SHP-1 inhibitor conjugates with pro-inflammatory compounds

Abstract

The present application provides conjugates of a SHP-1 inhibitor, such as TPI-1 or an analog or a derivative thereof, conjugated to a pro-inflammatory agent, such as a TLR agonist or an immune checkpoint inhibitor. The present application also provides methods of treating cancer in an individual that involves administering such SHP- 1 inhibitor-pro- inflammatory agent conjugates to the individual. The SHP-1 inhibitor can be conjugated to the pro-inflammatory agent directly or through a linker.

Description

Attorney Docket No.245162001040 SHP-1 INHIBITOR CONJUGATES WITH PRO-INFLAMMATORY COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims priority benefit of United States Provisional Patent Application No. 63 / 562,140, filed March 6, 2024; United States Provisional Patent Application No. 63 / 562,133, filed March 6, 2024; United States Provisional Patent Application No. 63 / 562,250, filed March 6, 2024; and United States Provisional Patent Application No. 63 / 562,237, filed March 6, 2024. The entire contents of those applications are hereby incorporated by reference herein. FIELD OF THE INVENTION

[0002] The present invention relates to compositions and methods for treating cancer involving administering a SHP-1 inhibitor conjugated to a pro-inflammatory agent. BACKGROUND OF THE INVENTION

[0003] In cancers such as solid tumors, intratumoral myeloid leukocytes, including macrophages (i.e., tumor-associated macrophage or TAM) and myeloid-derived suppressive cells (MDSC), play critical roles in controlling the tumor microenvironment (TME) immunosuppression that supports tumor growth and also confers tumor resistance to immunotherapeutic treatments. One important mechanism by which intratumoral myeloid leukocytes adapt an immunosuppressive phenotype and strengthen their immunosuppressive capacity following tumor therapies is through their cell surface inhibitory receptors (iRs)- mediated multi-pathways of negative regulation. Phosphorylation of iRs in their cytoplasmic domain immunoreceptor tyrosine-based inhibitory motifs (ITIMs) under tumor therapies leads to activation of SHP-1, the central signal modulator, which mediates dephosphorylation and hence deactivation of a number of signal transduction molecules, resulting in diminishment of therapeutics-induced anticancer proinflammatory responses (Fig.1). In solid tumors, essential cell surface iRs, such as SIRPα, 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, conduce their regulations via activation of SHP-1, which then mediate downstream inhibition. 1sf-6604130Attorney 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-SIRPα) and their ligands (e.g., anti-CD47) are being undertaken (3-5). However, these efforts of targeting each iR or its ligand singularly, but not all inhibitory pathways at once, achieve weak-to- partial efficacies in controlling solid tumors.

[0005] The disclosures of all publications, patents, patent applications and published patent applications referred to herein are hereby incorporated herein by reference in their entirety. BRIEF SUMMARY OF THE INVENTION

[0006] The present application in one aspect provides SHP-1 inhibitors which are covalently conjugated to pro-inflammatory agents, referred to herein as “SHP1I-PIA conjugates.” The SHP-1 inhibitor of the conjugate can be directly bonded to the pro-inflammatory agent. The 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. In some embodiments, the method comprises systemically administering the SHP1I-PIA conjugate. In some embodiments, the method comprises locally (e.g., intratumorally) administering the SHP1I-PIA conjugate. In any of these embodiments, the method can comprise administering the SHP1I-PIA conjugate to the individual intermittently. In some embodiments described herein, 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. In some embodiments described herein, 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. In some embodiments, 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. In some embodiments, the SHP-1 inhibitor comprises TPI-1. 2sf-6604130Attorney 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. In some embodiments, the method comprises administering the SHP1I-PIA conjugate to the individual intermittently. In some embodiments, 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.

[0010] In some embodiments according to any of the methods described above, 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.

[0013] In some embodiments according to any one of the methods described above, the method comprises administrating the SHP1I-PIA conjugate systemically and locally, optionally wherein the method comprises intratumorally administering the SHP1I-PIA conjugate.

[0014] In some embodiments according to any of the methods described above, the systemic administration of the SHP1I-PIA conjugate comprises oral administration, intravenous administration, subcutaneous administration intraperitoneal administration, and / or local administration (e.g., topical administration). 3sf-6604130Attorney Docket No.245162001040

[0015] In some embodiments according to any of the methods described above, the method comprises intratumorally administering the SHP1I-PIA conjugate.

[0016] In some embodiments according to any of the methods described above, the method comprises administering the SHP1I-PIA conjugate to a site that is different from the site of the cancer to be treated.

[0017] In some embodiments according to any of the methods described above, the pro- inflammatory agent comprises a TLR agonist. In some embodiments, the TLR agonist activates a TLR on a macrophage. In some embodiments, the TLR comprises TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, and / or TLR9. In some embodiments, 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.

[0018] In some embodiments according to any of the methods described above, the pro- inflammatory agent comprises a bacterial component; optionally the bacterial component comprises lipopolysaccharide (LPS).

[0019] In some embodiments according to any of the methods described above, the pro- inflammatory agent comprises a STING activator. In some embodiments, the STING activator comprises 2’3’-cGAMP.

[0020] In some embodiments according to any of the methods described above, the pro- inflammatory agent comprises a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent comprises azathioprine (AZA).

[0021] In some embodiments according to any of the methods described above, the pro- inflammatory agent comprises a pro-inflammatory cytokine. In some embodiments, the pro- inflammatory cytokine comprises IL-1 family cytokines (e.g., IL-1b, IL-18), IL-6, IL-17, TNF family cytokines (e.g., TNFα), and their combination with type I and type II interferons (IFNα, IFNβ and IFNγ).

[0022] In some embodiments according to any of the methods described above, the pro- inflammatory agent comprises a checkpoint inhibitor. In some embodiments, the checkpoint inhibitor comprises an anti-PD-L1 antibody, an anti-PD-1 antibody or an anti-CLTA4 antibody. 4sf-6604130Attorney Docket No.245162001040

[0023] . In some embodiments described herein, 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. In some embodiments, 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. In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0024] In some embodiments according to any of the methods described above, the SHP1I-PIA conjugate is administered intermittently.

[0025] In some embodiments according to any of the methods described above, 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-TNFα antibody and an anti-IL6 antibody. In some embodiments, the agent that reduces systemic inflammation and / or reduces inflammatory cytokine cascade or cytokine storm is administered simultaneously with the SHP1I-PIA conjugate. In some embodiments, 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. In some embodiments, 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.

[0026] In some embodiments according to any of the methods described above, the cancer is a solid tumor.

[0027] In some embodiments according to any of the methods described above, the cancer is a hematological cancer.

[0028] In some embodiments according to any of the methods described above, the cancer is a late stage cancer. 5sf-6604130Attorney Docket No.245162001040

[0029] In some embodiments according to any of the methods described above, the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor.

[0030] In some embodiments according to any of the methods described above, the individual is a human.

[0031] 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] FIGS. 1A-1D show the results of experiments assaying Ester and Amide conjugated R848-TPI-1 compounds for activation of macrophages in the presence of a cancer environment. 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 (TNFα 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. 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 1μM. FIG. 1E shows the dose-dependent effects of Ester and Amide conjugated R848-TPI-1 compounds on activation of macrophage production of TNFα, as measured by ELISA. In FIG. 1E, the amide curve is the upper curve and the ester curve is the lower curve

[0033] FIGS. 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 × 105, s.c.) into the right flank of C57BL6 mice. After 6sf-6604130Attorney Docket No.245162001040 tumors reached 200 mm3, 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. 2C shows TME analyses of MHC-I, MHC-II, CD80, and CD86-expressing populations by flow cytometry on post-treatment d2. FIG. 2D shows TME analyses of various cell types by flow cytometry on post-treatment d5.

[0034] FIG. 3A-3D show the results of dTPI-1 treatment in a murine lung cancer model (LLC). FIG. 3A shows the experimental design. LLC lung cancer were engrafted (5 × 105, s.c.) into the right flank of C57BL6 mice. After tumor stably formed (>200 mm3), the mice were treated with anti-PD-1 (αPD-1, 100ug, i.p. every 3 days), R848-TPI-1 Ester compound (3mg / kg) + αPD-1, or R848-TPI-1 Amide compound (3mg / kg) + αPD-1. 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 αPD-1, ester-conjugated R848-TPI-1 + αPD-1, and amide-conjugated R848-TPI-1 + αPD-1.

[0035] 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 IFNγ ± 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, TNFα, and IL-10 of human monocyte-derived macrophages with or without cancer cells, with or without R848 / IFNγ, and with or without dTPI-1 treatment. FIG. 4E shows cytokine profiling by ELISA of TNFα as a function of dTPI concentration.

[0036] FIGS. 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.

[0037] 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- 7sf-6604130Attorney Docket No.245162001040 drug lotion; anti-PD-1 (αPD-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. DETAILED DESCRIPTION OF THE INVENTION

[0038] 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. 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. Such a combination therapy also has the potential to cause an abscopal effect.

[0039] The results presented herein demonstrate that it is feasible to link a pro-inflammatory agent to a SHP-1 inhibitor and achieve a potent antitumor effect.

[0040] 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.

[0041] The present application in one aspect provides methods of treating a cancer in an individual, comprising administering to the individual a SHP1I-PIA conjugate. In 8sf-6604130Attorney Docket No.245162001040 embodiments, the individual is having an inflammatory reaction. In embodiments, the individual has an ongoing infection. In some embodiments, 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 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. In some embodiments, 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.

[0042] The SHP1I-PIA conjugate can be administered with an agent that reduces systemic inflammation (e.g., an anti-TNFα mAb) in order to reduce toxicity of the treatment, while not impairing the inflammatory effect within the tumor microenvironment. . Definitions

[0043] In general, terms used in the claims and the specification are intended to be construed as having the plain meaning understood by a person of ordinary skill in the art. Certain terms are defined below to provide additional clarity. In case of conflict between the plain meaning and the provided definitions, the provided definitions are to be used.

[0044] 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. In some embodiments, the individual is human. In some embodiments, an individual suffers from a disease, such as cancer. In some embodiments, the individual is in need of treatment.

[0045] 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. In some examples, 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. 9sf-6604130Attorney 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. In some cases, “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.

[0047] As used herein, 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. When there are multiple daily consecutive administrations of the SHP1I-PIA conjugate, 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. For example, the first cycle, which may have five days, may have one administration of the SHP1I-PIA conjugate, and the second cycle, which may have seven days, may have two administrations of the SHP1I-PIA conjugate.

[0048] As used herein the term “immunogenic” is the ability to elicit an immune response, e.g., via T-cells, B cells, or both.

[0049] As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For purposes of this invention, 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 10sf-6604130Attorney Docket No.245162001040 of the disease, increasing the quality of life, and / or prolonging survival. Also encompassed by “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.

[0050] As used herein, “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. Such comparisons are typically based on clinical studies, using a statistically significant number of individuals. 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.

[0051] 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. When the first and second therapies are administered simultaneously, 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).

[0052] As used herein, 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.

[0053] As used herein, 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. 11sf-6604130Attorney Docket No.245162001040

[0054] As used herein, by “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. 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.

[0055] As used herein, 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.

[0056] It is understood that embodiments of the application described herein include “consisting” and / or “consisting essentially of” embodiments.

[0057] Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.

[0058] As used herein, reference to “not” a value or parameter generally means and describes “other than” a value or parameter. For example, the method is not used to treat cancer of type X means the method is used to treat cancer of types other than X.

[0059] The term “about X-Y” used herein has the same meaning as “about X to about Y.”

[0060] The singular forms “a,” “an,” and “the” as used herein include plural referents unless the context clearly dictates otherwise.

[0061] “Alkyl” as used herein 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 “C1-C10alkyl”), having 6 to 10 carbon atoms (a “C6-C10alkyl”), 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”). Examples of 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. 12sf-6604130Attorney 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 “C1-C6alkylene”), 1 to 5 carbon atoms (a “C1-C5alkylene”), 1 to 4 carbon atoms (a “C1-C4 alkylene”) or 1 to 3 carbon atoms (a “C1-C3 alkylene”). Examples of alkylene include, but are not limited to, groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), butylene (-CH2(CH2)2CH2-), isobutylene (-CH2CH(CH3)CH2-), pentylene (-CH2(CH2)3CH2-), hexylene (-CH2(CH2)4CH2-), heptylene (-CH2(CH2)5CH2-), octylene (-CH2(CH2)6CH2-), and the like.

[0063] “Alkenyl” as used herein refers to and includes, unless otherwise stated, an unsaturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and having the number of carbon atoms designated (i.e., C2-C10means two to ten carbon atoms). An alkenyl group may have “cis” or “trans” configurations, or alternatively have “E” or “Z” configurations. Particular alkenyl groups are those having 2 to 20 carbon atoms (a “C2-C20alkenyl”), having 6 to 10 carbon atoms (a “C6-C10alkenyl”), having 2 to 8 carbon atoms (a “C2-C8 alkenyl”), having 2 to 6 carbon atoms (a “C2-C6 alkenyl”), or having 2 to 4 carbon atoms (a “C2-C4 alkenyl”). Examples of alkenyl group 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.

[0064] “Alkenylene” as used herein refers to the same residues as alkenyl, but having bivalency. Particular alkenylene groups are those having 2 to 20 carbon atoms (a “C2-C20 alkenylene”), having 2 to 10 carbon atoms (a “C2-C10 alkenylene”), having 6 to 10 carbon atoms (a “C6-C10alkenylene”), having 2 to 6 carbon atoms (a “C2-C6alkenylene”), 2 to 4 carbon atoms (a “C2-C4 alkenylene”) or 2 to 3 carbon atoms (a “C2-C3 alkenylene”). Examples of alkenylene include, but are not limited to, groups such as ethenylene (or vinylene) (-CH=CH-), propenylene (-CH=CHCH2-), 1,4-but-1-enylene (-CH=CH-CH2CH2-), 1,4-but-2-enylene (-CH2CH=CHCH2-), 1,6-hex-1-enylene (-CH=CH-(CH2)3CH2-), and the like. 13sf-6604130Attorney Docket No.245162001040

[0065] “Alkynyl” as used herein refers to and includes, unless otherwise stated, an unsaturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C) and having the number of carbon atoms designated (i.e., C2-C10means two to ten carbon atoms). 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 “C2-C8alkynyl”), having 2 to 6 carbon atoms (a “C2-C6alkynyl”), or having 2 to 4 carbon atoms (a “C2-C4 alkynyl”). Examples of alkynyl group 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.

[0066] “Alkynylene” as used herein 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 “C6-C10alkynylene”), having 2 to 6 carbon atoms (a “C2-C6alkynylene”), 2 to 4 carbon atoms (a “C2-C4 alkynylene”) or 2 to 3 carbon atoms (a “C2-C3 alkynylene”). Examples of alkynylene include, but are not limited to, groups such as ethynylene (or acetylenylene) (-C≡C-), propynylene (-C≡CCH2-), and the like.

[0067] “Cycloalkyl” as used herein refers to and includes, unless otherwise stated, saturated cyclic univalent hydrocarbon structures, having the number of carbon atoms designated (i.e., C3-C10means 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 "C3-C8cycloalkyl"), having 3 to 6 annular carbon atoms (a “C3-C6 cycloalkyl”), or having from 3 to 4 annular carbon atoms (a "C3-C4 cycloalkyl"). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0068] “Cycloalkylene” as used herein 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"). 14sf-6604130Attorney 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. When a cycloalkylene attaches to the remaining structures via two different ring carbon atoms, the connecting bonds may be cis- or trans- to each other. For example, 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.

[0069] “Cycloalkenyl” refers to and includes, unless otherwise stated, an unsaturated cyclic non-aromatic univalent hydrocarbon structure, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and having the number of carbon atoms designated (i.e., C3-C10means three to ten carbon atoms). Cycloalkenyl can consist of one ring, such as cyclohexenyl, or multiple rings, such as norbornenyl. A preferred cycloalkenyl is an unsaturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C3-C8 cycloalkenyl”). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, and the like.

[0070] “Cycloalkenylene” as used herein refers to the same residues as cycloalkenyl, but having bivalency.

[0071] “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 “C6-C14aryl”). 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. In one variation, 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.

[0072] “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 “C6-C14arylene”).

[0073] “Heteroaryl” as used herein 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) 15sf-6604130Attorney 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. In one variation, 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. In another variation, 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. In one variation, 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.

[0074] “Heteroarylene” as used herein refers to the same residues as heteroaryl, but having bivalency.

[0075] “Heterocycle”, “heterocyclic”, or “heterocyclyl” as used herein 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. In one 16sf-6604130Attorney Docket No.245162001040 variation, 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. In another variation, 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.

[0076] “Heterocyclylene” as used herein refers to the same residues as heterocyclyl, but having bivalency.

[0077] “Halo” or “halogen” 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. 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 (-CF3). Similarly, “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).

[0078] “Carbonyl” refers to the group C=O.

[0079] “Thiocarbonyl” refers to the group C=S.

[0080] “Oxo” refers to the moiety =O.

[0081] “D” refers to deuterium (2H).

[0082] “T” refers to tritium (3H).

[0083] 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.”

[0084] Unless a specific isotope of an element is indicated in a formula, 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 17sf-6604130Attorney 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.

[0085] “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. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, 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.

[0087] As used herein, by “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.

[0088] “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, for example, 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. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and 18sf-6604130Attorney 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.

[0089] The term “excipient” as used herein 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. 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. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression / encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc (dc = “directly compressible”), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending / gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0090] Unless otherwise stated, "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.

[0091] It is understood that aspects and embodiments described herein as “comprising” include “consisting of” and “consisting essentially of” embodiments. 19sf-6604130Attorney 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. Certain terms are discussed herein to provide additional guidance to the practitioner in describing the compositions, devices, methods, and the like of aspects of the invention, and how to make or use them. It will be appreciated that the same thing may be said in more than one way. Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein. No significance is to be placed upon whether or not a term is elaborated or discussed herein. Some synonyms or substitutable methods, materials and the like are provided. Recital of one or a few synonyms or equivalents does not exclude use of other synonyms or equivalents, unless it is explicitly stated. Use of examples, including examples of terms, is for illustrative purposes only and does not limit the scope and meaning of the aspects of the invention herein. Methods of treatment

[0093] The present application in one aspect provides methods of treating a cancer by administering a SHP1I-PIA conjugate, or an analog or a derivative thereof. 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).

[0094] In some embodiments, the SHP1I-PIA conjugate is administered intermittently. In some embodiments, 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. 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 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.

[0095] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, comprising administering to the individual a SHP1I-PIA conjugate, and wherein the SHP1I-PIA 20sf-6604130Attorney Docket No.245162001040 conjugate is administered systemically (e.g., intravenously or subcutaneously). 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 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. In some embodiments, 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). In some embodiments, 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). In some embodiments, 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. In some embodiments, the method further comprises locally (e.g., intratumorally) administering SHP1I-PIA conjugate into the individual. 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-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα 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. In some embodiments, 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. In some embodiments, the pro-inflammatory agent of the SHP1I-PIA conjugate comprises a TLR agonist (e.g., R848) and a pro-inflammatory cytokine 21sf-6604130Attorney Docket No.245162001040 (e.g., IFN-gamma). In some embodiments, the SHP-1 inhibitor of the SHP1I-PIA conjugate comprises TPI-1.

[0096] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, 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. In some embodiments, 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. 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 twice. In some embodiments, the SHP1I-PIA conjugate is administered twice (e.g., two consecutive days) every seven to twenty days. In some embodiments, the SHP1I-PIA conjugate is administered three times (e.g., three consecutive days) every ten to twenty days. In some embodiments, 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). In some embodiments, 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). In some embodiments, 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. In some embodiments, the method 22sf-6604130Attorney Docket No.245162001040 further comprises locally (e.g., intratumorally) administering the SHP1I-PIA conjugate to the individual. 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-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα 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. In some embodiments, 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. In some embodiments, the SHP-1 inhibitor of the SHP1I-PIA conjugate comprises TPI-1 or an analog or derivative thereof. In some embodiments, the SHP-1 inhibitor of the SHP1I-PIA conjugate comprises TPI-1.

[0097] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, comprising administering to the individual a SHP1I-PIA conjugate (where the SHP-1 inhibitor of the SHP1I-PIA conjugate is, e.g., TPI-1 or an analog or a derivative thereof, and the pro- inflammatory agent of the SHP1I-PIA conjugate is e.g., 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. 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 are separated by at least one day from the preceding or following SHP1I-PIA conjugate administration. In some embodiments, 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. In some embodiments, the SHP1I-PIA conjugate is administered for at least twice (e.g., at least two consecutive days) in each cycle. In some embodiments, the SHP1I-PIA conjugate is administered for at least three times (e.g., at least three consecutive days) in each cycle. In 23sf-6604130Attorney Docket No.245162001040 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). In some embodiments, 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). In some embodiments, 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. In some embodiments, the method further comprises locally (e.g., intratumorally) administering the SHP1I-PIA conjugate into the individual. 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- TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα 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. In some embodiments, the SHP-1 inhibitor of the SHP1I-PIA conjugate is TPI-1 or an analog or derivative thereof. In some embodiments, 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. In some embodiments, the SHP-1 inhibitor of the SHP1I-PIA conjugate comprises TPI-1.

[0098] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, comprising 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 5 days, and optionally wherein 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 (e.g., at least 3, 4, 5, or 6 times). In some embodiments, the SHP1I-PIA conjugate is administered intermittently. In some embodiments, the SHP1I-PIA conjugate is administered 24sf-6604130Attorney 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. 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. In some embodiments, 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. In some embodiments, 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). 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). In some embodiments, 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). In some embodiments, 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). In some embodiments, 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. In some embodiments, the method further comprises locally (e.g., intratumorally) administering the SHP1I-PIA conjugate into the individual. In some embodiments, 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-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα 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, 25sf-6604130Attorney 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. In some embodiments, the SHP-1 inhibitor of the SHP1I-PIA conjugate comprises TPI-1.

[0099] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, comprising 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 (e.g., for no more than 5, 4, or 3 days), and wherein 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. 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 for at least twice (e.g., at least two consecutive days) in each cycle. In some embodiments, the SHP1I-PIA conjugate is administered for at least three times (e.g., at least three consecutive days) in each cycle. 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). In some embodiments, 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). In some embodiments, 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, 26sf-6604130Attorney Docket No.245162001040 phomoxanthone A (PXA), and a PKC-theta activator. In some embodiments, the method further comprises locally (e.g., intratumorally) administering the SHP1I-PIA conjugate into the individual. In some embodiments, 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-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα 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). In some embodiments, the SHP-1 inhibitor of the SHP1I-PIA conjugate comprises TPI-1.

[0100] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, 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 (such as any of the immune cells described herein). In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, 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. In some embodiments, the immune cells are derived from the same individual. In some embodiments, the immune cells comprise monocytes or macrophages. In some embodiments, the immune cells comprise T cells (e.g., CAR-T cells). In some embodiments, the immune cells comprise NK cells (e.g., CAR-NK cells). In some embodiments, the immune cells comprise neutrophils (e.g., CAR-expressing neutrophils cells). In some 27sf-6604130Attorney Docket No.245162001040 embodiments, the immune cells comprise antigen presenting cells (APCs). In some embodiments, the immune cells are engineered to express a chimeric receptor that specifically binds to a tumor antigen. In some embodiments, 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. In some embodiments, 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. 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-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα 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). In some embodiments, the SHP-1 inhibitor of the SHP1I-PIA conjugate comprises TPI-1.

[0101] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, comprising 28sf-6604130Attorney Docket No.245162001040 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 be a TLR agonist, e.g., R848), wherein the SHP1I-PIA conjugate is administered at least twice (e.g., at least 3, 4, or 5 times). In some embodiments, 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. 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 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). In some embodiments, the pro- inflammatory agent of the SHP1I-PIA conjugate is a TLR agonist, and the TLR agonist activates TLR1 or TLR2, optionally wherein the TLR agonist comprises a triacylated lipoprotein, a peptidoglycan, zymosan, and / or Pam3CSK4. In some embodiments, 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. In some embodiments, 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). In some embodiments, 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. In some embodiments, the TLR agonist activates TLR5, optionally wherein the TLR agonist comprises flagellin, CBLB502, and / or M-VM3. In some embodiments, the TLR agonist activates TLR6. In some embodiments, the TLR agonist activates TLR7 or TLR8, optionally 29sf-6604130Attorney Docket No.245162001040 wherein the TLR agonist comprises ssRNA, CpG-A, poly G10, poly G3, and / or 324 BDB001. In some embodiments, the TLR agonist activates TLR7, optionally wherein the TLR agonist comprises bistriazolyl and / or R848. In some embodiments, the TLR agonist activates TLR8, optionally wherein the TLR agonist comprises VTX1463, VTX2337 (motolimod), and / or R848. In some embodiments, 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. In some embodiments, the TLR agonist activates TLR10, optionally wherein the TLR agonist comprises Pam3CSK4. In some embodiments, the TLR agonist activates TLR11, optionally wherein the TLR agonist comprises toxoplasma gondii profilin. In some embodiments, the TLR agonist activates TLR12. In some embodiments, 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. In some embodiments, the TLR agonist activates TLR9, TLR4 and TLR7 / 8. In some embodiments, the TLR agonist comprises CpG, polyI:C and / or R848. In some embodiments, the pro-inflammatory agent comprises an agent or is selected from the group consisting of R848, 3M-852A, Motolimod, Bropirimine and Vesatolimod. In some embodiments, 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- TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα 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). 30sf-6604130Attorney Docket No.245162001040

[0102] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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). In some embodiments, the TLR agonist activates at least three TLRs (e.g., TLR9, TLR4 and TLR7 / 8). In some embodiments, the TLR agonist comprises CpG, polyI:C and / or R848. In some embodiments, 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. In some embodiments, 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-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα 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 31sf-6604130Attorney 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).

[0103] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, 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). In some embodiments, 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. 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 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 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) or an antibody-drug conjugate (e.g., XMT-2056, CRD-5500). In some embodiments, 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, 32sf-6604130Attorney 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- TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα 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).

[0104] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, 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). In some embodiments, 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. 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 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. In some embodiments, the PAMP activator is triacyl lipopeptides, LPS, lipoprotein, peptidoglycan, zymosan, lipoteichoic acid, trypanosomal phospholipids, Pam3Cys porins, lipoarabinomannan, double-stranded RNA, 33sf-6604130Attorney 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. In some embodiments, the pro-inflammatory agent is a DAMP activator. In some embodiments, 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. In some embodiments, 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-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα 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.

[0105] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, 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). In some embodiments, 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. In some embodiments, the method 34sf-6604130Attorney 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). In some embodiments, 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 / SIRPα, CSF-1(M-CSF) / CSF-1R, IL-1 / IL-1R3 (IL-1RAP), IL-8, SEMA4D, Ang-2, CLEVER-1, Axl, or phosphatidylserine. In some embodiments, 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), CAN04, Canakinumab (ACZ885), BMS-986253, Pepinemab (VX15 / 2503), Trebananib, FP-1305, Enapotamab vedotin(EnaV), or Bavituximab. In some embodiments, 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- TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα 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).

[0106] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, comprising administering to the individual a SHP1I-PIA conjugate, where the SHP-1 inhibitor of the 35sf-6604130Attorney 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 TNFα), optionally wherein the SHP1I-PIA conjugate is administered at least twice (at least three, four, five, or six times). In some embodiments, 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. 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 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. In some embodiments, the pro- inflammatory cytokine comprises or is TNF, IFNγ, and / or GM-CSF. In some embodiments, the pro-inflammatory cytokine comprises IFNγ. 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. In some embodiments, 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- TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα 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 36sf-6604130Attorney Docket No.245162001040 of the SHP1I-PIA conjugate can comprise, e.g., TPI-1 or an analog or derivative thereof, e.g. TPI-1.

[0107] In some embodiments, there is provided a method of treating a cancer (e.g., a solid tumor, e.g., a hematological cancer, e.g., a late stage cancer) in an individual, 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). In some embodiments, 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. 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 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. In some embodiments, 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). In some embodiments, the chemotherapeutic agent of the SHP1I-PIA conjugate is an antimetabolite. In some embodiments, 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 37sf-6604130Attorney Docket No.245162001040 of 5-FU)). In some embodiments, the chemotherapeutic agent of the SHP1I-PIA conjugate is an antimicrotubular agent. In some embodiments, 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). In some embodiments, the chemotherapeutic agent of the SHP1I-PIA conjugate is hydroxyurea, tretinoin, arsenic trioxide, or a proteasome inhibitor (e.g., bortezomib). In some embodiments, 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- TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα 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).

[0108] 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. In some embodiments, the monocytes or macrophages are derived from the same individual. 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-TNFα antibody or an anti-IL6 antibody). In some embodiments, the method further comprises administering to the individual an anti-TNFα antibody, optionally wherein the anti-TNFα 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). 38sf-6604130Attorney Docket No.245162001040

[0109] In some embodiments, 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).

[0110] In some embodiments, 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).

[0111] In some embodiments, 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).

[0112] In some embodiments, the method comprises administering the SHP1I-PIA conjugate (e.g., TPI-1 or an analog or a derivative thereof) for at least two cycles. In some embodiments, the SHP1I-PIA conjugate (e.g., comprising TPI-1 or an analog or a derivative thereof) is administered for at least once (e.g., for twice, three times, four times) in each cycle. In some embodiments, 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).

[0113] In some embodiments, 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).

[0114] 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. In some embodiments, 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 (e.g., humans) include solids (dusting powders), semisolids (creams, ointments, pastes, and gels), and liquids (solutions, suspension concentrates, suspoemulsions, emulsifiable concentrates, paints, and tinctures).

[0115] Suitable routes of administration may, for example, include oral, rectal, transmucosal, topical, intestinal, intranasal, or intraocular administration. The compounds can also be 39sf-6604130Attorney 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.

[0116] In embodiments, the SHP1I-PIA conjugate formulation is sterile.

[0117] In some embodiments, the SHP1I-PIA conjugate is complexed with a delivery vehicle before being administered into the individual. In some embodiments, the delivery vehicle promotes the delivery into the tumor.

[0118] In some embodiments, the SHP1I-PIA conjugate modulates a monocyte or macrophage (e.g., a monocyte or macrophage derived from the individual to be treated) in vitro. Tumor microenvironment (TME) immunosuppression and SHP-1 signaling

[0119] 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). 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. It has 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. When 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. Thus, 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). 40sf-6604130Attorney Docket No.245162001040

[0121] 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.

[0122] Inhibition of SHP-1, however,can also cause deleterious effects. Motheaten mice (me / me or mev / mev) 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.

[0123] 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. To date, no SHP-1 inhibitors have progressed to Phase II trials. An agent that reduces systemic inflammation

[0124] In some cases, individuals develop systemic inflammation, i.e., cytokine release syndrome (CRS) after receiving (e.g.) immunotherapeutic treatment, however the inflammatory disorder is not fully understood. CRS can be induced by direct target cell lysis and the consecutive release of cytokines like TNFα or IFNγ, or by activation of T cells due to therapeutic stimuli that is followed by subsequent cytokine release. These cytokines trigger a chain reaction due to the activation of innate immune cells like macrophages and endothelial cells, which then induces further cytokine release. In particular, IL6, IL10, and IFNγ are most commonly found to be elevated in patients with CRS.

[0125] 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. The agents that reduce systemic inflammation include, but are not limited to, inhibitors of TNFα, IL6, IL10, and IFNγ. In some embodiments, the agent that reduces systemic inflammation is administered simultaneously with the SHP1I-PIA conjugate. In 41sf-6604130Attorney Docket No.245162001040 some embodiments, 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. In some embodiments, 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.).

[0126] 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. For example, 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 TNFα alone, IL6 alone, TNFα and IL6 in combination). Anti-TNFα antagonist

[0127] TNFα, a major proinflammatory cytokine, is secreted by activated macrophages, monocytes and lymphocytes. Administration of an anti-TNFα 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.

[0128] The methods of the present application therefore in some embodiments comprises administration of TNFα inhibitor, e.g., an anti-TNFα antagonist (e.g., in the context where the proinflammatory agent is not TNFα) in addition to the SHP1I-PIA conjugate. In some embodiments, the TNFα inhibitor is selected from the group consisting of a small molecule inhibitor, a neutralizing antibody, a TNFα receptor blockade antibody, a soluble TNFα receptor, a TNFα-targeting short interfering RNA (siRNA), a chemical inhibitor of TNFα mRNA stability, an inhibitor of TNFα converting enzyme (TACE), and derivatives thereof. In some embodiments, the TNFα inhibitor is an anti-TNFα neutralizing antibody. In some embodiments, the TNFα inhibitor is an anti-TNFα receptor blockade antibody. In some 42sf-6604130Attorney Docket No.245162001040 embodiments, the anti-TNFα antibody is a monoclonal antibody. In some embodiments, anti- TNFα antibody is a chimeric, humanized, and / or fully human antibody.

[0129] 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®. Others suitable anti-TNFα 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; Simponi™ (Golimimab, CNTO 148 (Centocor)) as described in PCT Publication No. WO 02 / 12502 and related patents and applications, the contents of which are hereby incorporated by reference in their entirety; ART621 (Arana Therapeutics), SSS 07 (Epitopmics and 3SBio) or antibodies that bind to the same epitope as Humira, Simponi, ART621, or SSS 07.

[0130] In some embodiments, the TNFα inhibitor, e.g., anti-TNFα antagonist, 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. WO 91 / 03553, and related patents and applications, the contents of which are hereby incorporated by reference in their entirety.

[0131] In some embodiments, the TNFα inhibitor, e.g., anti-TNFα antagonist, 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, Cimzia™ (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.

[0132] In some embodiments, the TNFα inhibitor (e.g., an anti-TNFα antibody) is administered within two weeks, 10 days, or one week prior to the administration of a 43sf-6604130Attorney Docket No.245162001040 SHP1I-PIA conjugate described herein. Exemplary TNFα inhibitors such an anti-TNFα antibody is usually stable for at least one or two weeks. In some embodiments, the TNFα inhibitor (e.g., an anti-TNFα antibody) is administered concurrently or simultaneously with the SHP1I-PIA conjugate. In some embodiments, the TNFα inhibitor (e.g., an anti-TNFα antibody) is administered immediately after (e.g., within 1 hour or 30 minutes) the administration of the SHP1I-PIA conjugate.

[0133] In some embodiments, the TNFα inhibitor is administered systemically. In some embodiments, the TNFα inhibitor is administered at least once a week, once every five days, once every three days, or daily. In some embodiments, the TNFα inhibitor is administered intermittently. In some embodiments, the TNFα 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. In some embodiments, administration of the TNFα inhibitor does not compromise or weakly compromises tumor clearance. Anti-IL6 antagonist

[0134] 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. In some embodiments, the anti-IL6 antagonist is an antibody. In one embodiment, 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). In one embodiment, 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). In one embodiment, the IL6 antagonist is olamkicept.

[0135] In some embodiments, 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. In some embodiments, the IL6 inhibitor is administered to the individual for at least two cycles, wherein each cycle has about three to about seven days. 44sf-6604130Attorney 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-LA-R1wherein PIA is a pro-inflammatory agent, LAis an optional linker, and R1is 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).

[0138] In some embodiments, the pro-inflammatory agent triggers a pro-inflammatory signal on macrophages. In some embodiments, 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. For example, a TLR agonist, which directly activates TLR on macrophages, or a radiotherapy which indirectly activates a pro-inflammatory signal on macrophages, when used with a SHP-1 inhibitor both demonstrated remarkable anti-tumor effects.

[0139] In some embodiments, 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. 45sf-6604130Attorney Docket No.245162001040

[0140] In some embodiments, 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.

[0141] In some embodiments, the pro-inflammatory agent comprises a TLR agonist (e.g., R848) and a cytokine (e.g., IFN-gamma). TLR agonists

[0142] In some embodiments, the pro-inflammatory agent comprises or is a TLR agonist.

[0143] 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. 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 β-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. It has also been suggested that 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 β-defensin 2, fibronectin extra domain A EDA, HMGB1, Snapin, and tenascin C. TLR5 recognizes bacterial flagellin, TLR7 and TLR8 bind viral ssRNA, whereas 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. See e.g., Kaczanowska et al., J Leukoc Biol. 2013 Jun;93(6):847-63.

[0144] 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, 46sf-6604130Attorney 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. On the other hand, stimulation of TLR 2, 3, 4, 5, 7 / 8, and 9, often combined with chemo- or immunotherapy, can lead to tumor inhibition via different pathways. See e.g., Grimmig et al., Int J Oncol. (2015) 47:857–66; Urban-Wojciuk et al., Front Immunol. 2019; 10: 2388.

[0145] In some embodiments, the TLR agonist activates any of the TLRs.

[0146] In some embodiments, the TLR agonist activates TLR1 or TLR2, optionally wherein the TLR agonist comprises a triacylated lipoprotein, a peptidoglycan, zymosan, and / or Pam3CSK4.

[0147] In some embodiments, 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.

[0148] In some embodiments, the TLR agonist activates TLR2, optionally wherein the TLR agonist comprises Pam3Cys, SMP-105, and / or CBLB612.

[0149] 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.

[0150] In some embodiments, 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.

[0151] In some embodiments, 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. 47sf-6604130Attorney Docket No.245162001040

[0155] In some embodiments, the TLR agonist activates TLR8, optionally wherein the TLR agonist comprises VTX1463, VTX2337 (motolimod), and / or R848.

[0156] In some embodiments, 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.

[0157] In some embodiments, the TLR agonist activates TLR10, optionally wherein the TLR agonist comprises Pam3CSK4.

[0158] In some embodiments, the TLR agonist activates TLR11, optionally wherein the TLR agonist comprises toxoplasma gondii profilin.

[0159] In some embodiments, the TLR agonist activates TLR12.

[0160] In some embodiments, the TLR agonist activates TLR13, optionally wherein the TLR agonist comprises VSV.

[0161] In some embodiments, the TLR agonist activates a TLR on a macrophage.

[0162] In some embodiments, 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.

[0166] In some embodiments, 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: 48sf-6604130Attorney Docket No.245162001040or a salt thereof, wherein LAis an optional linker and R1is 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. Radiopharmaceutical therapy in cancer: clinical advances and challenges. Nat Rev Drug Discov 19, 589–608 (2020). STING activator

[0169] In some embodiments, the pro-inflammatory agent comprises or is a STING activator.

[0170] 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). In addition to bacterial components, other forms of DNA from viruses, or the host cell, that find their way into the cytosol are recognized by an enzyme c-GMP-AMP (cGAMP) synthase (cGAS). Upon cytosolic DNA binding, 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. At the Golgi, 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-β). STING 49sf-6604130Attorney Docket No.245162001040 also triggers a robust pro-inflammatory cytokine response [e.g., tumor necrosis factor (TNF)] by activating Nuclear Factor-kappa B (NF-κB) 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. 2022 Feb 25;13:794776; Amougezar et al., Cancers (Basel). 2021 May 30;13(11):2695.

[0171] In some embodiments, the STING activator is a cyclic-guanosine monophosphate- adenosine monophosphate (cGAMP, e.g., 3’3’ cGAMP, e.g., 2’3’ cGAMP).

[0172] In some embodiments, the STING activator is a bacterial vector (e.g., SYNB1891, STACT-TREX-1).

[0173] In some embodiments, 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).

[0174] In some embodiments, 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).

[0175] In some embodiments, the STING activator is a nanovaccine (e.g., PC7A NP, cCAMP-NP, ONM-500).

[0176] In some embodiments, the STING activator is an antibody-drug conjugate (e.g., XMT-2056, CRD-5500).

[0177] In some embodiments, the STING activator is the compound SR-717 of the formula:. 50sf-6604130Attorney Docket No.245162001040

[0178] In some embodiments, the STING activator is the compound MSA-2 of the formula:.

[0179] In some embodiments, the STING activator is the compound SNX-281 of the formula:.

[0180] In some embodiments, the STING activator is the compound alpha-mangostin of the formula:. 51sf-6604130Attorney 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 LAconnecting alpha-mangostin and the SHP-1 inhibitor.

[0181] In some embodiments, the STING activator is the compound DMXAA of the formula:.

[0182] 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. PAMP / DAMP activators

[0183] In some embodiments, the pro-inflammatory agent comprises or is a PAMP / DAMP activator.

[0184] 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. Thus, PAMPs and DAMPs that bind to the same type of receptors initiate identical intracellular pathways terminating in identical effector functions. See e.g., Alisi et al., Hepatology. 2011 Nov;54(5):1500-2. 52sf-6604130Attorney Docket No.245162001040

[0185] In some embodiments, 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.

[0186] In some embodiments, the pro-inflammatory agent is a DAMP activator. Exemplary 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] In some embodiments, the pro-inflammatory agent comprises or is a chemotherapeutic agent.

[0188] In some embodiments, the chemotherapeutic agent is an alkylating agent. Exemplary 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).

[0189] In some embodiments, 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)).

[0190] In some embodiments, the chemotherapeutic agent is an antimicrotubular agent. Exemplary 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).

[0191] Other exemplary chemotherapeutic agents include hydroxyurea, tretinoin, arsenic trioxide, and proteasome inhibitors (e.g., bortezomib). 53sf-6604130Attorney Docket No.245162001040 Pro-inflammatory cytokines

[0192] In some embodiments, the pro-inflammatory agent is a pro-inflammatory cytokine.

[0193] In some embodiments, the pro-inflammatory cytokine promotes the M1 macrophages. See e.g., Duque et al., Front Immunol. 2014; 5: 491. In some embodiments, the pro- inflammatory cytokine comprises or is TNF, IFNγ, and / or GM-CSF.

[0194] In some embodiments, the pro-inflammatory cytokine comprises IL-6, TNFα, a cytokine from IL-1 family (e.g., IL-1α, IL-1β, IL-18, IL-33 and IL-36), and / or IFNγ.

[0195] In some embodiments, the pro-inflammatory cytokine comprises a cytokine from IL-1 family. In some embodiments, the pro-inflammatory cytokine comprises any one or more of IL-1α, IL-1β, 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). Checkpoint inhibitors

[0196] In some embodiments, 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).

[0197] In some embodiments, the checkpoint inhibitor targets CLTA-4, PD-1 or PD-L1 (e.g., an antibody targeting CTLA-4, PD-1 or PD-L1).

[0198] In some embodiments, 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 / SIRPα, CSF-1(M-CSF) / CSF-1R, IL-1 / IL-1R3 (IL-1RAP), IL-8, SEMA4D, Ang-2, CLEVER-1, Axl, or phosphatidylserine.

[0199] In some embodiments, 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), CAN04, Canakinumab (ACZ885), BMS- 54sf-6604130Attorney Docket No.245162001040 986253, Pepinemab (VX15 / 2503), Trebananib, FP-1305, Enapotamab vedotin(EnaV), or Bavituximab. Tyrosine Kinase Inhibitors

[0200] In some embodiments, a tyrosine kinase inhibitor can be used as, or in place of, the pro-inflammatory agent of the SHP1I-PIA conjugates.

[0201] The tyrosine kinase inhibitors referred to herein are agents of any kind or sort that inhibits the expression or activation of tyrosine kinase.

[0202] In some embodiments, 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. In some embodiments, 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.

[0203] In some embodiments, 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.

[0205] 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. Alternatively, 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.

[0206] A wide variety of linkers are available. When the optional linker LAis present in the conjugate of form PIA-LA-R1, where PIA is a pro-inflammatory agent and R1is a SHP-1 inhibitor, the optional linker LAcan be between 1 and 25 atoms in length. The length is 55sf-6604130Attorney Docket No.245162001040 defined by the chain that connects the PIA moiety to the R1moiety. ; there may be other substituents that define shorter chains. For example, the following linker:where the bonds crossed by a wavy line indicate where the linker attached to the PIA moiety on one end and the R1moiety on the other end, has a length of 9, from the first carbon marked with asterisk * to the second carbon marked with asterisks **.

[0207] The linker can comprise any number of carbon atoms and heteroatoms, such as N, O, or S. PEG linkers, such as –(CH2CH2O)n- or –(OCH2CH2)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. For example, when LAis –(CH2CH2O)n- or –(OCH2CH2)n-, where n is an integer between 1 and 8 inclusive, a PEG compound of the form OH–(CH2CH2O)n-H or HO2C–(OCH2CH2)n-NH2can be used to connect to appropriate functional groups on the pro-inflammatory agent or SHP-1 inhibitor.

[0208] In other embodiments, LAcan 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 RAgroups, where RAis C1-C4 alkyl, -OH, -O-C1-C6, oxo, F, Cl, Br, I, -CN, or -NO2. A wide variety of functional groups may be present on the reagent used to form the LA group. For example, sebacic acid, HO2C-(CH2)8-CO2H, may react with functional groups on the pro-inflammatory agent and SHP-1 inhibitor to provide a linker of the structure -C(=O)-(CH2)8-C(=O)-, which is a C10 alkyl chain substituted with two oxo groups.

[0209] LAcan be composed of multiple regions, such as when LAis L1-L2-L3, where: L1is 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 56sf-6604130Attorney Docket No.245162001040 of N, O, and S, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl are optionally substituted with one, two, or three RAgroups; L2is 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 RAgroups, and the aryl or heteroaryl are optionally substituted with one, two, or three RBgroups; and L3is C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, or heteroalkyl containing between two to eight 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 RAgroups;

[0210] where RAis C1-C4alkyl, -OH, -O-C1-C6, oxo, F, Cl, Br, I, -CN, or -NO2, and

[0211] RBis C1-C4 alkyl, -OH, -O-C1-C6, F, Cl, Br, I, -CN, or -NO2.

[0212] LAcan also be –O-(CH2CH2O)n-, –(OCH2CH2)n–O–, or -L4-PEG-L4-, where n is an integer between 1 and 8 inclusive, PEG is ethylene glycol or polyethylene glycol having between 2 and 8 ethylene glycol units, and each L4 is independently absent or -O-, -NH-, - CH2-, -O-(C=O)-, -(C=O)-O-,-NH-(C=O)-,or -(C=O)-NH-; or

[0213] LAcan be L5-L6-L7-L8-L9,

[0214] where L5is -O-, -NH-, -CH2-, -(C=O)-, -O-(C=O)-, -(C=O)-O-,-NH-(C=O)-,or - (C=O)-NH-; L6is absent or C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, or heteroalkyl containing between two to eight 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 RAgroups; L7is absent or C3-C8cycloalkyl, C6-C10aryl, three-to-twelve-membered heterocyclyl, or five- to-twelve-membered heteroaryl, wherein the cycloalkyl or heterocyclyl are optionally substituted with one, two, or three RAgroups, and the aryl or heteroaryl are optionally substituted with one, two, or three RBgroups; L8is absent or 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 of N, O, and S, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl are optionally substituted with one, two, or three RAgroups; 57sf-6604130Attorney Docket No.245162001040 with the proviso that at least one of L6, L7, or L8is not absent; and L9is -O-, -NH-, -CH2-, -(C=O)-, -O-(C=O)-, -(C=O)-O-,-NH-(C=O)-,or -(C=O)-NH-; where RAis C1-C4 alkyl, -OH, -O-C1-C6, oxo, F, Cl, Br, I, -CN, or -NO2, and RBis C1-C4alkyl, -OH, -O-C1-C6, F, Cl, Br, I, -CN, or -NO2.

[0215] Additional groups which can be used as LAlinkers include:, wherein the wavy bonds indicate the bonds attaching LAto the remainder of the molecule.

[0216] 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. 58sf-6604130Attorney Docket No.245162001040 SHP-1 inhibitors of the SHP1I-PIA conjugates

[0217] The SHP-1 inhibitors that can be used in the SHP1I-PIA conjugates referred to herein are agents of any kind or sort that inhibit the expression or activation of SHP-1. In some embodiments, the SHP-1 inhibitor directly targets SHP-1. In some embodiments, the SHP-1 inhibitor targets a molecule involved in SHP-1 signaling pathway in macrophages that is distinct from SHP-1.

[0218] In some embodiments, 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. In some embodiments, 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.

[0219] In some embodiments, 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.

[0220] In some embodiments, 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. In some embodiments, 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.

[0224] In some embodiments, the SHP-1 inhibitor is a covalent inhibitor. In some embodiments, the SHP-1 inhibitor is a noncovalent inhibitor.

[0225] In some embodiments, the SHP-1 inhibitor is a competitive inhibitor. In some embodiments, the SHP-1 inhibitor is Phomoxanthone A (PXA) or Phomoxanthone B (PXB). See e.g., Yang et al., ACS Omega. 2020 Sep 29;5(40):25927-25935 59sf-6604130Attorney Docket No.245162001040

[0226] In some embodiments, the SHP-1 inhibitor targets the catalytic site. In some embodiments, 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. Methods for screening and identifying SHP-1 inhibitors (e.g., SHP-1 inhibitors targeting the catalytic site) are known in the field. For example, 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] In some embodiments, 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.

[0228] In some embodiments, 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.

[0229] In some embodiments, the SHP-1 inhibitor comprises TPI-1.

[0230] In some embodiments, the SHP-1 inhibitor is PTP-I.

[0231] In some embodiments, the SHP-1 inhibitor is vitamin E. In some embodiments, the SHP-1 inhibitor is tocofersolan (TPGS). In some embodiments, the SHP-1 inhibitor is α- tocopherol acetate (αTA). In some embodiments, the SHP-1 inhibitor is α-tocopheryl succinate (αTOS). 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. In some embodiments, 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. 60sf-6604130Attorney Docket No.245162001040

[0235] In some embodiments, the SHP-1 inhibitor is a dominant negative SHP-1 or a constitutively active SHP-1 mutant. See e.g., WO2009 / 023333.

[0236] In some embodiments, 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.

[0237] In some embodiments, the SHP-1 inhibitor is SB8091. See, e.g., Kim et al., Cancer Res (2024) 84 (6_Supplement): 1183.

[0238] 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.

[0239] 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. For example, a carboxyl group can be introduced at the 3-position of the dichlorophenyl ring to provide:61sf-6604130Attorney 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 RCis RCAor -C1-C4 alkyl-RCA, where RCAis -COOH, -NH2, or -OH; or a pharmaceutically acceptable salt thereof.

[0240] Various methods for preparing TPI-1 analogs are available. In one such method, an RC-substituted 2,5-dichloroaniline is suitably protected on its RCgroup (the protected RCgroup is indicated as RCPin the scheme below). Then 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. Should a longer linker be desired between the TPI-1 derivative and the molecule conjugated through the carboxylic acid, 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. Suitable protecting group approaches for RCAinclude esters where RCA= -COOH, carbamates or 62sf-6604130Attorney Docket No.245162001040 cleavable alkyl groups where RCA= -NH2, and silyl ethers, cleavable alkyl groups, or esters where RCA= -OH.

[0241] Alternatively, an approach through Pd-catalyzed biaryl coupling may be utilized. An RCsubstituted 2,5-dichloroaniline is suitably protected on its RCgroup (the protected RCgroup is indicated as RCPin the scheme below). The amino group is converted to a halide through a diazonium intermediate using t-butyl nitrite and copper halide (CuX2, e.g., CuBr2) (Sandmeyer reaction). Treatment of the aryl halide with 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. Suitable protecting group approaches for the RCAgroup include esters where RCA= -COOH, carbamates or cleavable alkyl groups where RCA= -NH2, and silyl ethers, cleavable alkyl groups, or esters where RCA= -OH. 63sf-6604130Attorney Docket No.245162001040. 64sf-6604130Attorney Docket No.245162001040

[0242] TPI-1 can also be used in perdeuterated form. For example, the compoundcan 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. Individuals

[0243] In some embodiments, 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.

[0245] In some embodiments, 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 65sf-6604130Attorney Docket No.245162001040 cell death (e.g., radiotherapy). In some embodiments, 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).

[0246] In some embodiments, 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). In some embodiments, 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).

[0247] In some embodiments, the individual does not have an autoimmune disease.

[0248] In some embodiments, the individual is a female. In some embodiments, the individual is a male.

[0249] In some embodiments, the individual is a human. In some embodiments, the individual is at least about 50, 55, 60, 65, 70 or 75 years old.

[0250] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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).

[0251] In some embodiments, the individual is at risk of developing systemic inflammation and / or CRS. In some embodiments, the individual develops systemic inflammation and / or 66sf-6604130Attorney 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. For example, 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.

[0252] In some embodiments, the individual is administered an agent that reduces systemic inflammation. In some embodiments, the administration occurs prior to the development of systemic inflammation in the individual. In some embodiments, the individual develops mild cytokine release syndrome. In some embodiments, 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.

[0253] In some embodiments, the individual does not develop severe cytokine release syndrome. In some embodiments, the individual does not develop CRS of grade 2. In some embodiments, the individual does not develop CRS of grade 3. In some embodiments, 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. 2018 Sep 24;11(1):121; and Shimabukuro-Vornhagen, A. et al., J Immunother Cancer. 2018 Jun 15;6(1):56, hereby incorporated by reference in their entirety.

[0254] In some embodiments, the individual has developed CRS prior to administration of an agent that reduces systemic inflammation. In some embodiments, the individual has developed CRS of grade 1. In some embodiments, the individual has developed CRS of grade 2. In some embodiments, the individual has developed CRS of grade 3. In some embodiments, the individual has developed CRS of grade 4. In some embodiments, the individual who has developed CRS is administered an agent that reduces systemic inflammation. In some embodiments, the agent that reduces systemic inflammation 67sf-6604130Attorney 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). Table 1. Cytokine release syndrome medical grading systems.68sf-6604130Attorney Docket No.245162001040embodiments, the individual develops mild cytokine storm. In some embodiments, the individual does not develop severe or life-threatening cytokine storm. Cytokine storm appears to be mainly a result of non-specific T cell activation, whereas CRS is more often a direct consequence of antigen-specific T cell activation. The clinical manifestations of cytokine storm and CRS can be similar (Liu, D. and Zhao, J., J Hematol Oncol. 2018 Sep 24;11(1):121). Cancer

[0256] Cancer as described herein can be any type or kind. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematologic cancer.

[0257] In some embodiments, the cancer is an advanced cancer. In some embodiments, the cancer is a late stage cancer. In some embodiments, the cancer is a terminal cancer. In some embodiments, 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.

[0259] Examples of 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 69sf-6604130Attorney 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, oligodenglioma, meningioma, craniopharyngioma, haemangioblastomas, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, and glioblastoma), breast cancer, bronchial adenomas / carcinoids, carcinoid tumor (e.g., gastrointestinal carcinoid tumor), carcinoma of unknown primary, central nervous system lymphoma, cervical cancer, colon cancer, colorectal cancer, chronic myeloproliferative disorders, endometrial cancer (e.g., uterine cancer), ependymoma, esophageal cancer, Ewing's family of tumors, eye cancer (e.g., intraocular melanoma and retinoblastoma), gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, (e.g., extracranial, extragonadal, ovarian), gestational trophoblastic tumor, head and neck cancer, hepatocellular (liver) cancer (e.g., hepatic carcinoma and heptoma), hypopharyngeal cancer, islet cell carcinoma (endocrine pancreas), laryngeal cancer, laryngeal cancer, leukemia, lip and oral cavity cancer, oral cancer, liver cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung), lymphoid neoplasm (e.g., lymphoma), medulloblastoma, melanoma, mesothelioma, metastatic squamous neck cancer, mouth cancer, multiple endocrine neoplasia syndrome, myelodysplastic syndromes, myelodysplastic / myeloproliferative diseases, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine cancer, oropharyngeal cancer, ovarian cancer (e.g., ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor), pancreatic cancer, parathyroid cancer, penile cancer, cancer of the peritoneal, pharyngeal cancer, pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, pleuropulmonary blastoma, lymphoma, primary central nervous system lymphoma (microglioma), pulmonary lymphangiomyomatosis, rectal cancer, renal cancer, renal pelvis and ureter cancer (transitional cell cancer), rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., non- melanoma (e.g., squamous cell carcinoma), melanoma, and Merkel cell carcinoma), small intestine cancer, squamous cell cancer, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, tuberous sclerosis, urethral cancer, vaginal cancer, vulvar cancer, Wilms' tumor, and post-transplant lymphoproliferative disorder (PTLD), abnormal vascular 70sf-6604130Attorney Docket No.245162001040 proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs' syndrome.

[0260] In some embodiments, the cancer is a virus-infection-related cancer. In some embodiments, 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). In some embodiments, the cancer is human herpes virus 8 (HHV8) related cancer (e.g., Kaposi sarcoma). In some embodiments, the cancer is human T-lymphotrophic virus (HTLV-1)-related cancer (e.g., adult T cell leukemia or lymphoma). In some embodiments, the cancer is Epstein-Barr virus (EBV) related cancer (e.g., Burkitt lymphoma, Hodgkin’s and non-Hodgkin’s lymphoma, stomach cancer). In some embodiments, the cancer is hepatitis B virus (HBV) related cancer (e.g., liver cancer). In some embodiments, the cancer is hepatitis C virus) related cancer (e.g., liver cancer, non-Hodgkin’s lymphoma).

[0261] In some embodiments, 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.

[0262] In some embodiments, 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)).

[0263] In some embodiments, the cancer is a recurrent or refractory cancer.

[0264] In some embodiments, the cancer is refractory to one or more of irradiation therapy, chemotherapy, or 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. In some aspects, 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. For example, in some aspects, the amount of SHP1I-PIA conjugate 71sf-6604130Attorney 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.

[0266] The SHP1I-PIA conjugate can be administered by any suitable means, for example, by bolus infusion, by injection, e.g., intravenous or subcutaneous injections. In some embodiments, the SHP1I-PIA conjugate is administered systemically (e.g., intravenously, subcutaneously, or intraperitoneally). In some embodiments, the SHP1I-PIA conjugate is administered locally (e.g., intratumorally).

[0267] In some embodiments, 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. In some embodiments, the SHP1I-PIA conjugate is administered orally.

[0268] It is also contemplated that the SHP1I-PIA conjugates described herein can be delivered via any proper vehicles or methods. In some embodiments, 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. In some embodiments, 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. In some embodiments, the SHP1I-PIA conjugate is connected with an antibody construct with via a linker (e.g., a cleavable linker). In some embodiments, the antibody construct specifically recognizes a tumor associated antigen. In some embodiments, the antibody construct comprises an antibody recognizing a tumor antigen. In some embodiments, the antibody construct is an antibody drug conjugate (ADC).

[0270] In some embodiments, 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). See examples 72sf-6604130Attorney Docket No.245162001040 of these methods or devices in e.g., Alsaggar et al., J Drug Target. 2018 Jun-Jul;26(5-6):385- 397; Zhao et al., Cell. 2020 Apr 2;181(1):151-167, which are incorporated by reference in their entirety.

[0271] In embodiments, 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. 2021 Oct; 26(19): 5905; Oh et al., Chem. Asian J. 2022, 17, e202200333, which are incorporated by reference in their entirety. Compositions comprising the SHP1I-PIA conjugate

[0272] The present application also provides compositions (e.g., pharmaceutical compositions) comprising the SHP1I-PIA conjugate for treatment as described above.

[0273] In some embodiments, there is provided a composition (e.g., a pharmaceutical 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). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0274] In some embodiments, there is provided a composition (e.g., a pharmaceutical 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 TLR agonist (e.g., CpG, polyI:C and / or R848)). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0275] In some embodiments, there is provided a composition (e.g., a pharmaceutical 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)). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0276] In some embodiments, there is provided a composition (e.g., a pharmaceutical 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)). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. 73sf-6604130Attorney Docket No.245162001040

[0277] In some embodiments, there is provided a composition (e.g., a pharmaceutical 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 TNFα)). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0278] In some embodiments, there is provided a composition (e.g., a pharmaceutical 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 checkpoint inhibitor (e.g., an anti-PD-L1 antibody, an anti-PD-1 antibody or an anti-CLTA4 antibody)). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0279] In some embodiments, there is provided a composition (e.g., a pharmaceutical 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)). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0280] In some embodiments, there is provided a composition (e.g., a pharmaceutical 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)). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0281] In some embodiments, there is provided a composition (e.g., a pharmaceutical 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)). In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. 74sf-6604130Attorney Docket No.245162001040 General Synthetic Procedures

[0282] The SHP1I-PIA conjugates described herein can be prepared by a variety of synthetic methods. The following synthetic methods are provided by way of illustration and not by way of limitation.

[0283] The SHP-1 inhibitor TP-1 can be conjugated to a pro-inflammatory agent in several ways, for example, as described below in Scheme 1. 75sf-6604130Attorney Docket No.245162001040 Scheme 1

[0284] The TP-1 derivative 2,5-dichloro-2',5'-dioxo-2',5'-dihydro-[1,1'-biphenyl]-3- carboxylic acid S1-1 can be esterified with a linking group PG-O-(C=O)-LP-OH (S1-2), where PG is a protecting group (such as t-butyl) and LP is part of the linking group, such as an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, or heteroaryl group, or any combination of those groups. 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- 76sf-6604130Attorney Docket No.245162001040 yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) can be used as coupling agents, in conjunction with the hindered bases diisopropyl ethylamine (DIPEA or DIEA) or triethylamine (TEA). The esterification gives intermediate S1-3, which can then be deprotected to form intermediate S1-4 with a free carboxyl group. The 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.

[0285] Similar compounds, but with an amide linkage to the TPI-1 derivative, can be prepared in a similar manner as follows in Scheme 2. 77sf-6604130Attorney Docket No.245162001040 Scheme 2

[0286] The TP-1 derivative 2,5-dichloro-2',5'-dioxo-2',5'-dihydro-[1,1'-biphenyl]-3- carboxylic acid S2-1 can be reacted with a linking group PG-O-(C=O)-LP-NH2 (S1-2), where PG is a protecting group (such as t-butyl) and LP is part of the linking group, such as an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, or heteroaryl group, or any combination of those groups. 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- 78sf-6604130Attorney Docket No.245162001040 yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) can be used as coupling agents, in conjunction with the hindered bases diisopropyl ethylamine (DIPEA or DIEA) or triethylamine (TEA). The reaction gives intermediate S1-3, which can then be deprotected to form intermediate S1-4 with a free carboxyl group. The 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. EXAMPLES

[0287] The synthetic (S) and biological (B) examples below are intended to be purely exemplary of the invention and should therefore not be considered to limit the invention in any way. The following examples and detailed description are offered by way of illustration and not by way of limitation. Compounds were named using the Struct=Name software of ChemDraw Professional Version 21. SYNTHETIC EXAMPLES Example S-179sf-6604130Attorney Docket No.245162001040R848-linker-TPI-1 ester conjugate (1-6): 4-((2-((1-(4-amino-2-(ethoxymethyl)-1H- imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl)amino)-4-oxobutyl 2,5- dichloro-2',5'-dioxo-2',5'-dihydro-[1,1'-biphenyl]-3-carboxylate

[0288] 2,5-dichloro-2',5'-dioxo-2',5'-dihydro-[1,1'-biphenyl]-3-carboxylic acid (1-1) (TPI-1 functionalized with a carboxylic acid group) (1.25 eq.) is added to a solution of 1.4 eq. hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) and 2 eq. diisopropylethylamine (DIPEA) in dimethylformamide (DMF) at 0°C. After 30 minutes, 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). The t-butyl group is removed using trifluoroacetic acid (TFA) in dichloromethane (DCM) to give 4-((2,5-dichloro-2',5'-dioxo-2',5'-dihydro-[1,1'-biphenyl]-3- carbonyl)oxy)butanoic acid (1-4). Compound (1-4) 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 nucleophile (1-5) (1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5- c]quinolin-4-amine) (1.05 eq). The reaction proceeds at 0°C for 15 minutes to give (1-6), 4- ((2-((1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2- yl)oxy)ethyl)amino)-4-oxobutyl 2,5-dichloro-2',5'-dioxo-2',5'-dihydro-[1,1'-biphenyl]-3- carboxylate. 80sf-6604130Attorney Docket No.245162001040 Example S-2R848-linker-TPI-1 amide conjugate (2-6): N-(4-((2-((1-(4-amino-2-(ethoxymethyl)-1H- imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl)amino)-4-oxobutyl)-2,5- dichloro-2',5'-dioxo-2',5'-dihydro-[1,1'-biphenyl]-3-carboxamide

[0289] 2,5-dichloro-2',5'-dioxo-2',5'-dihydro-[1,1'-biphenyl]-3-carboxylic acid (2-1) (TPI-1 functionalized with a carboxylic acid group) is added to a solution of HATU and DIPEA in DMF at 0°C. After 30 minutes, the amine t-butyl 4-aminobutanoate (2-2) is added. The reaction affords t-butyl 4-(2,5-dichloro-2',5'-dioxo-2',5'-dihydro-[1,1'-biphenyl]-3- carboxamido)butanoate (2-3). The t-butyl group is removed using trifluoroacetic acid (TFA) in dichloromethane (DCM) to give 4-(2,5-dichloro-2',5'-dioxo-2',5'-dihydro-[1,1'-biphenyl]- 3-carboxamido)butanoic acid (2-4). 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 81sf-6604130Attorney 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). The reaction proceeds at 0°C for 10 minutes to give (2-6), N- (4-((2-((1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2- yl)oxy)ethyl)amino)-4-oxobutyl)-2,5-dichloro-2',5'-dioxo-2',5'-dihydro-[1,1'-biphenyl]-3- carboxamide. Example S-3 Preparation of Perdeuterated 2-(2,5-Dichlorophenyl)-1,4-Benzoquinone

[0290] The procedure for coupling 1,4-benzoquinone with 1,4-dichlorobenzene to prepare 2- (2,5-dichlorophenyl)cyclohexa-2,5-diene-1,4-dione (i.e., 2-(2,5-dichlorophenyl)-1,4- benzoquinone) of Itahara, T., J. Org. Chem. 1985, 50, 5546-5550 is modified for preparation of the deuterated compound. A solution containing 1,4-benzoquinone, 1,4-dichlorobenzene, and palladium acetate in acetic acid is refluxed under nitrogen for 14 hours. The reaction mixture is evaporated and the residue is purified on a silica gel column eluted with benzene to give 2-(2,5-dichlorophenyl)-1,4-benzoquinone. 82sf-6604130Attorney Docket No.245162001040

[0291] 2-(2,5-dichlorophenyl)-1,4-benzoquinone-d6 is prepared by using perdeuterated starting materials. 1-4 benzoquinone-d4 (CAS Registry No. 2237-14-1) is commercially available from vendors such as Sigma-Aldrich or Clearsynth (Eliot, Maine). 1,4- dichlorobenzene-d4 (CAS Registry No. 3855-82-1) is also commercially available from vendors such as Sigma-Aldrich or Santa Cruz Biotechnology (Dallas, Texas). 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. 83sf-6604130Attorney Docket No.245162001040

[0293] A solution of NaNO2in 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. The diazonium salt solution is added slowly to an aqueous solution of 1,4- benzoquinone-d4 and sodium acetate. The precipitate is filtered off and washed with water to give 2-(2,5-dichlorophenyl)-1,4-benzoquinone-d6. BIOLOGICAL EXAMPLES

[0294] 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. These experiments demonstrate that R848-TPI-1 Ester and Amide conjugates possess properties of both R848, which through TLR7 / 8 triggers proinflammatory 84sf-6604130Attorney Docket No.245162001040 response, and TPI-1, which inhibits SHP-1 activity. In the tumor microenvironment (TME), simultaneous activation of intratumoral macrophages (TAM) while inhibiting SHP-1 activity is required for skewing TAM toward proinflammatory activation and antigen presentation, which leads to activation of T cell immunity and elimination of cancer. 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. 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 (1μM each), in the absence or presence of ovarian cancer cells (OVCAR5). Parallel treatments were performed using non-conjugated compounds R848 and TPI-1 (1μM 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. 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. 1C shows the results of assaying macrophage proinflammatory (TNFα 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. As shown, Ester and Amide conjugated R848-TPI-1 compounds resembled R848 + TPI-1, capable of skewing macrophages toward proinflammatory direction with high production of TNFα and IL-6 and low IL-10 even in the presence of cancer cell ligation. FIG. 1D shows macrophage expression of cell surface antigen presentation 85sf-6604130Attorney 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. As shown, 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 TNFα (in FIG. 1E, the amide curve is the upper curve and the ester curve is the lower curve).

[0297] As shown, in the absence of cancer cells, R848 treatment induced the typical proinflammatory response in macrophages, resulting in high production of TNFα and IL-6 and low IL-10. However, the presence of cancer cells skewed R848-induced macrophage activation towards anti-inflammatory direction with high IL-10, while diminishing TNFα and IL-6. This was because 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. Addition of TPI-1 (R848 + TPI-1) to inhibit SHP-1 abrogated negative regulation, unleashing R848-induced proinflammatory response and antigen presentation.

[0298] Treating macrophages with R848-TPI-1 Ester and Amide conjugates led to high production of TNFα and IL-6 and low IL-10 in the presence of cancer cells. These results suggest that both R848-TPI-1 Ester and Amide conjugates resembled R848 + TPI-1, not only did it activate TLR7 / 8 proinflammatory pathway but it also abrogated SHP-1 mediated negative regulation.

[0299] Conclusion: Treating macrophages with R848 in the presence of cancer cells failed to induce proinflammatory response (but enhanced anti-inflammatory IL-10 production), whereas treatment with R848 + TPI-1 enabled macrophages to overcome the presence of cancer cell ligation and unleashed TLR-triggered potent proinflammatory response. Treating R848 + TPI-1 also unleashed macrophage antigen presentation in the presence of cancer cell environment.

[0300] Both R848-TPI-1 Ester and Amide conjugates demonstrated effects that resemble R848 + TPI-1, enabling macrophages to drive proinflammatory response and antigen presentation in the presence of cancer cell ligation. 86sf-6604130Attorney Docket No.245162001040 Example B-2 Topical and / or systemic treatment using dTPI-1 in a murine lung cancer model Model-1: KPC pancreatic ductal adenocarcinoma.

[0301] KPC pancreatic ductal adenocarcinoma were established in the flank area of syngeneic mice C57BL6. After tumors were stably formed (> 200mm3), 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-TNFα was given to prevent treatment- associated CRS.

[0302] Results are in 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. In FIG. 2C, 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. In FIG. 2D, TME analyses on d5 revealed significant increases in CD8 T cells (Tc) and NK cells, while immunosuppressive components including MDSC were reduced.

[0303] Conclusions: These results show that treating KPC tumors with R848-TPI-1 Ester or Amide conjugated compound dose-dependently induced strong immunity response in vivo, effectively restraining cancer progression or having induced tumor regression. TME analyses confirmed that R848-TPI-1 conjugates had induced TAM proinflammatory activation and the capacity of immunogenic antigen presentation, leading to reprogramming of the TME and increases in CD8 T cells and NK cells, while reducing immunosuppressive MDSC, together contributing to tumor suppression. Model-2: LLC lung cancer

[0304] Murine lung cancer (LLC-luc) was s.c. engrafted into the right flank of syngeneic C57BL6 mice. After cancer formation, mice were treated with either with anti-PD-1 (αPD-1, 100ug, i.p. every 3 days), or R848-TPI-1 Ester compound (3mg / kg, s.c. daily) + αPD-1, or R848-TPI-1 Amide compound (3mg / kg, s.c. daily) + αPD-1. A dose of anti-TNFα was given to mice 3h before the first dose of topical therapies for prophylactic neutralization of TNFα to ameliorate treatment-associated CRS. The experimental design is shown in FIG. 3A. 87sf-6604130Attorney 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 (mm3) 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. In FIG. 3D, TME analyses revealed that both Ester and Amide treatments combined with αPD-1 significantly increased CD8 T cells (Tc), which attributed to tumor elimination.

[0306] Conclusion: Both R848-TPI-1 Ester compound and Amide compound induced strong anti-cancer T cell immunity against lung cancer. The effects by R848-TPI-1 compounds are likely synergistic with immune check point inhibitor anti-PD-1. Example B-3 In vitro assays of dTPI-1 for the capability to inhibit SHP-1 in macrophages within a tumor environment

[0307] Human monocytes-derived macrophages in culture were stimulated with TLR agonist R848 (1μg / ml) and IFNγ (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. After 20min of stimulation, cells were lysed in 1% Triton containing PBS, followed by assaying protein tyrosine phosphatase activity in supernatants using pNPP as the substrate. To study how dTPI-1 affects macrophage expression of the cell surface antigen presentation machinery and production of inflammatory cytokines, the macrophage and TK10 co-culture after stimulation with R848 ± dTPI-1 were cultured overnight (18h), followed by detecting macrophage surface MHC-I and -II, CD80, CD86, and CD40. Cell culture medium was collected, in which macrophage secreted cytokines were detected by ELISA.

[0308] 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 IFNγ ± 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. Strong SHP-1 activity (labeled) was induced in macrophages by aTLR stimulation plus cancer cell ligating macrophage iRs. As shown, 88sf-6604130Attorney 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 (TNFα) production.

[0309] These results demonstrate that dTPI-1 dose-dependently inhibited macrophage iRs ligation-induced activation of SHP-1 upon TLR agonist stimulation, confirming dTPI-1 is an effective SHP-1 inhibitor. These studies show that inhibition of SHP-1 overcomes cancer cells-imposed inhibition on macrophages, unleashing macrophage proinflammatory response and antigen presentation within a tumor environment. Example B-4 R848 and / or dTPI-1 treatment in a murine metastatic melanoma model

[0310] Lung metastases of B16 melanoma were established in syngeneic mice C57BL6. After melanoma were formed in lungs (day 12), mice were treated with TLR agonists (aTLR: R848 and polyI:C), dTPI-1, or aTLR and dTPI-1 combination. A dose of prophylactic anti- TNFα was given to mice 3h before treatments to ameliorate treatment-associated CRS. FIG. 5A shows the experimental scheme.

[0311] 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. Example B-5 Topical and / or systemic treatment using dTPI-1 in a murine lung cancer model

[0312] 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.

[0313] FIG. 6A shows the experimental design. The treatments include: 89sf-6604130Attorney Docket No.245162001040 Control treatment (ctl.); mice were given topical non-drug lotion (vehicle) only. αPD-1; anti-PD-1 mAb (100μg, i.p., once every 3 days) was given to mice with topical non-drug lotion treatment. Topical treatments with TLR agonists (aTLR) + dTPI-1 + αPD-1. TLR agonists Resiquimod (R848) and PolyI:C, together with dTPI-1, were prepared in Johnson’s lotion, each at 100μg / ml, topical application 2x per day, each 100-200μl lotion. Anti- PD-1 mAb (100μg, i.p., once every 3 days) Topical treatments with Stine activators (aSting) + dTPI-1 + αPD-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 100μg / ml in lotion, were given as topical application, 2x per day, each 100-200μl lotion.

[0314] A dose of anti-TNFα was given to mice 3h before the first dose of topical therapies for prophylactic neutralization of TNFα to ameliorate treatment-associated CRS.

[0315] Results are shown in FIGS. 6B-6D. FIG. 6B are bioluminescence images that show that LLC tumor burden changes post treatment. In FIGS. 6C-6D, 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] In conclusion, 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. TME analyses suggest that the effects of TLR agonists or Sting activators plus dTPI- 1 were through activate intratumoral macrophages (TAM) for proinflammatory response and antigen presentation that activate strong anti-cancer T cell immunity.

[0317] The disclosures of all publications, patents, patent applications and published patent applications referred to herein by an identifying citation are hereby incorporated herein by reference in their entirety. Web sites referenced using “World-Wide-Web” at the beginning of the Uniform Resource Locator (URL) can be accessed by replacing “World-Wide-Web” with www. 90sf-6604130Attorney Docket No.245162001040

[0318] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention. 91sf-6604130

Claims

Attorney Docket No.245162001040 CLAIMS What is claimed is:

1. A conjugate comprising a SHP-1 inhibitor covalently conjugated to a pro-inflammatory agent, wherein the conjugate is of the formula PIA-LA-R1, or a salt thereof, wherein PIA is a pro-inflammatory agent, LAis an optional linker, and R1is a SHP-1 inhibitor or a tyrosine kinase inhibitor.

2. The conjugate of claim 1, or a salt thereof, wherein the pro-inflammatory agent comprises a TLR agonist, a STING activator, a PAMP / DAMP molecule, a checkpoint inhibitor, a pro- inflammatory cytokine, a chemotherapeutic agent, or a bacterial component.

3. The conjugate of claim 1, or a salt thereof, wherein the pro-inflammatory agent comprises a TLR agonist.

4. The conjugate of claim 3, or a salt thereof, wherein the TLR agonist activates a TLR on a macrophage.

5. The conjugate of claim 3, or a salt thereof, wherein the TLR agonist activates TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, and / or TLR9.

6. The conjugate of claim 3, or a salt thereof, wherein the TLR agonist comprises a DNA molecule or an RNA molecule.

7. The conjugate of claim 3, or a salt thereof, wherein the TLR agonist comprises a cytosine– phosphate–guanine (CpG) oligodeoxynucleotide, polyinosinic-polycytidylic acid (polyI:C), R837, R848, flagellin, zymosan, or HMGB1.

8. The conjugate of claim 3, or a salt thereof, wherein the TLR agonist comprises R837.

9. The conjugate of claim 3, or a salt thereof, wherein the TLR agonist comprises R848. 92sf-6604130Attorney Docket No.245162001040 10. The conjugate of claim 9 of the formula:or a salt thereof, wherein LAis an optional linker and R1is a SHP-1 inhibitor.

11. The conjugate of claim 10 of the formula:, or a salt thereof. 93sf-6604130Attorney Docket No.245162001040 12. The conjugate of claim 10 of the formula:, or a salt thereof.

13. The conjugate of claim 10 of the formula:, or a salt thereof.

14. The conjugate of claim 1, or a salt thereof, wherein the pro-inflammatory agent comprises a STING activator. 94sf-6604130Attorney Docket No.245162001040 15. The conjugate of claim 14 of the formula:or a salt thereof, wherein LAis an optional linker and R1is a SHP-1 inhibitor.

16. The conjugate of claim 14 of the formula:or a salt thereof, wherein LAis an optional linker and R1is a SHP-1 inhibitor. 95sf-6604130Attorney Docket No.245162001040 17. The conjugate of claim 14 of the formula:or a salt thereof, wherein LAis an optional linker and R1is a SHP-1 inhibitor.

18. The conjugate of claim 14 of the formula:or a salt thereof, wherein one G substituent is -LA-R1and the other two G substituents are H, LAis an optional linker, and R1is a SHP-1 inhibitor. 96sf-6604130Attorney Docket No.245162001040 19. The conjugate of claim 14 of the formula:or a salt thereof, wherein LAis an optional linker and R1is a SHP-1 inhibitor.

20. The conjugate of claim 14, wherein the STING activator comprises 2’3’-cGAMP 21. The conjugate of claim 1 or claim 2, or a salt thereof, wherein the pro-inflammatory agent comprises a PAMP / DAMP molecule.

22. The conjugate of claim 1 or claim 2, or a salt thereof, wherein the pro-inflammatory agent comprises a checkpoint inhibitor.

23. The conjugate of claim 22, or a salt thereof, wherein the checkpoint inhibitor comprises an anti-PD-L1 antibody, an anti-PD-1 antibody or an anti-CLTA4 antibody.

24. The conjugate of claim 1 or claim 2, or a salt thereof, wherein the pro-inflammatory agent comprises a pro-inflammatory cytokine.

25. The conjugate of claim 24, or a salt thereof, wherein the pro-inflammatory cytokine comprises IL-1b, IL-18, IL-6, and / or TNFα.

26. The conjugate of claim 1 or claim 2, or a salt thereof, wherein the pro-inflammatory agent comprises a chemotherapeutic agent. 97sf-6604130Attorney Docket No.245162001040 27. The conjugate of claim 26, or a salt thereof, wherein the chemotherapeutic agent comprises azathioprine (AZA).

28. The conjugate of claim 1 or claim 2, or a salt thereof, wherein the pro-inflammatory agent comprises a bacterial component.

29. The conjugate of claim 28, or a salt thereof, wherein the bacterial component comprises a lipopolysaccharide.

30. The conjugate of any one of claims 1-10 or 14-29, or a salt thereof, wherein optional linker LAis between 1 and 25 atoms in length.

31. The compound of any one of claims 1-10 or 14-29, or a salt thereof, wherein LAis –(CH2CH2O)n- or –(OCH2CH2)n-, where n is an integer between 1 and 8 inclusive; or LAis C1-C12alkyl, C2-C12alkenyl, C2-C12alkynyl, 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 RAgroups; or LAis L1-L2-L3, where L1is 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 of N, O, and S, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl are optionally substituted with one, two, or three RAgroups; L2is C3-C8cycloalkyl, C6-C10aryl, three-to-twelve-membered heterocyclyl, or five-to-twelve-membered heteroaryl, wherein the cycloalkyl or heterocyclyl are optionally substituted with one, two, or three RAgroups, and the aryl or heteroaryl are optionally substituted with one, two, or three RBgroups; and L3is 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 of N, O, and S, wherein the 98sf-6604130Attorney Docket No.245162001040 alkyl, alkenyl, alkynyl, or heteroalkyl are optionally substituted with one, two, or three RAgroups; where RAis C1-C4 alkyl, -OH, -O-C1-C6, oxo, F, Cl, Br, I, -CN, or -NO2, and RBis C1-C4alkyl, -OH, -O-C1-C6, F, Cl, Br, I, -CN, or -NO2.

32. The compound of any one of claims 1-10 or 14-29, or a salt thereof, wherein LAis:, wherein the wavy bonds indicate the bonds attaching LAto the remainder of the molecule.

33. The conjugate of any one of claims 1-10 or 14-32, or a salt thereof, wherein R1is selected from the group consisting of a small molecule, a nucleic acid, a siRNA, a shRNA, an antisense RNA, a microRNA, a protein agent, an antibody agent that targets SHP-1 or activated SHP-1, TPI-1 or an analog or a derivative thereof, vitamin E, a vitamin E derivative, a tocopherol, a tocotrienol, phomoxanthone A (PXA), and a PKC-theta activator. 99sf-6604130Attorney Docket No.245162001040 34. The conjugate of any one of claims 1-10 or 14-32, or a salt thereof, wherein R1comprises a small organic molecule.

35. The conjugate of claim 34, or a salt thereof, wherein the small organic molecule comprises a tocopherol or a tocotrienol.

36. The conjugate of claim 34, or a salt thereof, wherein the small organic molecule comprises alpha-tocopherol.

37. The conjugate of claim 34, or a salt thereof, wherein the small organic molecule comprises phomoxanthone A (PXA).

38. The conjugate of claim 34, or a salt thereof, wherein R1is.

39. The conjugate of claim 38, or a salt thereof, wherein 100sf-6604130Attorney Docket No.245162001040is perdeuterated.

40. The conjugate of any one of claims 1-10 or 14-33, or a salt thereof, wherein R1comprises a nucleic acid.

41. The conjugate of claim 40, or a salt thereof, wherein the nucleic acid comprises a siRNA, a shRNA, an antisense RNA, or a microRNA.

42. The conjugate of any one of claims 1-10 or 14-33, or a salt thereof, wherein R1comprises a protein.

43. The conjugate of claim 42, or a salt thereof, wherein the protein comprises an antibody that binds SHP-1 or activated SHP-1 44. The conjugate of claim 42, or a salt thereof, wherein the protein contains an SH2 domain.

45. The conjugate of any one of claims 1-10 or 14-33, or a salt thereof, wherein the SHP-1 inhibitor comprises a PKC-theta activator.

46. The conjugate of any one of claims 1-10 or 14-33, or a salt thereof, wherein R1comprises a tyrosine kinase inhibitor.

47. The conjugate of any one of claims 1-10 or 14-33, or a salt thereof, wherein R1comprises an agent that inhibits a tyrosine kinase or SHP-1 signaling (“TK / SHP-1 inhibitor”). 101sf-6604130Attorney Docket No.245162001040 48. The conjugate of any one of claims 1-10 or 14-33, or a salt thereof, wherein R1comprises a tyrosine kinase inhibitor that inhibits ITIM phosphorylation.

49. A method of treating a cancer in an individual, comprising administering to the individual a conjugate comprising a SHP-1 inhibitor covalently conjugated to a pro- inflammatory agent, or a salt thereof.

50. A method of treating a cancer in an individual, comprising administering to the individual the conjugate of any one of claims 1-48, or a salt thereof.

51. The method of claim 49 or claim 50, wherein the method comprises administering the conjugate or a salt thereof to the individual systemically.

52. The method of claim 51, wherein the systemic administration comprises oral administration, intravenous administration, subcutaneous administration, and / or intraperitoneal administration.

53. The method of claim 49 or claim 50, wherein the method comprises administering the conjugate or a salt thereof to the individual intratumorally.

54. The method of any one of claims 49-53, wherein the method comprises administering the conjugate or a salt thereof to the individual intermittently.

55. The method of any one of claims 49-54, further comprising administering to the individual an effective amount of an anti-TNFα antibody.

56. The method of any one of claims 49-55, wherein the cancer is a solid tumor.

57. The method of any one of claims 49-55, wherein the cancer is a hematological cancer.

58. The method of any one of claims 49-55, wherein the cancer is a late stage cancer. 102sf-6604130Attorney Docket No.245162001040 59. The method of any one of claims 49-57, wherein the cancer is resistant or refractory to a radiation therapy, a chemotherapeutic agent, and / or a checkpoint inhibitor. 60 The method of any one of claims 49-59, wherein the individual is a human.

61. The compound of any one of claims 1-10 or 14-29, or a salt thereof, wherein LAis –O-(CH2CH2O)n-, –(OCH2CH2)n–O–, or -L4-PEG-L4-, where n is an integer between 1 and 8 inclusive, PEG is ethylene glycol or polyethylene glycol having between 2 and 8 ethylene glycol units, and each L4 is independently absent or -O-, -NH-, -CH2-, -O-(C=O)-, -(C=O)-O-,-NH-(C=O)-,or -(C=O)- NH-; or LAis L5-L6-L7-L8-L9, where L5is -O-, -NH-, -CH2-, -(C=O)-, -O-(C=O)-, -(C=O)-O-,-NH-(C=O)-,or - (C=O)-NH-; L6is absent or 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 of N, O, and S, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl are optionally substituted with one, two, or three RAgroups; L7is absent or C3-C8cycloalkyl, C6-C10aryl, three-to-twelve-membered heterocyclyl, or five-to-twelve-membered heteroaryl, wherein the cycloalkyl or heterocyclyl are optionally substituted with one, two, or three RAgroups, and the aryl or heteroaryl are optionally substituted with one, two, or three RBgroups; L8is absent or 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 of N, O, and S, wherein the alkyl, alkenyl, alkynyl, or heteroalkyl are optionally substituted with one, two, or three RAgroups; with the proviso that at least one of L6, L7, or L8is not absent; and L9is -O-, -NH-, -CH2-, -(C=O)-, -O-(C=O)-, -(C=O)-O-,-NH-(C=O)-,or - (C=O)-NH-; where RAis C1-C4 alkyl, -OH, -O-C1-C6, oxo, F, Cl, Br, I, -CN, or -NO2, and RBis C1-C4alkyl, -OH, -O-C1-C6, F, Cl, Br, I, -CN, or -NO2. 103sf-6604130

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