inflammatory (IL-10) response stimulated by R848 ⁇ TPI-1, or Ester and Amide conjugated R848-TPI-1 compounds, in the absence and the presence of cancer cells.
  • Ester and Amide conjugated R848-TPI-1 compounds resembled R848 + TPI-1, capable of skewing macrophages toward proinflammatory direction with high production of TNF ⁇ and IL-6 and low IL-10 even in the presence of cancer cell ligation.
  • FIG. 1C shows the results of assaying macrophage proinflammatory (TNF ⁇ and IL-6) or anti-inflammatory (IL-10) response stimulated by R848 ⁇ TPI-1, or Ester and Amide conjugated R848-TPI-1 compounds, in the absence and the presence of cancer cells.
  • Ester and Amide conjugated R848-TPI-1 compounds resembled R848 + TPI-1, capable of skewing macrophages toward
  • FIG. 1D shows macrophage expression of cell surface antigen presentation 85 sf-6604130 Attorney Docket No.245162001040 machinery following stimulation with R848 ⁇ TPI-1, or Ester and Amide conjugated R848- TPI-1 compounds, in the absence and the presence of cancer cells.
  • treatment with Ester and Amide conjugated R848-TPI-1 resembled R848 + TPI-1 and enabled macrophages to overcome cancer cell-imposed inhibition, leading to elevation of cell surface MHC-I and – II, CD40, CD80 and CD86 expression.
  • FIG. 1E shows the dose-dependent effects of Ester and Amide conjugated R848-TPI-1 compounds on activation of macrophage production of TNF ⁇ (in FIG.
  • the amide curve is the upper curve and the ester curve is the lower curve).
  • R848 treatment induced the typical proinflammatory response in macrophages, resulting in high production of TNF ⁇ and IL-6 and low IL-10.
  • the presence of cancer cells skewed R848-induced macrophage activation towards anti-inflammatory direction with high IL-10, while diminishing TNF ⁇ and IL-6.
  • cancer cells mediated ligation of macrophage surface inhibitory receptors (iRs) and activation of SHP-1, which then mediated master negative-regulation that suppresses proinflammatory response.
  • iRs macrophage surface inhibitory receptors
  • KPC pancreatic ductal adenocarcinoma KPC pancreatic ductal adenocarcinoma.
  • KPC pancreatic ductal adenocarcinoma were established in the flank area of syngeneic mice C57BL6. After tumors were stably formed (> 200mm 3 ), mice were treated with R848-TPI-1 Ester or Amide conjugated compound daily in a dose escalation manner (FIG. 2A). Prior to treatment (3h), prophylactic anti-TNF ⁇ was given to prevent treatment- associated CRS.
  • Results are in FIG.
  • FIG. 2B-2D which show dose-dependent efficacies of R848-TPI-1 Ester and Amide conjugated compounds treating KPC pancreatic cancer.
  • FIG. 2B shows KPC tumor volume changes over time (in days) following treatments.
  • TME analyses on d2 revealed that treatments with R848-TPI-1 conjugated compounds skewed intratumoral macrophages (TAM) toward the proinflammatory phenotype with elevated expression of antigen presentation machinery, suggesting that TAM mediated antigen presentation and induced anti-cancer T cell immunity.
  • TME analyses on d5 revealed significant increases in CD8 T cells (Tc) and NK cells, while immunosuppressive components including MDSC were reduced.
  • Tc CD8 T cells
  • NK cells while immunosuppressive components including MDSC were reduced.
  • mice were treated with either with anti-PD-1 ( ⁇ PD-1, 100ug, i.p. every 3 days), or R848-TPI-1 Ester compound (3mg/kg, s.c. daily) + ⁇ PD-1, or R848-TPI-1 Amide compound (3mg/kg, s.c. daily) + ⁇ PD-1.
  • a dose of anti-TNF ⁇ was given to mice 3h before the first dose of topical therapies for prophylactic neutralization of TNF ⁇ to ameliorate treatment-associated CRS.
  • the experimental design is shown in FIG. 3A.
  • 87 sf-6604130 Attorney Docket No.245162001040 [0305] Results are shown in FIG. 3B-D.
  • FIG. 3B shows bioluminescence images of LLC tumor burden changes post treatments.
  • FIG. 3C shows that tumor volume (mm 3 ) shrunk over time post-treatment over 13 days after LLC was treated with ester-conjugated R848-TPI-1 or amide-conjugated R848-TPI-1, but not when treated with the control.
  • FIG. 3D TME analyses revealed that both Ester and Amide treatments combined with ⁇ PD-1 significantly increased CD8 T cells (Tc), which attributed to tumor elimination.
  • Tc CD8 T cells
  • Example B-3 In vitro assays of dTPI-1 for the capability to inhibit SHP-1 in macrophages within a tumor environment
  • Human monocytes-derived macrophages in culture were stimulated with TLR agonist R848 (1 ⁇ g/ml) and IFN ⁇ (40ng/ml), in the absence or the presence of human renal cancer cells (TK10) and dTPI-1.
  • the study system is shown in FIG. 4A.
  • the ratio of macrophage: TK10 1:3.
  • cells were lysed in 1% Triton containing PBS, followed by assaying protein tyrosine phosphatase activity in supernatants using pNPP as the substrate.
  • FIGS. 4B-4E Results are shown in FIGS. 4B-4E.
  • FIG. 4A shows the study system. Human monocyte-derived macrophages without or with cancer cells surrounding were stimulated with TLR agonist (aTLR) R848 and IFN ⁇ ⁇ dTPI-1.
  • TLR agonist aTLR
  • FIG. 4B shows the results of protein tyrosine phosphatase (PTP) activity assays. Strong SHP-1 activity (labeled) was induced in macrophages by aTLR stimulation plus cancer cell ligating macrophage iRs. As shown, 88 sf-6604130 Attorney Docket No.245162001040 dTPI-1 dose-dependently inhibited SHP-1 activity induced by aTLR with cancer cell ligation.
  • FIG. 4C shows inhibition of SHP-1 by dTPI-1 unleashed macrophage antigen presentation inhibited by the cancer environment.
  • the presence of cancer cell ligation abrogated aTLR induced macrophage antigen presentation, whereas inhibition of SHP-1 by dTPI-1 reversed it.
  • FIG. 4D shows inhibition of SHP-1 by dTPI-1 also unleashed macrophage proinflammatory cytokine production inhibited by the cancer environment.
  • FIG. 4E shows the dose- dependent effect of dTPI-1 for unleashing proinflammatory cytokine (TNF ⁇ ) production.
  • mice were treated with TLR agonists (aTLR: R848 and polyI:C), dTPI-1, or aTLR and dTPI-1 combination.
  • a dose of prophylactic anti- TNF ⁇ was given to mice 3h before treatments to ameliorate treatment-associated CRS.
  • FIG. 5A shows the experimental scheme.
  • Results are shown in FIG. 5B, which are lung images of melanoma prior to treatment (d12) and after different treatments. None of the single treatment with either R848 or dTPI-1 suppressed melanoma progression. However, the combination of R848 or dTPI-1 effectively controlled the disease, even inducing regression of melanoma in lungs.
  • Murine lung cancer (LLC-luc) was engrafted into syngeneic C57BL6 mice in a multi- point cutaneous/subcutaneous manner into the dorsal skinfold. Lung cancer lesions were formed in 10-15 days and were traced by bioluminescence imaging. Topical and/or systemic treatments started when tumors were well formed.
  • FIG. 6A shows the experimental design. The treatments include: 89 sf-6604130 Attorney Docket No.245162001040 Control treatment (ctl.); mice were given topical non-drug lotion (vehicle) only.
  • ⁇ PD-1; anti-PD-1 mAb (100 ⁇ g, i.p., once every 3 days) was given to mice with topical non-drug lotion treatment.
  • TLR agonists Resiquimod (R848) and PolyI:C, together with dTPI-1 were prepared in Johnson’s lotion, each at 100 ⁇ g/ml, topical application 2x per day, each 100-200 ⁇ l lotion.
  • Anti- PD-1 mAb (100 ⁇ g, i.p., once every 3 days) Topical treatments with Stine activators (aSting) + dTPI-1 + ⁇ PD-1.
  • Stine activators including MSA-2, ADU-S100 and cGAMP were prepared in Johnson’s lotion, each at 5mg/ml , together with dTPI-1 prepared at 100 ⁇ g/ml in lotion, were given as topical application, 2x per day, each 100-200 ⁇ l lotion.
  • a dose of anti-TNF ⁇ was given to mice 3h before the first dose of topical therapies for prophylactic neutralization of TNF ⁇ to ameliorate treatment-associated CRS.
  • Results are shown in FIGS. 6B-6D.
  • FIG. 6B are bioluminescence images that show that LLC tumor burden changes post treatment. In FIGS.
  • TME analyses revealed that aTLR+dTPI-1 or aStine+TPI-1 treatments skewed intratumoral macrophages toward the proinflammatory phenotype with elevated expression of antigen presentation machinery (FIG. 6C), resulting in increased CD8 T cells (Tc) and reduction of MDSC in the TME (FIG. 6D) [0316]
  • LLC lung cancer strongly resisted anti-PD-1 immune checkpoint inhibitor; however, treatment to this cancer with TLR agonists or Sting activators combined with dTPI-1 achieved strong anti-cancer immunity, leading to clearance of the malignant lesions.
  • TAM intratumoral macrophages

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Abstract

La présente demande concerne des conjugués d'un inhibiteur de SHP-1, tel que TPI-1 ou un analogue ou un dérivé de celui-ci, conjugués à un agent pro-inflammatoire, tel qu'un agoniste de TLR ou un inhibiteur de point de contrôle immunitaire. La présente demande concerne également des méthodes de traitement du cancer chez un individu qui impliquent l'administration de tels conjugués d'inhibiteur de SHP-1-agent pro-inflammatoire à l'individu. L'inhibiteur de SHP-1 peut être conjugué à l'agent pro-inflammatoire directement ou par l'intermédiaire d'un lieur.
PCT/US2025/018593 2024-03-06 2025-03-05 Conjugués inhibiteurs de shp-1 avec des composés pro-inflammatoires Pending WO2025188909A1 (fr)

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