Methods and compositions for treating hematological cancers

Abstract

The present disclosure features methods and compositions for the treatment of hematological cancers.

Description

[0001] METHODS AND COMPOSITIONS FOR TREATING HEMATOLOGICAL CANCERS

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] The present application claims priority to U.S. Provisional Patent Application No. 63 / 534,237, filed on August 23, 2023. The contents of that application are incorporated herein by reference in its entirety.

[0004] TECHNICAL FIELD

[0005] The present disclosure relates to methods and compositions for treating hematological cancers.

[0006] BACKGROUND

[0007] Acute myeloid leukemia (AML) is an aggressive and heterogeneous disease with less than 30% of patients with AML surviving past 5 years. More than half of patients with AML relapse and 40-60% of patients become refractory to chemotherapeutic agents despite highly toxic, intensive therapy. Less than 13% of patients with relapsed or refractory AML (RR-AML) survive past 5 years and patients that do survive suffer significant toxi cities related to intensive chemotherapy regimens.

[0008] Treatment for patients with AML continues to rely heavily on conventional chemotherapy with a shift towards lower-intensity regimens using hypomethylating agents or low-dose cytarabine with venetoclax. Other more targeted approaches including therapies against genetic mutations or immune checkpoint inhibitors have not been as successful in AML compared to other cancers. Lack of response, resistance, and / or eventual relapse to these therapies are attributed to the polyclonal nature of the disease.

[0009] SUMMARY

[0010] Antigen-directed therapies such as antibody-drug conjugates (ADCs), bi-specific antibodies, and chimeric antigen receptor T cells (CAR Ts) have produced compelling clinical responses in a few types of cancer but have underperformed in many other cancers. The success of these antigen-directed therapies requires the target antigen to be expressed at sufficient levels among cancer cells while at low or undetectable levels on critical healthy tissues in order to drive the efficacy and the therapeutic window. Most cancers lack such antigens, which causes suboptimal clinical benefits of these therapies due to limited efficacy resulting from low levels of target antigen on tumor cells or toxicity resulting from high levels of target antigen on normal cells. In many cases, the failure of an antigen-directed therapy has less to do with a lack of potency or specificity of the agent, but more to do with heterogenous and suboptimal target expression in the tumor in patients. CD33 and CD 123 are the two most commonly expressed antigens in AML, but antigen-directed therapies targeting either of them have had limited clinical success, partially attributed to intrapatient and interpatient heterogeneity.

[0011] The present invention is based on the discovery that MEK1 / 2 inhibitors, SHP2 inhibitors, RAS, S0S1, RAF, and / or ERK inhibitors result in an increase in the expression of CD123 in CD 123 -positive hematological cancer cells and CD 123 -negative hematological cancer cells, and makes the CD 123 -positive and CD 123 -negative hematological cancer cells more sensitive to treatment with a CD 123 -targeted therapeutic agent. The present invention is also based on the discovery that MEK1 / 2 inhibitors, SHP2 inhibitors, RAS, S0S1, RAF, and ERK inhibitors do not result in a significant increase in CD123 expression in non-cancerous cells.

[0012] In view of these discoveries, provided herein are methods of treating a hematological cancer in a subject, the method including administering to the subject an effective amount of a MEK1 / 2 inhibitor and an effective amount of a CD 123 -targeted therapeutic agent.

[0013] In some embodiments, the method includes administering the MEK1 / 2 inhibitor to the subject prior to administering the CD 123 -targeted therapeutic agent to the subject. In some embodiments, the method includes administering the MEK1 / 2 inhibitor to the subject at substantially the same time as administering the CD 123 -targeted therapeutic agent to the subject. In some embodiments, the subject was previously administered a CD 123 -targeted therapeutic agent without a MEK1 / 2 inhibitor, and the subject was not responsive to treatment with the CD 123 -targeted therapeutic agent without the MEK1 / 2 inhibitor.

[0014] In some embodiments, the CD 123 -targeted therapeutic agent is an antibody or an antigen-binding antibody fragment. In some embodiments, the antibody is talacotuzumab.

[0015] In some embodiments, the CD 123 -targeted therapeutic agent is an antibody drug conjugate (ADC). In some embodiments, the ADC is selected from the group of pivekimab sunirine, SGN-CD123A, BYON4413, and VIP943. In some embodiments, the CD 123 -targeted therapeutic agent is a fusion protein. In some embodiments, the fusion protein is tagraxofusp.

[0016] In some embodiments, the CD 123 -targeted therapeutic agent is a T cell engager or an NK cell engager. In some embodiments, the T cell engager or the NK cell engager is selected from the group consisting of: APVO436, flotetuzumab, vibecotamab, SAR443579, IGM-2537, and AFM28.

[0017] In some embodiments, the CD 123 -targeted therapeutic agent is a darpin. In some embodiments, the darpin is MP0533.

[0018] In some embodiments, the CD 123 -targeted therapeutic agent is a CAR T cell or a CAR NK cell. In some embodiments, the CAR T cell is ACLX-002 or AUTO1.

[0019] In some embodiments, the MEK1 / 2 inhibitor is an allosteric inhibitor. In some embodiments, the MEK1 / 2 inhibitor is selected from the group consisting of: trametinib, cobimetinib, selumetinib, binimetinib, mirdametinib, pimasertib, avutometinib, and GDC-0623.

[0020] In some embodiments, the MEK1 / 2 inhibitor is an ATP-competitive inhibitor. In some embodiments, the ATP-competitive inhibitor is MAP855.

[0021] In some embodiments, the MEK1 / 2 inhibitor is a proteolysis targeted chimera (PROTAC). In some embodiments, the PROTAC is MS432.

[0022] In some embodiments, the MEK1 / 2 inhibitor is a glue. In some embodiments, the glue is Trameti lue.

[0023] In some embodiments, the hematological cancer is a CD 123 -positive hematological cancer. In some embodiments, the subject has previously been identified or diagnosed as having a CD 123 -positive hematological cancer.

[0024] In some embodiments, the hematological cancer is a CD 123 -negative hematological cancer. In some embodiments, the subject has previously been identified or diagnosed as having a CD 123 -negative hematological cancer.

[0025] In some embodiments, the hematological cancer is a lymphoma or a leukemia. In some embodiments, the leukemia is acute myeloid leukemia (AML) or B cell lymphoblastic leukemia (B-ALL). In some embodiments, the hematological cancer is blastic plasmacytoid dendritic cell neoplasm (BPDCN).

[0026] Also provided herein are pharmaceutical compositions including an effective amount of a MEK1 / 2 inhibitor and an effective amount of a CD 123 -targeted therapeutic agent. In some embodiments, the CD 123 -targeted therapeutic agent is an antibody or an antigen-binding antibody fragment. In some embodiments, the antibody is talacotuzumab.

[0027] In some embodiments, the CD 123 -targeted therapeutic agent is an antibody drug conjugate (ADC). In some embodiments, the ADC is selected from the group of pivekimab sunirine, SGN-CD123A, BYON4413, and VIP943.

[0028] In some embodiments, the CD 123 -targeted therapeutic agent is a fusion protein. In some embodiments, the fusion protein is tagraxofusp.

[0029] In some embodiments, the CD 123 -targeted therapeutic agent is a T cell engager or an NK cell engager. In some embodiments, the T cell engager or the NK cell engager is selected from the group consisting of: APVO436, flotetuzumab, vibecotamab, SAR443579, IGM-2537, and AFM28.

[0030] In some embodiments, the CD 123 -targeted therapeutic agent is a darpin. In some embodiments, the darpin is MP0533.

[0031] In some embodiments, the CD 123 -targeted therapeutic agent is a CAR T cell or a CAR NK cell. In some embodiments, the CAR T cell is ACLX-002 or AUTO1.

[0032] In some embodiments, the MEK1 / 2 inhibitor is an allosteric inhibitor. In some embodiments, the MEK1 / 2 inhibitor is selected from the group consisting of: trametinib, cobimetinib, selumetinib, binimetinib, mirdametinib, pimasertib, avutometinib, and GDC-0623.

[0033] In some embodiments, the MEK1 / 2 inhibitor is an ATP-competitive inhibitor. In some embodiments, the ATP-competitive inhibitor is MAP855.

[0034] In some embodiments, the MEK1 / 2 inhibitor is a proteolysis targeted chimera (PROTAC). In some embodiments, the PROTAC is MS432.

[0035] In some embodiments, the MEK1 / 2 inhibitor is a glue. In some embodiments, the glue is Trametiglue.

[0036] Also provided herein are methods of increasing expression of CD123 in a hematological cancer cell, the method including contacting the hematological cancer cell with a MEK1 / 2 inhibitor.

[0037] In some embodiments, the MEK1 / 2 inhibitor is an allosteric inhibitor. In some embodiments, the MEK1 / 2 inhibitor is selected from the group consisting of: trametinib, cobimetinib, selumetinib, binimetinib, mirdametinib, pimasertib, avutometinib, and GDC-0623. In some embodiments, the MEK1 / 2 inhibitor is an ATP-competitive inhibitor. In some embodiments, the ATP-competitive inhibitor is MAP855.

[0038] In some embodiments, the MEK1 / 2 inhibitor is a proteolysis targeted chimera (PROTAC). In some embodiments, the PROTAC is MS432.

[0039] In some embodiments, the MEK1 / 2 inhibitor is a glue. In some embodiments, the glue is Trametiglue.

[0040] In some embodiments, the hematological cancer cell is in vitro. In some embodiments, the hematological cancer cell is in a subject. In some embodiments, the hematological cancer cell is a leukemia cell or a lymphoma cell. In some embodiments, the leukemia cell is an acute myeloid leukemia cell or B cell lymphoblastic leukemia cell. In some embodiments, the hematological cancer cell is a blastic plasmacytoid dendritic cell neoplasm (BPDCN) cell.

[0041] Also provided herein are methods of sensitizing a subject having a hematological cancer for treatment with a CD 123 -targeted therapeutic agent, the method including administering an effective amount of a MEK1 / 2 inhibitor to the subject.

[0042] Also provided herein are methods of increasing the therapeutic effect of a CD123- targeted therapeutic agent in a subject having a hematological cancer, the method including administering an effective amount of a MEK1 / 2 inhibitor to the subject.

[0043] In some embodiments, the increased therapeutic effect is an increase in hematological cancer cell death.

[0044] In some embodiments, the MEK1 / 2 inhibitor is an allosteric inhibitor. In some embodiments, the MEK1 / 2 inhibitor is selected from the group consisting of: trametinib, cobimetinib, selumetinib, binimetinib, mirdametinib, pimasertib, avutometinib, and GDC-0623.

[0045] In some embodiments, the MEK1 / 2 inhibitor is an ATP-competitive inhibitor. In some embodiments, the ATP-competitive inhibitor is MAP855.

[0046] In some embodiments, the MEK1 / 2 inhibitor is a proteolysis targeted chimera (PROTAC). In some embodiments, the PROTAC is MS432.

[0047] In some embodiments, the MEK1 / 2 inhibitor is a glue. In some embodiments, the glue is Trametiglue.

[0048] In some embodiments, the hematological cancer is a CD 123 -positive hematological cancer. In some embodiments, the hematological cancer is a CD 123 -negative hematological cancer. In some embodiments, the hematological cancer is a leukemia or a lymphoma. In some embodiments, the leukemia is acute myeloid leukemia or B cell acute lymphoblastic leukemia (B-ALL). In some embodiments, the hematological cancer is blastic plasmacytoid dendritic cell neoplasm (BPDCN).

[0049] Also provided herein are methods of treating a hematological cancer in a subject, the method including administering to the subject an effective amount of a SHP2 inhibitor and an effective amount of a CD 123 -targeted therapeutic agent.

[0050] In some embodiments, the method includes administering the SHP2 inhibitor to the subject prior to administering the CD 123 -targeted therapeutic agent to the subject. In some embodiments, the method includes administering the SHP2 inhibitor to the subject at substantially the same time as administering the CD 123 -targeted therapeutic agent to the subject. In some embodiments, the subject was previously administered a CD 123 -targeted therapeutic agent without a SHP2 inhibitor, and the subject was not responsive to treatment with the CD 123- targeted therapeutic agent without the SHP2 inhibitor.

[0051] In some embodiments, the CD 123 -targeted therapeutic agent is an antibody or an antigen-binding antibody fragment. In some embodiments, the antibody is talacotuzumab.

[0052] In some embodiments, the CD 123 -targeted therapeutic agent is an antibody drug conjugate (ADC). In some embodiments, the ADC is selected from the group of pivekimab sunirine, SGN-CD123A, BYON4413, and VIP943.

[0053] In some embodiments, the CD 123 -targeted therapeutic agent is a fusion protein. In some embodiments, the fusion protein is tagraxofusp.

[0054] In some embodiments, the CD 123 -targeted therapeutic agent is a T cell engager or an NK cell engager. In some embodiments, the T cell engager or the NK cell engager is selected from the group consisting of: APVO436, flotetuzumab, vibecotamab, SAR443579, IGM-2537, and AFM28.

[0055] In some embodiments, the CD 123 -targeted therapeutic agent is a darpin. In some embodiments, the darpin is MP0533.

[0056] In some embodiments, the CD 123 -targeted therapeutic agent is a CAR T cell or a CAR NK cell. In some embodiments, the CAR T cell is ACLX-002 or AUTO1.

[0057] In some embodiments, the SHP2 inhibitor is an allosteric inhibitor. In some embodiments, the SHP2 inhibitor is selected from the group consisting of: batoprotafib, RMC- 4550, SHP099, RMC-4630, GDC-1971 (RLY-1971), PF-07284892, BBP-398 (IACS-13909), and JAB -3068.

[0058] In some embodiments, the hematological cancer is a CD 123 -positive hematological cancer. In some embodiments, the subject has previously been identified or diagnosed as having a CD 123 -positive hematological cancer. In some embodiments, the hematological cancer is a CD 123 -negative hematological cancer. In some embodiments, the subject has previously been identified or diagnosed as having a CD 123 -negative hematological cancer.

[0059] In some embodiments, the hematological cancer is a lymphoma or a leukemia. In some embodiments, the leukemia is acute myeloid leukemia (AML) or B cell lymphoblastic leukemia (B-ALL). In some embodiments, the hematological cancer is blastic plasmacytoid dendritic cell neoplasm (BPDCN).

[0060] Also provided herein are pharmaceutical compositions including an effective amount of a SHP2 inhibitor and an effective amount of a CD 123 -targeted therapeutic agent.

[0061] In some embodiments, the CD 123 -targeted therapeutic agent is an antibody or an antigen-binding antibody fragment. In some embodiments, the antibody is talacotuzumab.

[0062] In some embodiments, the CD 123 -targeted therapeutic agent is an antibody drug conjugate (ADC). In some embodiments, the ADC is selected from the group of pivekimab sunirine, SGN-CD123A, BYON4413, and VIP943.

[0063] In some embodiments, the CD 123 -targeted therapeutic agent is a fusion protein. In some embodiments, the fusion protein is tagraxofusp.

[0064] In some embodiments, the CD 123 -targeted therapeutic agent is a T cell engager or an NK cell engager. In some embodiments, the T cell engager or the NK cell engager is selected from the group consisting of APVO436, flotetuzumab, vibecotamab, SAR443579, IGM-2537, and AFM28.

[0065] In some embodiments, the CD 123 -targeted therapeutic agent is a darpin. In some embodiments, the darpin is MP0533.

[0066] In some embodiments, the CD 123 -targeted therapeutic agent is a CAR T cell or a CAR NK cell. In some embodiments, the CAR T cell is ACLX-002 or AUTO1.

[0067] In some embodiments, the SHP2 inhibitor is an allosteric inhibitor. In some embodiments, the SHP2 inhibitor is selected from the group consisting of batoprotafib, RMC- 4550, SHP099, RMC-4630, GDC-1971 (RLY-1971), PF-07284892, BBP-398 (IACS-13909), and JAB -3068.

[0068] Also provided herein are methods of increasing expression of CD123 in a hematological cancer cell, the method including contacting the hematological cancer cell with a SHP2 inhibitor.

[0069] In some embodiments, the SHP2 inhibitor is an allosteric inhibitor. In some embodiments, the SHP2 inhibitor is selected from the group consisting of batoprotafib, RMC- 4550, SHP099, RMC-4630, GDC-1971 (RLY-1971), PF-07284892, BBP-398 (IACS-13909), and JAB -3068.

[0070] In some embodiments, the hematological cancer cell is in vitro. In some embodiments, the hematological cancer cell is in a subject.

[0071] In some embodiments, the hematological cancer cell is a leukemia cell or a lymphoma cell. In some embodiments, the leukemia cell is an acute myeloid leukemia cell or B cell lymphoblastic leukemia cell. In some embodiments, the hematological cancer cell is a blastic plasmacytoid dendritic cell neoplasm (BPDCN) cell.

[0072] Also provided herein are methods of sensitizing a subject having a hematological cancer for treatment with a CD 123 -targeted therapeutic agent, the method including administering an effective amount of a SHP2 inhibitor to the subject.

[0073] Also provided herein are methods of increasing the therapeutic effect of a CD123- targeted therapeutic agent in a subject having a hematological cancer, the method including administering an effective amount of a SHP2 inhibitor to the subject.

[0074] In some embodiments, the increased therapeutic effect is an increase in hematological cancer cell death.

[0075] In some embodiments, the SHP2 inhibitor is an allosteric inhibitor. In some embodiments, the SHP2 inhibitor is selected from the group consisting of: batoprotafib, RMC- 4550, SHP099, RMC-4630, GDC-1971 (RLY-1971), PF-07284892, BBP-398 (IACS-13909), and JAB -3068.

[0076] In some embodiments, the hematological cancer is a CD 123 -positive hematological cancer. In some embodiments, the hematological cancer is a CD 123 -negative hematological cancer.

[0077] In some embodiments, the hematological cancer is a leukemia or a lymphoma. In some embodiments, the leukemia is acute myeloid leukemia or B cell acute lymphoblastic leukemia (B-ALL). In some embodiments, the hematological cancer is blastic plasmacytoid dendritic cell neoplasm (BPDCN).

[0078] Also provided herein are methods of treating a hematological cancer in a subject, the method including administering to the subject an effective amount of a RAS inhibitor and an effective amount of a CD 123 -targeted therapeutic agent.

[0079] In some embodiments, the method includes administering the RAS inhibitor to the subject prior to administering the CD 123 -targeted therapeutic agent to the subject. In some embodiments, the method includes administering the RAS inhibitor to the subject at substantially the same time as administering the CD 123 -targeted therapeutic agent to the subject. In some embodiments, the subject was previously administered a CD 123 -targeted therapeutic agent without a RAS inhibitor, and the subject was not responsive to treatment with the CD 123- targeted therapeutic agent without the RAS inhibitor.

[0080] In some embodiments, the CD 123 -targeted therapeutic agent is an antibody or an antigen-binding antibody fragment. In some embodiments, the antibody is talacotuzumab.

[0081] In some embodiments, the CD 123 -targeted therapeutic agent is an antibody drug conjugate (ADC). In some embodiments, the ADC is selected from the group of pivekimab sunirine, SGN-CD123A, BYON4413, and VIP943.

[0082] In some embodiments, the CD 123 -targeted therapeutic agent is a fusion protein. In some embodiments, the fusion protein is tagraxofusp.

[0083] In some embodiments, the CD 123 -targeted therapeutic agent is a T cell engager or an NK cell engager. In some embodiments, the T cell engager or the NK cell engager is selected from the group consisting of: APVO436, flotetuzumab, vibecotamab, SAR443579, IGM-2537, and AFM28.

[0084] In some embodiments, the CD 123 -targeted therapeutic agent is a darpin. In some embodiments, the darpin is MP0533.

[0085] In some embodiments, the CD 123 -targeted therapeutic agent is a CAR T cell or a CAR NK cell. In some embodiments, the CAR T cell is ACLX-002 or AUT01.

[0086] In some embodiments, the RAS inhibitor is an allosteric inhibitor. In some embodiments, the RAS inhibitor is RMC-6236 and / or RMC-7977. In some embodiments, the hematological cancer is a CD 123 -positive hematological cancer. In some embodiments, the subject has previously been identified or diagnosed as having a CD 123 -positive hematological cancer.

[0087] In some embodiments, the hematological cancer is a CD 123 -negative hematological cancer. In some embodiments, the subject has previously been identified or diagnosed as having a CD 123 -negative hematological cancer.

[0088] In some embodiments, the hematological cancer is a lymphoma or a leukemia. In some embodiments, the leukemia is acute myeloid leukemia (AML) or B cell lymphoblastic leukemia (B-ALL). In some embodiments, the hematological cancer is blastic plasmacytoid dendritic cell neoplasm (BPDCN).

[0089] Also provided herein are pharmaceutical compositions including an effective amount of a RAS inhibitor and an effective amount of a CD 123 -targeted therapeutic agent.

[0090] In some embodiments, the CD 123 -targeted therapeutic agent is an antibody or an antigen-binding antibody fragment. In some embodiments, the antibody is talacotuzumab.

[0091] In some embodiments, the CD 123 -targeted therapeutic agent is an antibody drug conjugate (ADC). In some embodiments, the ADC is selected from the group of pivekimab sunirine, SGN-CD123A, BYON4413, and VIP943.

[0092] In some embodiments, the CD 123 -targeted therapeutic agent is a fusion protein. In some embodiments, the fusion protein is tagraxofusp.

[0093] In some embodiments, the CD 123 -targeted therapeutic agent is a T cell engager or an NK cell engager. In some embodiments, the T cell engager or the NK cell engager is selected from the group consisting of: APVO436, flotetuzumab, vibecotamab, SAR443579, IGM-2537, and AFM28.

[0094] In some embodiments, the CD 123 -targeted therapeutic agent is a darpin. In some embodiments, the darpin is MP0533.

[0095] In some embodiments, the CD 123 -targeted therapeutic agent is a CAR T cell or a CAR NK cell. In some embodiments, the CAR T cell is ACLX-002 or AUTO1.

[0096] In some embodiments, the RAS inhibitor is an allosteric inhibitor. In some embodiments, the RAS inhibitor is RMC-6236 and / or RMC-7977.

[0097] Also provided herein are methods of increasing expression of CD123 in a hematological cancer cell, the method including contacting the hematological cancer cell with a RAS inhibitor. In some embodiments, the RAS inhibitor is an allosteric inhibitor. In some embodiments, the RAS inhibitor is RMC-6236 and / or RMC-7977.

[0098] In some embodiments, the hematological cancer cell is in vitro. In some embodiments, the hematological cancer cell is in a subject.

[0099] In some embodiments, the hematological cancer cell is a leukemia cell or a lymphoma cell. In some embodiments, the leukemia cell is an acute myeloid leukemia cell or B cell lymphoblastic leukemia cell. In some embodiments, the hematological cancer cell is a blastic plasmacytoid dendritic cell neoplasm (BPDCN) cell.

[0100] Also provided herein are methods of sensitizing a subject having a hematological cancer for treatment with a CD 123 -targeted therapeutic agent, the method including administering an effective amount of a RAS inhibitor to the subject.

[0101] Also provided herein are methods of increasing the therapeutic effect of a CD123- targeted therapeutic agent in a subject having a hematological cancer, the method including administering an effective amount of a RAS inhibitor to the subject.

[0102] In some embodiments, the increased therapeutic effect is an increase in hematological cancer cell death.

[0103] In some embodiments, the RAS inhibitor is an allosteric inhibitor. In some embodiments, the RAS inhibitor is RMC-6236 and / or RMC-7977.

[0104] In some embodiments, the hematological cancer is a CD 123 -positive hematological cancer. In some embodiments, the hematological cancer is a CD 123 -negative hematological cancer.

[0105] In some embodiments, the hematological cancer is a leukemia or a lymphoma. In some embodiments, the leukemia is acute myeloid leukemia or B cell acute lymphoblastic leukemia (B-ALL). In some embodiments, the hematological cancer is blastic plasmacytoid dendritic cell neoplasm (BPDCN).

[0106] Also provided herein are antibody drug conjugates including: (i) an antibody that specifically binds to CD123; and (ii) a MEK1 / 2 inhibitor conjugated to the antibody.

[0107] Also provided herein are antibody drug conjugates including: (i) an antibody that specifically binds to CD123; and (ii) a SHP2 inhibitor conjugated to the antibody.

[0108] Also provided herein are antibody drug conjugates including: (i) an antibody that specifically binds to CD123; and (ii) a RAS inhibitor conjugated to the antibody. In some embodiments, the antibody drug conjugate includes a toxin conjugated to the antibody.

[0109] Also provided herein are pharmaceutical composition including any of the antibody drug conjugates described herein.

[0110] Also provided herein are kits including any of the antibody drug conjugates described herein or any of the pharmaceutical compositions described herein.

[0111] Also provided herein are methods of treating a hematological cancer in a subject, the method including administering to the subject an effective amount of any of the antibody drug conjugates described herein or any of the pharmaceutical compositions described herein.

[0112] Also provided herein are antibody drug conjugates including: (i) an antibody that specifically binds to CD123; and (ii) a MEK1 / 2 inhibitor conjugated to the antibody.

[0113] Also provided herein are antibody drug conjugates including: (i) an antibody that specifically binds to CD123; and (ii) a SHP2 inhibitor conjugated to the antibody.

[0114] Also provided herein are antibody drug conjugates including: (i) an antibody that specifically binds to CD123; and (ii) a RAS inhibitor conjugated to the antibody.

[0115] In some embodiments, the antibody drug conjugate includes a toxin conjugated to the antibody.

[0116] Also provided herein are pharmaceutical composition including any of the antibody drug conjugates described herein.

[0117] Also provided herein are kits including any of the antibody drug conjugates described herein or any of the pharmaceutical compositions described herein.

[0118] Also provided herein are methods of treating a hematological cancer in a subject, the method including administering to the subject an effective amount of any of the antibody drug conjugates described herein or any of the pharmaceutical compositions described herein.

[0119] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the term belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The present disclosure is controlling to the extent it conflicts with any incorporated publication. The term “about” or “approximately” as used herein means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within an acceptable standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to ±20%, preferably up to ±10%, more preferably up to ±5%, and more preferably still up to ±1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated, the term “about” is implicit and in this context means within an acceptable error range for the particular value.

[0120] The term “MEK1 / 2 inhibitor” is meant a molecule that preferentially binds to and inhibits the activity of MEK1 / 2 over other MEK family kinases. Non-limiting examples of MEK1 / 2 inhibitors are described herein. Additional examples of MEK1 / 2 inhibitors are known in the art.

[0121] The term “SHP2 inhibitor” is meant a molecule that preferentially binds to and inhibits the activity of SHP2, a SH2 domain-containing protein tyrosine phosphatase. Non-limiting examples of SHP2 inhibitors are described herein. Additional examples of SHP2 inhibitors are known in the art.

[0122] The term “RAS inhibitor” is meant a molecule that preferentially binds to and inhibits the activity of RAS, a GDP / GTP-binding protein involved in cell growth, differentiation, and survival. Non-limiting examples of RAS inhibitors are described herein. Additional examples of RAS inhibitors are known in the art.

[0123] The term “SCSI inhibitor” is meant a molecule that preferentially binds to and inhibits the activity of S0S1, (“son of sevenless homolog 1”). S0S1 is a guanine nucleotide exchange factor that regulates RAS activity and is involved in stimulating cell growth and division. Nonlimiting examples of S0S1 inhibitors are known in the art.

[0124] The term “ERK inhibitor” is meant a molecule that preferentially binds to and inhibits the activity of ERK, (“extracellular signal -regulated kinases”). ERK is a kinase involved in cellular processes including proliferation, differentiation, and survival. Non-limiting examples of ERK inhibitors are known in the art.

[0125] The term “RAF inhibitor” is meant a molecule that preferentially binds to and inhibits the activity of RAF, (“rapidly accelerated fibrosarcoma”). RAF kinases are serine / threonine specific kinases involved in the MAPK cascade. RAF kinases phosphorylate MEK1 / 2 protein and regulate cellular functions such as proliferation, differentiation, survival, and migration.

[0126] The phrase “CD 123 -targeted therapeutic agent” refers to any therapeutic agent that specifically targets and / or kills CD 123 -positive cancer cells. At a minimum, a CD 123 -targeted therapeutic agent includes a domain or substructure that specifically binds to CD123 present on the surface of a hematological cancer cell (e.g., a CD 123 -positive hematological cancer cell). In some embodiments, a CD 123 -targeted therapeutic agent can further include an additional cytotoxic or cytostatic agent. Non-limiting examples of cytotoxic or cytostatic agents include a toxin, a radioisotope, drug (e.g., a chemotherapeutic agent), or small molecule. Non-limiting examples of additional cytotoxic or cytostatic agents are known in the art. Non-limiting examples of CD 123 -targeted therapeutic agents include antibody-drug conjugates, antibodies or an antigen-binding fragments thereof, fusion proteins, T cell engagers, NK cell engagers, darpins, CAR-T cells, and / or CARNK cells. Specific non-limiting examples of CD 123 -targeted therapeutic agents are described herein. Additional examples of CD 123 -targeted therapeutic agents are known in the art.

[0127] The phrase “effective amount of a MEK1 / 2 inhibitor” means an amount of MEK1 / 2 inhibitor sufficient to increase expression of CD 123 on the surface of a hematological cancer cell (e.g., a CD 123 -positive hematological cancer cell) (e.g., any of the types of hematological cancer cells described herein).

[0128] The phrase “effective amount of a SHP2 inhibitor” means an amount of SHP2 inhibitor sufficient to increase expression of CD123 on the surface of a hematological cancer cell (e.g., a CD 123 -positive hematological cancer cell) (e.g., any of the types of hematological cancer cells described herein).

[0129] The phrase “effective amount of a RAS inhibitor” means an amount of RAS inhibitor sufficient to increase expression of CD 123 on the surface of a hematological cancer cell (e.g., a CD 123 -positive hematological cancer cell) (e.g., any of the types of hematological cancer cells described herein).

[0130] The phrase “effective amount of a S0S1 inhibitor” means an amount of S0S1 inhibitor sufficient to increase expression of CD123 on the surface of a hematological cancer cell (e.g., a CD 123 -positive hematological cancer cell) (e.g., any of the types of hematological cancer cells described herein). The phrase “effective amount of a ERK inhibitor” means an amount of ERK inhibitor sufficient to increase expression of CD123 on the surface of a hematological cancer cell (e.g., a CD 123 -positive hematological cancer cell) (e.g., any of the types of hematological cancer cells described herein).

[0131] The phrase “effective amount of a RAF inhibitor” means an amount of RAF inhibitor sufficient to increase expression of CD 123 on the surface of a hematological cancer cell (e.g., a CD 123 -positive hematological cancer cell) (e.g., any of the types of hematological cancer cells described herein).

[0132] The phrase “effective amount of a CD 123 -targeted therapeutic agent” means an amount of a CD 123 -targeted therapeutic agent that results in, directly or indirectly, the cytotoxicity of a hematological cancer cell (e.g., a CD 123 -positive cancer cell) and / or cessation of expansion of a hematological cancer cell (e.g., a CD 123 -positive cancer cell).

[0133] The phrase “CD 123 -negative hematological cancer cell” means a hematological cancer cell that does not have a detectable level of CD123 on its surface, e.g., as determined using fluorescence-assisted cell sorting. As described herein, a MEK1 / 2 inhibitor can be used to induce / increase the level of CD 123 in a CD 123 -negative hematological cancer cell, resulting in a hematological cancer cell that has a detectable level of CD123 (i.e., a CD123-positive hematological cancer cell), e.g., as determined using fluorescence-assisted cell sorting.

[0134] The phrase “CD 123 -negative hematological cancer” means a hematological cancer that is characterized by CD 123 -negative hematological cancer cells.

[0135] The phrase “CD 123 -positive hematological cancer cell” means a hematological cancer cell that has a detectable level of CD 123 on its surface, e.g., as determined by fluorescence- assisted cell sorting.

[0136] The phrase “CD 123 -positive hematological cancer” means a hematological cancer characterized by CD123-positive hematological cancer cells.

[0137] The term “antibody” is used herein in its broadest sense and includes certain types of immunoglobulin molecules that include one or more antigen-binding domains that specifically bind to an antigen or epitope. An antibody specifically includes, e.g., intact antibodies (e.g., intact immunoglobulins, e.g., human IgG (e.g., human IgGl, human IgG2, human IgG3, human IgG4)), human IgGA (e.g., human IgGAl or IgGA2), human IgD, human IgE, human IgM, antibody fragments, and multi-specific antibodies. One example of an antigen-binding domain is an antigen-binding domain formed by a VH -VL dimer. Non-limiting examples of antibodies include a VH domain, a VHH domain, a VNAR domain, an scFv, a BiTe, a (scFv)2, a nanobody, a nanobody-HSA, a DART, a TandAb, a scDiabody, a scDiabody-CH3, scFv-CH-CL-scFv, a HSAbody, scDiabody -HAS, a tandem-scFv, an Adnectin, a DARPin, a fibronectin, a DEP conjugate, a VHH-scAb, a VHH-Fab, a Dual scFab, a F(ab’)2, a diabody, a crossMab, a DAF (two-in-one), a DAF (four-in-one), a DutaMab, a DT-IgG, a knobs-in-holes common light chain, a knobs-in-holes assembly, a charge pair, a Fab-arm exchange, a SEEDbody, a LUZ-Y, a Fcab, a K -body, an orthogonal Fab, a DVD-IgG, a IgG(H)-scFv, a scFv-(H)IgG, IgG(L)-scFv, scFv- (L)IgG, IgG(L,H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4-Ig, Zybody, DVI-IgG, Diabody-CH3, a triple body, a miniantibody, a minibody, a TriBi minibody, scFv-CH3 KIH, Fab-scFv, a F(ab’)2-scFv2, a scFv-KIH, a Fab- scFv-Fc, a tetravalent HCAb, a scDiabody-Fc, a Diabody-Fc, a tandem scFv-Fc, a VHH-Fc, a tandem VHH-Fc, a VHH-Fc KiH, a Fab-VHH-Fc, an Intrabody, a dock and lock, an ImmTAC, an IgG-IgG conjugate, a Cov-X-Body, and a scFvl-PEG-scFv2. Additional examples of an antibody are described herein. Additional examples of an antibody are known in the art.

[0138] The term “antibody drug conjugate” as used herein in its broadest sense includes an antibody (as defined herein) and at least one a linker (as defined herein) and at least one payload. In some examples, the at least one payload can be a toxin and / or a MEK1 / 2 inhibitor (e.g., any of the exemplary MEK1 / 2 inhibitors described herein or known in the art), a SHP2 inhibitor (e.g., any of the exemplary SHP2 inhibitors described herein or known in the art), and / or a RAS inhibitor (e g., any of the exemplary RAS inhibitors described herein or known in the art). In some embodiments, an antibody drug conjugate includes only one type of payload (e.g., a toxin). In other embodiments, an antibody drug conjugate can include two different types of payloads (dual payloads) (See e.g., Yamazaki, C.M., Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance, Nature Communications, 123528 (2021)). In some examples, the first payload is a toxin (e.g., monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), etc.). In some examples, the second payload is a MEK1 / 2 inhibitor (e.g., any of the MEK1 / 2 inhibitors described herein), a SHP2 inhibitor (e.g., any of the SHP2 inhibitors described herein), or a RAS inhibitor (e.g., any of the RAS inhibitors described herein). As used herein a “linker” refers to a chemical moiety that connects an antibody of antibody drug conjugate and a payload. In some embodiments, a linker can connect the antibody and the payload covalently or non-covalently. In some embodiments, the linker can be cleavable or non-cleavable. For example, in some embodiments, a covalent linker can be cleaved during internalization by the cell. In some embodiments, the linker is not cleavable. In some embodiments, a linker can be a peptide of about 3 amino acids to about 25 amino acids (e.g., about 3 amino acids to about 20, or about 3 amino acids to about 12 amino acids). In some examples, a linker can be a bond (e.g., an amide bond, an ester bond, an ether bond, and a disulfide bond). In some embodiments, the linker is an organic polymer (e.g., a polyethylene glycol) and / or an organic chain (e.g., a hydrocarbon chain).

[0139] Non-limiting exemplary methods for covalently and non-covalently linking a payload to an antibody (e.g., as defined herein) are known in the art.

[0140] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an antibody drug conjugate” includes a plurality of such antibody drug conjugates. Furthermore, the use of terms that can be described using equivalent terms include the use of those equivalent terms. Thus, for example, the use of the term “subject” is to be understood to include the terms “patient,” “individual” and other terms used in the art to indicate one who is subject to a treatment.

[0141] Various embodiments of the features of this disclosure are described herein. However, it should be understood that such embodiments are provided merely by way of example, and numerous variations, changes, and substitutions can occur to those skilled in the art without departing from the scope of this disclosure. It should also be understood that various alternatives to the specific embodiments described herein are also within the scope of this disclosure.

[0142] DESCRIPTION OF DRAWINGS

[0143] The following drawings illustrate certain embodiments of the features and advantages of this disclosure. These embodiments are not intended to limit the scope of the appended claims in any manner. Like reference symbols in the drawings indicate like elements.

[0144] FIG. 1A shows CD123 upregulation in MV-4-11 AML cell line treated with various MEK inhibitors in comparison to inhibitors of other kinases at 1000 nM. FIG. IB shows CD123 upregulation in MOLM-13 AML cell line treated with various MEK inhibitors in comparison to inhibitors of other kinases at 1000 nM.

[0145] FIG. 2 shows that among the allosteric MEK 1 / 2 inhibitors, the differences in sensitivity to CD123 upregulation in v / 7ro(MV-4-l 1 cell line) is associated with the in vitro (biochemical) potency of the MEK inhibitor.

[0146] FIG. 3A is a schematic summary of signaling pathways downstream of growth factor receptors in AML.

[0147] FIG. 3B is a schematic summary of signaling pathways downstream of growth factor receptors in AML.

[0148] FIG. 4 shows that inhibiting the MAPK signaling cascade at different points has varying effects on CD123 levels in MV-4-11 cells. Treatment of MV-4-11 cells with RAF inhibitors, which target upstream of the MEK signaling cascade, have little effect on CD 123 levels, whereas CD123 is upregulated following treatment with inhibitors of MEK signaling and ERK inhibitors which target downstream of the MEK signaling cascade.

[0149] FIG. 5 shows CD123 upregulation in MV-4-11 AML cells resulting from treatment with a MEK inhibitor can be reversed by treating cells with a CBP / p300 inhibitor, such as A-485.

[0150] FIG. 6 shows MV-4-11 AML cells primed with 10 nM trametinib have increased sensitivity to a CD123 ADC compared to vehicle (dimethyl sulfoxide) (DMSO) treated cells.

[0151] FIG. 7 shows CD123 fold-change in bone marrow progenitor populations and MV-4-11 AML cells after treatment with 31 ,6nM trametinib.

[0152] FIG. 8 shows CD123 upregulation in MV-4-11 and MOLM-13 AML cells treated with various SHP2 inhibitors at 316 nM.

[0153] FIG. 9 shows CD 123 upregulation in MV-4-11 treated with various Ras inhibitors at 31.6 nM.

[0154] FIG. 10 shows CD 123 upregulation in MV-4-11 AML cells resulting from treatment with a SHP2 inhibitor can be reversed by treating cells with a CBP / p300 inhibitor, such as A- 485.

[0155] FIG. 11 shows MV-4-11 AML cells primed with 100 nM batoprotafib have increased sensitivity to a CD123 ADC compared to vehicle (dimethyl sulfoxide) (DMSO) treated cells.

[0156] FIGs. 12A-C show the structure of a MEK inhibitor (Figure 12A), a proteolysis-targeting chimera (“PROTAC”) (Figure 12B), and a glue (Figure 12C). FIGs. 13A-B show the structures of two SHP2 inhibitors: batoprotafib (Figure 13 A) and RMC-4550 (Figure 13B).

[0157] FIGs. 14A-B show the structure of two RAS inhibitors: RMC-6236 (Figure 14A) and RMC-7977 (Figure 14B).

[0158] DETAILED DESCRIPTION

[0159] The success of antigen-directed therapies is limited by heterogeneous expression of the target on tumor cells and, in many cases, in normal cells and has been limited to certain types of cancers. Antigen heterogeneity is defined by two components: (1) percentage of cells that are positive and (2) antigen expression level. When both components are not sufficiently high, this limits the clinical activity of antigen-directed therapies. The expression of the target on normal cells can drive toxicity, resulting in a narrow therapeutic window in which these agents can be safely administered. In many cases, the failure of an antigen-directed therapy is not due to the lack of potency or specificity of the agent, but rather due to suboptimal expression of the target antigen. There is no target antigen that is restricted to and highly expressed uniformly on AML cells. The two most common AML antigens, CD33 and CD 123, are expressed on a high percentage of AML blasts, however the broad ranges of expression levels in AML have limited the efficacy of CD33 and CD123 antigen-directed therapies for most patients with AML.

[0160] The present disclosure features methods and compositions for using MEK1 / 2 inhibitors, SHP2 inhibitors, RAS inhibitors, S0S1 inhibitors, ERK inhibitors, and / or RAF inhibitors to improve patient responses to CD 123 -targeted therapeutic agents by increasing the expression of CD123 on the surface of hematological cancer cells (e.g., CD 123 -positive hematological cancer cells or CD 123 -negative hematological cancer cells). Provided herein are methods for treating a subject having a hematological cancer (e.g., a CD123-positive hematological cancer or a CD133- negative hematological cancer) that include administering to the subject an effective amount of a MEK1 / 2 inhibitor, a SHP2 inhibitor, a RAS inhibitor, a S0S1 inhibitor, an ERK inhibitor, and / or a RAF inhibitor and an effective amount of a CD 123 -targeted therapeutic agent. Also provided herein are methods for sensitizing a subject having a hematological cancer (e.g., a CD123- positive hematological cancer or a CD 123 -negative hematological cancer) for treatment with a CD 123 -targeted therapeutic agent that include administering an effective amount of a MEK1 / 2 inhibitor, a SHP2 inhibitor, a RAS inhibitor, a S0S1 inhibitor, an ERK inhibitor, and / or a RAF inhibitor to the subject. Also provided herein are methods for increasing the therapeutic effect of a CD 123 -targeted therapeutic agent in a subject having a hematological cancer (e.g., a CD123- positive hematological cancer or a CD 123 -negative hematological cancer) that include administering an effective amount of a MEK1 / 2 inhibitor, a SHP2 inhibitor, a RAS inhibitor, a S0S1 inhibitor, an ERK inhibitor, and / or a RAF inhibitor to the subject. In some embodiments, the subject was previously administered a CD 123 -targeted therapeutic agent without a MEK1 / 2 inhibitor, a SHP2 inhibitor, a RAS inhibitor, a SCSI inhibitor, an ERK inhibitor, and / or a RAF inhibitor and the subject was not responsive to treatment with the CD 123 -targeted therapeutic agent without the MEK1 / 2 inhibitor, a SHP2 inhibitor, a RAS inhibitor, a SCSI inhibitor, an ERK inhibitor, and / or a RAF inhibitor.

[0161] Also provided herein are pharmaceutical compositions including an effective amount of a MEK1 / 2 inhibitor and an effective amount of a CD 123 -targeted therapeutic agent.

[0162] Also provided herein are pharmaceutical compositions including an effective amount of a SHP2 inhibitor and an effective amount of a CD 123 -targeted therapeutic agent.

[0163] Also provided herein are pharmaceutical compositions including an effective amount of a RAS inhibitor and an effective amount of a CD 123 -targeted therapeutic agent.

[0164] Also provided herein are pharmaceutical compositions including an effective amount of a S0S1 inhibitor and an effective amount of a CD 123 -targeted therapeutic agent.

[0165] Also provided herein are pharmaceutical compositions including an effective amount of a ERK inhibitor and an effective amount of a CD 123 -targeted therapeutic agent.

[0166] Also provided herein are pharmaceutical compositions including an effective amount of a RAF inhibitor and an effective amount of a CD 123 -targeted therapeutic agent.

[0167] Also provided herein are methods of increasing expression of CD123 in a hematological cancer cell (e.g., a CD 123 -positive hematological cancer cell or a CD 123 -negative hematological cancer cell) that include contacting the hematological cancer cell with a MEK1 / 2 inhibitor.

[0168] Also provided herein are methods of increasing expression of CD123 in a hematological cancer cell (e.g., a CD 123 -positive hematological cancer cell or a CD 123 -negative hematological cancer cell) that include contacting the hematological cancer cell with a SHP2 inhibitor.

[0169] Also provided herein are methods of increasing expression of CD123 in a hematological cancer cell (e.g., a CD 123 -positive hematological cancer cell or a CD 123 -negative hematological cancer cell) that include contacting the hematological cancer cell with a RAS inhibitor. Also provided herein are methods of increasing expression of CD123 in a hematological cancer cell (e.g., a CD 123 -positive hematological cancer cell or a CD 123 -negative hematological cancer cell) that include contacting the hematological cancer cell with a SCSI inhibitor.

[0170] Also provided herein are methods of increasing expression of CD123 in a hematological cancer cell (e.g., a CD 123 -positive hematological cancer cell or a CD 123 -negative hematological cancer cell) that include contacting the hematological cancer cell with a ERK inhibitor.

[0171] Also provided herein are methods of increasing expression of CD123 in a hematological cancer cell (e.g., a CD 123 -positive hematological cancer cell or a CD 123 -negative hematological cancer cell) that include contacting the hematological cancer cell with a RAF inhibitor.

[0172] In some embodiments, the hematological cancer cell is in vitro. In some embodiments, the hematological cancer cell is in a subject. In some embodiments the hematological cancer cell is a leukemia cell. In some embodiments, the hematological cancer cell is a lymphoma cell. In some embodiments, the hematological cancer cell is a myeloma cell. Non-limiting examples of hematological cancer cells include acute myeloid leukemia cells, B cell lymphoblastic leukemia cells, and blastic plasmacytoid dendritic cell neoplasm cells

[0173] In various methods described herein, a MEK1 / 2 inhibitor, a SHP2 inhibitor, a RAS inhibitor, a S0S1 inhibitor, an ERK inhibitor, and / or a RAF inhibitor is administered to a subject. The subject can be a human, mouse, rat, rabbit, dog, cat, or a non-human primate (e.g., monkey). In some embodiments, the subject has previously been identified or diagnosed as having a hematological cancer (e.g., a CD 123 -positive hematological cancer or a CD123- negative hematological cancer). Any appropriate method can be used to identify a subject as having a hematological cancer (e.g., a CD 123 -positive hematological cancer or a CD123- negative hematological cancer). For example, blood tests, urine tests, laboratory tests (e.g., fluorescence in situ hybridization (FISH)), imaging techniques (e.g., X-ray, magnetic resonance imaging (MRI), computerized tomography (CT) scanning, and positron emission tomography (PET) scanning), and biopsy techniques can be used to identify a subject as having a hematological cancer (e g., a CD 123 -positive hematological cancer or a CD 123 -negative hematological cancer).

[0174] Generally, hematological cancers (e.g., a CD 123 -positive hematological cancer or a CD 123 -negative hematological cancer) are broadly classified into lymphomas, myelomas, and leukemias. Each of these broad categories includes several, more specific types of hematological cancer. In some embodiments, the hematological cancer (e.g., a CD 123 -positive hematological cancer or a CD 123 -negative hematological cancer) can be a lymphoma. In some embodiments, the hematological cancer (e.g., a CD 123 -positive hematological cancer or a CD 123 -negative hematological cancer) can be a leukemia. In some embodiments, the hematological cancer (e.g., a CD 123 -positive hematological cancer or a CD 123 -negative hematological cancer) can be a myeloma. Non-limiting examples of hematological cancers (e.g., a CD 123-positive hematological cancer or a CD 123 -negative hematological cancer) include acute lymphoblastic leukemia, acute myeloid leukemia, B cell lymphoblastic leukemia, blastic plasmacytoid dendritic cell neoplasm, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, AIDS-related lymphoma, cutaneous t-cell lymphoma, Hodgkin’s lymphoma, Hodgkin’s lymphoma during pregnancy, mycosis fungoides, non-Hodgkin’s lymphoma, nonHodgkin’s lymphoma during pregnancy, primary central nervous system lymphoma, Sezary syndrome, cutaneous t-cell lymphoma, Waldenstrom macroglobulinemia, chronic myeloproliferative neoplasms, Langerhans cell histiocytosis, multiple myeloma, plasma cell neoplasm, myelodysplastic syndromes, and myelodysplastic / myeloproliferative neoplasms.

[0175] In various methods described herein, expression of CD 123 on the surface of hematological cancer cells (e.g., CD 123 -positive hematological cancer cells or CD 123 -negative hematological cancer cells) is increased as a result, at least in part, of administration of a MEK1 / 2 inhibitor, a SHP2 inhibitor, a RAS inhibitor, a S0S1 inhibitor, an ERK inhibitor, and / or a RAF inhibitor to a subject and / or contacting a hematological cancer cell (e.g., a CD123- positive hematological cancer cells or CD 123 -negative hematological cancer cells) with a MEK1 / 2 inhibitor, a SHP2 inhibitor, a RAS inhibitor, a S0S1 inhibitor, an ERK inhibitor, and / or a RAF inhibitor. The term “increased expression” as used herein with respect to a level of CD123 expression refers to any level that is greater than a reference level of CD123 expression. The term “reference level of CD123 expression” refers to the level of CD123 expression typically observed in control samples. Control samples can include, without limitation, samples from healthy subjects or primary cell lines derived from healthy and non-tumorigenic cell lines, or a sample obtained from a subject prior to administration of a MEK1 / 2 inhibitor, a SHP2 inhibitor, a RAS inhibitor, a SCSI inhibitor, an ERK inhibitor, and / or a RAF inhibitor. In some cases, an increased level of CD123 expression can be a level that is at least more than 1-fold (e.g., at least 2-fold, at least 5-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25- fold, at least 35-fold, or at least 50-fold) greater relative to a reference level of CD123 expression. In some cases, an increased level of CD123 expression is a level that is about 1-fold to about 50-fold (e.g., about 1-fold to about 45-fold, about 1-fold to about 40-fold, about 1-fold to about 35-fold, about 1-fold to about 30-fold, about 1-fold to about 25-fold, about 1-fold to about 20-fold, about 1-fold to about 15-fold, about 1-fold to about 10-fold, about 1-fold to about 5-fold, about 10-fold to about 50-fold, about 10-fold to about 45-fold, about 10-fold to about 40- fold, about 10-fold to about 35-fold, about 10-fold to about 30-fold, about 10-fold to about 25- cold, about 10-fold to about 20-fold, about 20-fold to about 50-fold, about 20-fold to about 45- fold, about 20-fold to about 40-fold, about 20-fold to about 35-fold, about 20-fold to about 30- fold, about 30-fold to about 50-fold, about 30-fold to about 45-fold, about 30-fold to about 40- fold, or about 40-fold to about 50-fold) greater relative to a reference level of CD123 expression. In some cases, when control samples have an undetectable level of CD 123 expression, an increased level can be any detectable level of CD 123 expression. It will be appreciated that levels from comparable samples are used when determining whether or not a particular level is an increased level.

[0176] In various methods described herein, a MEK1 / 2 inhibitor (e.g., any of the MEK1 / 2 inhibitors described herein) is administered to the subject. In some embodiments, the MEK 1 / 2 inhibitor is an allosteric inhibitor. Non-limiting examples of MEK1 / 2 inhibitors include trametinib, cobimetinib, selumetinib, binimetinib, mirdametinib, pimasertib, avutometinib, refametinib, E6201, CH5126766, HL-085, SHR7390, TQ-B3234, CS-3006, FCN-159, and GDC-0623. Additional examples of MEK inhibitors are known in the art.

[0177] In some embodiments, the MEK 1 / 2 inhibitor is an ATP-competitive inhibitor. In some embodiments, the ATP-competitive inhibitor is MAP855.

[0178] In some embodiments, the MEK 1 / 2 inhibitor is a proteolysis targeted chimera (PROTAC). In some embodiments, the PROTAC is MS432.

[0179] In some embodiments, the MEK 1 / 2 inhibitor is a glue. In some embodiments, the glue is Trametiglue.

[0180] In various methods described herein, a SHP2 inhibitor (e.g., any of the SHP2 inhibitors described herein) is administered to the subject. Non-limiting examples of SHP2 inhibitors include batoprotafib, RMC-4550, SHP099, RMC-4630, GDC- 1971 (RLY-1971), PF-07284892, BBP-398 (IACS-13909), and JAB-3068. Additional examples of SHP2 inhibitors are known in the art.

[0181] In various methods described herein, a RAS inhibitor (e.g., any of the RAS inhibitors described herein) is administered to the subject. Non-limiting examples of RAS inhibitors include RMC-6236 and RMC-7977. Additional examples of RAS inhibitors are known in the art.

[0182] In various methods described herein, a CD 123 -targeted therapeutic agent (e.g., any of the CD 123 -targeted therapeutic agents described herein) is administered to the subject. In some embodiments, the MEK1 / 2 inhibitor can be administered to the subject prior to administering the CD 123 -targeted therapeutic agent to the subject. In some embodiments, the MEK1 / 2 inhibitor can be administered to the subject at substantially the same time as the CD123-tareted therapeutic agent is administered. In some embodiments, the CD 123 -targeted therapeutic agent can be an antibody or an antigen-binding fragment thereof. A non-limiting example of an antibody or antigen-binding fragment thereof is talacotuzumab.

[0183] In some embodiments, the CD 123 -targeted therapeutic agent can be an ADC. Nonlimiting examples of ADCs include pivekimab sunirine, SGN-CD123A, BYON4413, and VIP943. In some embodiments, the CD 123 -targeted therapeutic agent can be a fusion protein. A non-limiting example of a fusion protein is tagraxofusp. In some embodiments, the CD123- targeted therapeutic agent can be a T cell engager or an NK cell engager. Non-limiting examples of T cell engagers or an NK cell engagers include APVO436, flotetuzumab, vibecotamab, SAR443579, IGM-2537, and AFM28. In some embodiments, the CD 123 -targeted therapeutic agent can be a darpin. A non-limiting example of a darpin is MP0533. In some embodiments, the CD 123 -targeted therapeutic agent can be a CAR T cell or a CAR NK cell. Non-limiting examples of CAR T cells or CAR NK cells include ACLX-002 and AUTO1.

[0184] In some embodiments, a CD 123 -targeted therapeutic agent and a MEK1 / 2 inhibitor are formulated as separate pharmaceutical compositions. In other embodiments, a CD 123 -targeted therapeutic agent and a MEK1 / 2 inhibitor are formulated together in a single pharmaceutical composition.

[0185] A pharmaceutical composition comprising a CD 123 -targeted therapeutic agent can be formulated for intravenous administration, inraarticular administration, subcutaneous administration, or intramuscular administration. A pharmaceutical composition comprising a MEK1 / 2 inhibitor can be formulated for intravenous administration, inraarticular administration, subcutaneous administration, intramuscular administration, or oral administration.

[0186] A pharmaceutical composition comprising a SHP2 inhibitor can be formulated for intravenous administration, inraarticular administration, subcutaneous administration, intramuscular administration, or oral administration.

[0187] A pharmaceutical composition comprising a RAS inhibitor can be formulated for intravenous administration, inraarticular administration, subcutaneous administration, intramuscular administration, or oral administration.

[0188] A pharmaceutical composition comprising a SO SI inhibitor can be formulated for intravenous administration, inraarticular administration, subcutaneous administration, intramuscular administration, or oral administration.

[0189] A pharmaceutical composition comprising an ERK inhibitor can be formulated for intravenous administration, inraarticular administration, subcutaneous administration, intramuscular administration, or oral administration.

[0190] A pharmaceutical composition comprising a RAF inhibitor can be formulated for intravenous administration, inraarticular administration, subcutaneous administration, intramuscular administration, or oral administration.

[0191] A pharmaceutical composition comprising a CD 123 -targeted therapeutic agent and a MEK1 / 2 inhibitor can be formulated for intravenous administration, intraarticular administration, subcutaneous administration, or intramuscular administration.

[0192] A pharmaceutical composition comprising a CD 123 -targeted therapeutic agent and a SHP2 inhibitor can be formulated for intravenous administration, intraarticular administration, subcutaneous administration, or intramuscular administration.

[0193] A pharmaceutical composition comprising a CD 123 -targeted therapeutic agent and a RAS inhibitor can be formulated for intravenous administration, inraarticular administration, subcutaneous administration, or intramuscular administration.

[0194] A pharmaceutical composition comprising a CD 123 -targeted therapeutic agent and a S0S1 inhibitor can be formulated for intravenous administration, inraarticular administration, subcutaneous administration, or intramuscular administration. A pharmaceutical composition comprising a CD 123 -targeted therapeutic agent and an ERK inhibitor can be formulated for intravenous administration, inraarticular administration, subcutaneous administration, or intramuscular administration.

[0195] A pharmaceutical composition comprising a CD 123 -targeted therapeutic agent and a RAF inhibitor can be formulated for intravenous administration, inraarticular administration, subcutaneous administration, or intramuscular administration.

[0196] Any appropriate method can be used to identify increased expression of CD 123 on the surface of CD123-positive hematological cancer cells or CD 123 -negative hematological cancer cells. For example, immunological techniques (e.g., immunohistochemistry, radioimmunoassay, and enzyme-linked immune sorbent assay), flow cytometry, cytogenetic analysis (e.g., fluorescent in situ hybridization, spectral karyotyping, comparative genomic hybridization), genetic analysis (e.g., sequencing, reverse transcription, gel electrophoresis, DNA micro-array analysis), and proteomics can be used.

[0197] Any appropriate sample form a subject having a hematological cancer can be assessed as described herein (e.g., to determine expression of CD123 on the surface of CD123-positive hematological cancer cells or lack of detectable expression of CD123 on the surface of CD123- negative hematological cancer cells). In some cases, a sample can be a biological sample. In some cases, a sample can contain one or more hematological cancer cells. In some cases, a sample can contain one or more biological molecules (e.g., nucleic acids such as DNA and RNA, polypeptides, carbohydrates, lipids, hormones, and / or metabolites). Examples of samples that can be assessed as described herein include, without limitation, fluid samples (e.g., whole blood). In some cases, one or more biological molecules can be isolated from a sample.

[0198] In various methods described herein, the methods described result in increased expression of CD123 on the surface of a hematological cancer cell (e.g., a CD 123 -positive hematological cancer cell or a CD 123 -negative hematological cancer cell). In some embodiments, when treating a hematological cancer in a subject as described herein, the treatment can result in increased expression of CD 123 on the surface of a CD 123 -positive hematological cancer cell or a CD 123 -negative hematological cancer cell. For example, the expression of CD123 on the surface of a hematological cancer cell (e.g., a CD 123 -positive or CD 123 -negative hematological cancer cell) within a subject can be increased by using the methods and materials described herein. In some cases, the methods and materials described herein can increase the expression of CD123 on the surface of a CD 123 -positive hematological cancer cell or a CD 123 -negative hematological cancer cell by, for example, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or more, e.g., as compared to a reference level of CD 123 expression (e g., any of the exemplary reference levels of CD 123 expression described herein). In some cases, the methods and materials described herein can increase the expression of CD123 on the surface of a CD 123 -positive hematological cancer cell or a CD123- negative hematological cancer cell by, for example, by about 10% to about 1,000% (e g., about 10% to about 900%, about 10% to about 800%, about 10% to about 700%, about 10% to about 600%, about 10% to about 500%, about 10% to about 400%, about 10% to about 300%, about 10% to about 200%, about 10% to about 100%, about 10% to about 50%, about 50% to about 1,000%, about 50% to about 900%, about 50% to about 800%, about 50% to about 700%, about 50% to about 600%, about 50% to about 500%, about 50% to about 400%, about 50% to about 300%, about 50% to about 200%, about 50% to about 100%, about 100% to about 1,000%, about 100% to about 900%, about 100% to about 800%, about 100% to about 700%, about 100% to about 600%, about 100% to about 500%, about 100% to about 400%, about 100% to about 300%, about 100% to about 200%, about 500% to about 1,000%, about 500% to about 900%, about 500% to about 800%, about 500% to about 700, or about 800% to about 1,000%), e.g., as compared to a reference level of CD 123 expression (e.g., any of the exemplary reference levels of CD 123 expression described herein).

[0199] In some embodiments, when treating a subject having a hematological cancer (e.g., a CD 123 -positive hematological cancer or a CD 123 -negative hematological cancer) as described herein, the treatment can be effective to sensitize the subject to treatment with a CD 123 -targeted therapeutic agent. For example, the sensitivity to a CD 123 -targeted therapeutic agent of a subject can be increased using the methods and materials described herein. In some cases, the methods and materials described herein can be used to increase the sensitivity of a subject to a CD 123 -targeted therapeutic agent by, for example, an increase of about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more, e.g., as compared to the sensitivity of the subject or a similar subject to a CD 123 -targeted therapeutic agent in the absence of treatment with a MEK1 / 2 inhibitor, a SHP2 inhibitor, a RAS inhibitor, a SOS1 inhibitor, an ERK inhibitor, or a RAF inhibitor). In some embodiments, when treating a subject having a hematological cancer (e g., a CD 123 -positive hematological cancer or a CD 123 -negative hematological cancer) as described herein, the treatment can be effective to increase the therapeutic effect of a CD 123 -targeted therapeutic agent. For example, the therapeutic effect of a CD 123 -targeted therapeutic agent in a subject can be increased using the methods and materials described herein. In some cases, the methods and materials described herein can be used to increase the therapeutic effect of a CD 123 -targeted therapeutic agent by, for example, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more, e.g., as compared to the therapeutic effect of the CD 123 -targeted therapeutic agent in the subject or a similar subject when treated with the CD 123 -targeted therapeutic agent in the absence of treatment with a MEK1 / 2 inhibitor, a SHP2 inhibitor, a RAS inhibitor, a S0S1 inhibitor, an ERK inhibitor, or a RAF inhibitor.

[0200] For example, the death of CD123-postive hematological cancer cells or CD 123 -negative hematological cancer cells in a subject can be increased using the methods and materials described herein. In some cases, the methods and materials descried herein can be used to increase the cell death of CD 123 -positive hematological cancer cells or CD 123 -negative hematological cancer cells in the subject by, for example, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95% or more, e.g., as compared to the cell death of CD 123 -positive hematological cancer cells or CD 123 -negative hematological cancer cells in the subject or a similar subject when treated with the CD123- targeted therapeutic agent in the absence of treatment with a MEK1 / 2 inhibitor, a SHP2 inhibitor, or a RAS inhibitor.

[0201] In some cases, when treating a subject having a hematological cancer (e.g., a CD123- positive hematological cancer or CD 123 -negative hematological cancer) as described herein, the treatment can be effective to improve survival of the subject. For example, the methods and materials described herein can be used to improve disease-free survival (e.g., relapse-free survival). For example, the methods and materials described herein can be used to improve progression-free survival. For example, the methods and materials described herein can be used to improve the survival of a mammal having hematological cancer (e.g., a CD 123 -positive hematological cancer or a CD 123 -negative hematological cancer) by, for example, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95% or more, e.g., as compared to a similar subject not receiving a treatment or receiving a different therapeutic treatment. For example, the methods and materials described herein can be used to improve the survival of a mammal having hematological cancer (e.g., a CD 123 -positive hematological cancer or a CD 123 -negative hematological cancer) by, for example, at least 6 months (e.g., about 6 months, about 8 months, about 10 months, about 1 year, about 1.5 years, about 2 years, about 2.5 years, about 3 years or more).

[0202] In some cases, during a course of treatment, the number of CD 123 -positive hematological cancer cells or CD 123 -negative hematological cancer cells present within a subject, and / or the severity of one or more symptoms related to the condition being treated (e.g., a hematological cancer, e.g., a CD 123 -positive hematological cancer or a CD 123 -negative hematological cancer) can be monitored. Any appropriate method can be used to determine whether or not the number of CD 123 -positive hematological cancer cells or CD 123 -negative hematological cancer cells present within a subject is reduced. In some embodiments, the methods described herein result in a reduction in the level of CD 123 -positive hematological cancer cells or CD 123 -negative hematological cancer cells in a subject, e.g., by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%), e.g., as compared to the level of CD 123 -positive hematological cancer cells or CD 123 -negative hematological cancer cells in the subject prior to treatment. In some embodiments, the methods described herein result in about a 1% to about a 99% reduction (e.g., about a 1% to about a 95% reduction, about a 1% to about a 90% reduction, about a 1% reduction to about a 85% reduction, about a 1% reduction to about a 80% reduction, about a 1% reduction to about a 75% reduction, about a 1% to about a 70% reduction, about a 1% to about a 65% reduction, about a 1% to about a 60% reduction, about a 1% to about a 55% reduction, about a 1% to about a 50% reduction, about a 1% to about a 45% reduction, about a 1% to about a 40% reduction, about a 1% to about 35% reduction, about a 1% to about a 30% reduction, about a 1% to about a 25% reduction, about a 1% to about a 20% reduction, about a 1% to about a 15% reduction, about a 1% to about a 10% reduction, about a 10% to about a 99% reduction, about a 10% to about a 95% reduction, about a 10% to about a 90% reduction, about a 10% reduction to about a 85% reduction, about a 10% reduction to about a 80% reduction, about a 10% reduction to about a 75% reduction, about a 10% to about a 70% reduction, about a 10% to about a 65% reduction, about a 10% to about a 60% reduction, about a 10% to about a 55% reduction, about a 10% to about a 50% reduction, about a 10% to about a 45% reduction, about a 10% to about a 40% reduction, about a 10% to about 35% reduction, about a 10% to about a 30% reduction, about a 10% to about a 25% reduction, about a 10% to about a 20% reduction, about a 10% to about a 15% reduction, about a 20% to about a 99% reduction, about a 20% to about a 95% reduction, about a 20% to about a 90% reduction, about a 20% reduction to about a 85% reduction, about a 20% reduction to about a 80% reduction, about a 20% reduction to about a 75% reduction, about a 20% to about a 70% reduction, about a 20% to about a 65% reduction, about a 20% to about a 60% reduction, about a 20% to about a 55% reduction, about a 20% to about a 50% reduction, about a 20% to about a 45% reduction, about a 20% to about a 40% reduction, about a 20% to about 35% reduction, about a 20% to about a 30% reduction, about a 20% to about a 25% reduction, about a 30% to about a 99% reduction, about a 30% to about a 95% reduction, about a 30% to about a 90% reduction, about a 30% reduction to about a 85% reduction, about a 30% reduction to about a 80% reduction, about a 30% reduction to about a 75% reduction, about a 30% to about a 70% reduction, about a 30% to about a 65% reduction, about a 30% to about a 60% reduction, about a 30% to about a 55% reduction, about a 30% to about a 50% reduction, about a 30% to about a 45% reduction, about a 30% to about a 40% reduction, about a 30% to about 35% reduction, about a 40% to about a 99% reduction, about a 40% to about a 95% reduction, about a 40% to about a 90% reduction, about a 40% reduction to about a 85% reduction, about a 40% reduction to about a 80% reduction, about a 40% reduction to about a 75% reduction, about a 40% to about a 70% reduction, about a 40% to about a 65% reduction, about a 40% to about a 60% reduction, about a 40% to about a 55% reduction, about a 40% to about a 50% reduction, about a 40% to about a 45% reduction, about a 50% to about a 99% reduction, about a 50% to about a 95% reduction, about a 50% to about a 90% reduction, about a 50% reduction to about a 85% reduction, about a 50% reduction to about a 80% reduction, about a 50% reduction to about a 75% reduction, about a 50% to about a 70% reduction, about a 50% to about a 65% reduction, about a 50% to about a 60% reduction, about a 50% to about a 55% reduction, about a 60% to about a 99% reduction, about a 60% to about a 95% reduction, about a 60% to about a 90% reduction, about a 60% reduction to about a 85% reduction, about a 60% reduction to about a 80% reduction, about a 60% reduction to about a 75% reduction, about a 60% to about a 70% reduction, about a 60% to about a 65% reduction, about a 70% to about a 99% reduction, about a 70% to about a 95% reduction, about a 70% to about a 90% reduction, about a 70% reduction to about a 85% reduction, about a 70% reduction to about a 80% reduction, about a 70% reduction to about a 75% reduction, about a 80% to about a 99% reduction, about a 80% to about a 95% reduction, about a 80% to about a 90% reduction, about a 80% reduction to about a 85% reduction, about a 80% to about a 99% reduction, about a 80% to about a 95% reduction, or about a 90% to about a 99% reduction, or about a 90% to about a 95% reduction) in the level of CD 123 -positive hematological cancer cells or CD123- negative hematological cancer cells in the subject, e.g., as compared to the level of CD123- positive hematological cancer cells or CD 123 -negative hematological cancer cells in the subject prior to treatment. For example, imaging techniques or analysis of blood samples using fluorescence-assisted cell sorting (FACS) can be used to assess the number or level of CD123- positive hematological cancer cells or CD 123 -negative hematological cancer cells present within a subject.

[0203] Some embodiments of any of the methods described herein further include administration of one or more additional anti-cancer therapeutic agents. Non-limiting examples of additional anti-cancer agents include, but are not limited to, antimetabolic drugs (e.g., 5 -fluorouracil (5- FU), 6-mercaptopurine (6-MP), capecitabine, cytarabine, floxuridine, fludarabine, gemcitabine, hydroxycarbamide, methotrexate, 6-thioguanine, cladribine, nelarabine, pentostatin, or pemetrexed), plant alkaloids (e.g., vinblastine, vincristine, vindesine, camptothecin, 9- methoxycamptothecin, coronaridine, taxol, naucleaorals, diprenylated indole alkaloid, montamine, schischkiniin, protoberberine, berberine, sanguinarine, chelerythrine, chelidonine, liriodenine, clivorine, -carboline, antofine, tylophorine, cryptolepine, neocryptolepine, corynoline, sampangine, carbazole, crinamine, montanine, ellipticine, paclitaxel, docetaxel, etoposide, tenisopide, irinotecan, topotecan, or acridone alkaloids), proteasome inhibitors (e.g., lactacystin, disulfiram, epigallocatechin-3 -gallate, marizomib (salinosporamide A), oprozomib (ONX-0912), delanzomib (CEP-18770), epoxomicin, MG132, beta-hydroxy betamethylbutyrate, bortezomib, carfdzomib, or ixazomib), antitumor antibiotics (e.g., doxorubicin, daunorubicin, epirubicin, mitoxantrone, idarubicin, actinomycin, plicamycin, mitomycin, or bleomycin), histone deacetylase inhibitors (e.g., vorinostat, panobinostat, belinostat, givinostat, abexinostat, depsipeptide, entinostat, phenyl butyrate, valproic acid, trichostatin A, dacinostat, mocetinostat, pracinostat, nicotinamide, cambinol, tenovin 1, tenovin 6, sirtinol, ricolinostat, tefinostat, kevetrin, quisinostat, resminostat, tacedinaline, chidamide, or selisistat), tyrosine kinase inhibitors (e.g., axitinib, dasatinib, encorafinib, erlotinib, imatinib, nilotinib, pazopanib, and sunitinib), and chemotherapeutic agents (e.g., all-trans retinoic acid, azacitidine, azathioprine, doxifluridine, epothilone, hydroxyurea, imatinib, teniposide, tioguanine, valrubicin, vemurafenib, and lenalidomide).

[0204] Also provided herein are pharmaceutical compositions that include an effective amount of a MEK1 / 2 inhibitor and an effective amount of a CD 123 -targeted therapeutic agent.

[0205] Also provided herein are pharmaceutical compositions that include an effective amount of a SHP2 inhibitor and an effective amount of a CD 123 -targeted therapeutic agent.

[0206] Also provided herein are pharmaceutical compositions that include an effective amount of a RAS inhibitor and an effective amount of a CD 123 -targeted therapeutic agent.

[0207] Also provided herein are pharmaceutical compositions that include an effective amount of a S0S1 inhibitor and an effective amount of a CD 123 -targeted therapeutic agent.

[0208] Also provided herein are pharmaceutical compositions that include an effective amount of an ERK inhibitor and an effective amount of a CD 123 -targeted therapeutic agent.

[0209] Also provided herein are pharmaceutical compositions that include an effective amount of a RAF inhibitor and an effective amount of a CD 123 -targeted therapeutic agent.

[0210] The CD 123 -targeted therapeutic agent can be any of the exemplary CD 123 -targeted therapeutic agents described herein (e.g., an antibody or an antigen-binding antibody fragment (e.g., talacotuzumab), an antibody drug conjugate (e.g., pivekimab sunirine, SGN-CD123A, BYON4413, and VIP943), a fusion protein (e.g., tagraxofusp), a T cell engager or an NK cell engager (e.g., APVO436, flotetuzumab, vibecotamab, SAR443579, IGM-2537, and AFM28), a darpin (e.g., MP0533), a CAR T cell or a CAR NK cell (e.g., ACLX-002 or AUTO1). In some embodiments, the MEK1 / 2 inhibitor can be an allosteric inhibitor. In some embodiments, the MEK1 / 2 inhibitor can be trametinib, cobimetinib, selumetinib, binimetinib, mirdametinib, pimasertib, avutometinib, and GDC-0623. The pharmaceutical compositions can be formulated for intravenous administration, inraarticular administration, subcutaneous administration, or intramuscular administration. In some embodiments, the pharmaceutical composition can include a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient. Also provided herein are kits that include one or more doses of any of the pharmaceutical compositions described herein (e.g., one or more doses of a pharmaceutical composition comprising a CD 123 -targeted therapeutic agent and a MEK1 / 2 inhibitor, a SHP2 inhibitor, a RAS inhibitor, a SOS1 inhibitor, an ERK inhibitor, or a RAF inhibitor), or one or more doses of a first pharmaceutical composition comprising a CD 123 -targeted therapeutic agent and one or more doses of a second pharmaceutical composition comprising a MEK1 / 2 inhibitor, a SHP2 inhibitor, a RAS inhibitor, a S0S1 inhibitor, an ERK inhibitor, or a RAF inhibitor).

[0211] Antibody Drug Conjugates

[0212] The present disclosure also features antibody drug conjugate compositions, kits, and methods of treating hematological cancers in a subject that include an antibody conjugated to an inhibitor (e.g., any of the exemplary MEK1 / 2 inhibitors described herein or known in the art, any of the exemplary SHP2 inhibitors described herein or known in the art, any of the exemplary RAS inhibitors described herein or known in the art, any SOS1 inhibitors known in the art, any ERK inhibitors known in the art, or any RAF inhibitors known in the art).

[0213] Thus, provided herein are antibody drug conjugates including: (i) an antibody that specifically binds to CD123; and (ii) a MEK1 / 2 inhibitor conjugated to the antibody. Also provided herein are antibody drug conjugates including: (i) an antibody that specifically binds to CD123; and (ii) a SHP2 inhibitor conjugated to the antibody. Also provided herein are antibody drug conjugates including: (i) an antibody that specifically binds to CD123; and (ii) a RAS inhibitor conjugated to the antibody.

[0214] In some embodiments, the antibody drug conjugate includes a toxin conjugated to the antibody.

[0215] Also provided herein are pharmaceutical composition including any of the antibody drug conjugates described herein (e.g., pharmaceutical compositions that include an antibody drug conjugate with an antibody that specifically binds to CD123 and an inhibitor (e.g., any of the exemplary MEK1 / 2 inhibitors described herein or known in the art, any of the exemplary SHP2 inhibitors described herein or known in the art, any of the exemplary RAS inhibitors described herein or known in the art, any SCSI inhibitors known in the art, any ERK inhibitors known in the art, or any RAF inhibitors known in the art).

[0216] Also provided herein are kits including any of the antibody drug conjugates described herein or any of the pharmaceutical compositions described herein. Also provided herein are methods of treating a hematological cancer in a subject, the method including administering to the subject an effective amount of any of the antibody drug conjugates described herein or any of the pharmaceutical compositions described herein.

[0217] EXAMPLES

[0218] Example 1: Priming of AML cells with MEK-inhibitors

[0219] An automated, high-throughput screening platform was used to identify therapeutic agents that increase expression of CD 123 in AML cell lines.

[0220] Cell lines and patient samples

[0221] AML cell lines were obtained from ATCC (Manassas, VA) or DSMZ (Braunschweig, Germany) and grown according to the supplier’s recommendations. Fresh whole bone marrow (BM) from healthy donors were obtained from AllCells (Alameda, CA) or Lonza (Walkersville, MD).

[0222] Antibodies and secondary antibody drug conjugates

[0223] Appropriate isotype controls (Biolegend, San Diego, CA) were used in each experiment and DAPI (4',6-diamidino-2-phenylindole, Thermofisher, Waltham, MA) solution was used to distinguish between live and dead cells.

[0224] Priming assay

[0225] Cell line priming was measured using a fluorescently-labeled monoclonal anti-CD123 antibody. Cells were plated in a 384 well plate at a predetermined optimal plating density. An Echo 650T Acoustic Liquid Handler (Beckman Coulter Life Sciences, San Jose, CA) was used to dispense therapeutic agents. Therapeutic agents were evaluated using a 6 point dose response in triplicate. DMSO vehicle control wells were included on each plate and used for normalization. Dosed cells were incubated at 37°C, 5% CO2 and then stained for flow cytometry with CD 123.DAPI stain (Thermofisher) was used to distinguish between live and dead cells. Plates were blocked,, stained,, and washed with phosphate-buffered saline (PBS) and then resuspended in DAPI to run on the ZE5 flow cytometer (Bio-Rad, Hercules, CA). The flow cytometry data was analyzed using FlowJo (Ashland, OR) to determine the CD 123 geometric mean fluorescent intensity (gMFI) and normalized to DMSO vehicle control wells. An automated, high-throughput screening platform was used to identify therapeutic agents that increase expression of CD 123 in AML cell lines. A flow cytometry readout was used to identify priming agents that preferentially upregulate target antigens of interest.

[0226] Figures 1A and IB show that inhibitors of MEK1 / 2 consistently increased expression of CD123 in MV-4-11 (FIG. 1A) and M0LM13 (FIG. IB) AML cells, whereas treatment with inhibitors of other kinase targets did not. Every allosteric MEK inhibitor tested upregulated CD 123 in tests. Allosteric MEK inhibitors tested were selumetinib, mirdametinib, avutometinib, GDC-0623, pimasertib, binimetinib, trametinib, and cobimetinib (MedChemExpress, Monmouth Junction, NJ) at 1000 nM. The other kinase inhibitors tested were fostamatinib, PLX8394, sorafenib, vemurafenib, quizartinib, sunitinib, and pexidartinib (MedChemExpress) at 1000 nM.

[0227] Beyond allosteric MEK inhibitors, other MEK targeted small molecules including MAP855 (Figure 12A), MS432 (Figure 12B), and Trametiglue (Figure 12C) (MedChemExpress, Monmouth Junction, NJ) also upregulated CD123 (Figure. 1A). MAP855 (an ATP-competitive inhibitor of MEK1 / 2), MS432 (a MEK1 / 2 PROTAC degrader), and Trametiglue (a MEK1 / 2 molecular glue) were tested at 1000 nM, 3160 nM, and 10 nM respectively.

[0228] Figure 2 shows that among the allosteric MEK1 / 2 inhibitors tested (Figure 1), the differences in sensitivity to CD123 upregulation in MV-4-11 cells is associated with the in vitro (biochemical) potency of the MEK inhibitor for its target, the MEK / BRAF complex. For each MEK inhibitor, the half maximal effective concentration (EC50) was compared to the biochemical half maximal inhibitory concentration (IC50) for the MEK / BRAF complex. The biochemical potency of each MEK inhibitor was shown to be correlated with the concentration of MEK inhibitor required to upregulate CD 123 in the MV-4-11 cell line (spearman’s R = .813; p<0.05), suggesting that MEK inhibitor-mediated upregulation of CD123 is indeed due to on- target inhibition of MEK1 / 2 and not off-target effects.

[0229] Figure 4 show that targeting MAPK signaling cascade at different levels has varying effects on CD 123 expression. Inhibition of RAF (Figure 4), the upstream kinase for MEK (Figure 3A), had little effect on CD123 expression, whereas inhibition of MEK and ERK1 (Figure 4), the immediate downstream phosphorylation target of MEK (Figure 3 A), upregulated CD 123 expression. The same MEK inhibitors tested in Figure 1 were used for Figure 4. RAF inhibitors tested were tovorafenib, dabrafenib, naporafenib, PLX8394, exarafenib, and vemurafenib (MedChemExpress). MEK and RAF inhibitors were tested at 1000 nM and the Erk inhibitor, ASN007 (MedChemExpress) was tested at 100 nM.

[0230] Figure 5 shows that simultaneous treatment of MV-4-11 AML cells with both a MEK inhibitor (trametinib at 1000 nM) and an inhibitor of CBP / p300 (A-485 at 100 nM), a lysine acetyl transferase which remodels chromatin and drives changes in transcription of different receptor tyrosine kinases that has been previously reported to be activated by MEK inhibition, prevented upregulation of CD123. These results further illustrate the role that MEK1 / 2 inhibition has in upregulating CD 123.

[0231] Example 2: Sensitization of AML cells

[0232] Cells that are “primed” with a MEK inhibitor were shown to be more sensitive to CD 123 directed therapy.

[0233] Cytotoxicity assay

[0234] Cytotoxicity assays were set up using a primary unconjugated anti-CD123 monoclonal antibody and a secondary anti-Fc Fab conjugated to duocarmycin DM (DMDM) Cells were primed with trametinib and cultured in a flask at pre-optimized seeding density and concentrations.. The cytotoxicity assay was set up by dosing cell plates with a 6-point dose response curve of unconjugated primary CD 123 antibody and its appropriate isotype control (in triplicate), in the presence and absence of trametinib priming. Plates were incubated for l Omin at 37C before dosing with secondary anti-Fc DMDM Fab at a 1 :4 molar ratio to the primary antibody concentration. Dosed cells were incubated for 120 hours post ADC addition and read out using flow cytometry.

[0235] Figure 6 shows that MV-4-11 AML cells treated with MEK inhibitor (trametinib) have increased sensitivity to a CD 123 ADC than vehicle-treated (DMSO) cells. The data demonstrate that the CD123 ADC sensitivity for trametinib-treated cells was 25-fold lower than cells that were not treated with trametinib (vehicle treated) (EC50 of 0.2 vs. 5 nanomolar respectively).

[0236] Example 3: MEK inhibition in bone marrow progenitor cells

[0237] MEK does not affect expression of CD 123 of normal bone marrow progenitor populations Within two days of collection of healthy bone marrow (two donors), mononuclear cells (MNC) were isolated from bone marrow using Ficoll-Paque® PLUS medium (density 1.076 g / ml, Cytiva, Marlborough, MA) density centrifugation. Any contaminating red blood cells (if present) were lysed using an ammonium chloride-based RBC lysis buffer (Biolegend) for 5 minutes at 4°C. Mononuclear cells were resuspended in media and plated in 96-well plates. Trametinib was evaluated in a 6-point dose response in triplicate. After incubation, cells were stained for flow cytometry with fluorescently-labeled antibodies. Plates were blocked, stained washed with PBS and then resuspended in PBS to run on the ZE5 flow cytometer (Bio-Rad). Flow cytometry data was analyzed using FlowJo and all Trametinib treated wells were normalized to intra-plate DMSO control wells.

[0238] Figure 7 shows that while MV-4-11 AML cells treated with an optimized concentration of MEK inhibitor (trametinib) show a nearly 3-fold increase in CD123 expression, the expression of CD 123 is not significantly affected by MEK inhibitor (trametinib) treatment in bone marrow progenitor cells.

[0239] Example 4: Priming of AML cells with SHP2 inhibitors and Ras inhibitors

[0240] Figures 8 and 9 show that inhibition of SHP2 or Ras increased expression in AML cells. In contrast to RAF / MEK / ERK, the SHP2 phosphatase and the RAS GTPase are non-kinase regulators of MAPK signaling (Figure 3B). SHP2 inhibitors tested were batoprotafib (Figure 13A) and RMC-4550 (Figure 13B) (MedChemExpress, Monmouth Junction, NJ) at 316 nM. SHP2 inhibitors were tested in MV-4-11 and MOLM-13 AML cell lines. Ras inhibitors tested were RMC-6236 (Figure 14A) and RMC-7977 (Figure 14B) (MedChemExpress, Monmouth Junction, NJ) at 31.6 nM. Ras inhibitors were tested in the MV-4-11 AML cell line.

[0241] Figure 10 shows that simultaneous treatment of MV-4-11 AML cells with both a SHP2 inhibitor (batoprotafib at 3160 nM) and an inhibitor of CBP / p300 (A-485 at 100 nM), a lysine acetyl transferase which remodels chromatin and drives changes in transcription of different receptor tyrosine kinases that has been previously reported to be activated by MEK inhibition, prevented upregulation of CD 123. These results further illustrate the role that SHP2 inhibition has in upregulating CD123 is similar to MEK inhibition (Figure 5). Example 5: Sensitization of AML cells

[0242] Figure 11 shows that MV-4-11 AML cells treated with SHP2 inhibitor (100 nM batoprotafib) have increased sensitivity to a CD123 ADC than vehicle-treated (DMSO) cells. The data demonstrate that the CD 123 ADC sensitivity for batoprotafib -treated cells was 5-fold lower than cells that were not treated with batoprotafib (vehicle treated) (EC50 of 1 vs. 5 nanomolar respectively). The cytotoxicity assay was conducted as in Example 2 but with the SHP2 inhibitor, batoprotafib, used as the priming agent instead of the MEK inhibitor, trametinib.

Claims

WHAT IS CLAIMED IS:

1. A method of treating a hematological cancer in a subject, the method comprising administering to the subject an effective amount of a MEK1 / 2 inhibitor and an effective amount of a CD 123 -targeted therapeutic agent.

2. The method of claim 1, wherein the method comprises administering the MEK1 / 2 inhibitor to the subject prior to administering the CD 123 -targeted therapeutic agent to the subject.

3. The method of claim 1, wherein the method comprises administering the MEK1 / 2 inhibitor to the subject at substantially the same time as administering the CD 123 -targeted therapeutic agent to the subject.

4. The method of any one of claims 1-3, wherein the subject was previously administered a CD 123 -targeted therapeutic agent without a MEK1 / 2 inhibitor, and the subject was not responsive to treatment with the CD 123 -targeted therapeutic agent without the MEK1 / 2 inhibitor.

5. The method of any one of claims 1-4, wherein the CD 123 -targeted therapeutic agent is an antibody or an antigen-binding antibody fragment.

6. The method of claim 5, wherein the antibody is talacotuzumab.

7. The method of any one of claims 1-4, wherein the CD 123 -targeted therapeutic agent is an antibody drug conjugate (ADC).

8. The method of claim 7, wherein the ADC is selected from the group of pivekimab sunirine, SGN-CD123A, BYON4413, and VIP943.

9. The method of any one of claims 1-4, wherein the CD 123 -targeted therapeutic agent is a fusion protein.

10. The method of claim 9, wherein the fusion protein is tagraxofusp.

11. The method of any one of claims 1-4, wherein the CD 123 -targeted therapeutic agent is a T cell engager or an NK cell engager.

12. The method of claim 11, wherein the T cell engager or the NK cell engager is selected from the group consisting of: APVO436, flotetuzumab, vibecotamab, SAR443579, IGM-2537, and AFM28.

13. The method of any one of claims 1-4, wherein the CD 123 -targeted therapeutic agent is a darpin.

14. The method of claim 13, wherein the darpin is MP0533.

15. The method of any one of claims 1-4, wherein the CD 123 -targeted therapeutic agent is a CAR T cell or a CAR NK cell.

16. The method of claim 15, wherein the CAR T cell is ACLX-002 or AUTO1.

17. The method of any one of claims 1-16, wherein the MEK1 / 2 inhibitor is an allosteric inhibitor.

18. The method of claim 17, wherein the MEK1 / 2 inhibitor is selected from the group consisting of: trametinib, cobimetinib, selumetinib, binimetinib, mirdametinib, pimasertib, avutometinib, and GDC-0623.

19. The method of any one of claims 1-16, wherein the MEK1 / 2 inhibitor is an ATP- competitive inhibitor.

20. The method of claim 19, wherein the ATP-competitive inhibitor is MAP855.21 . The method of any one of claims 1-16, wherein the MEK1 / 2 inhibitor is a proteolysis targeted chimera (PROTAC).

22. The method of claim 21, wherein the PROTAC is MS432.

23. The method of any one of claims 1-16, wherein the MEK1 / 2 inhibitor is a glue.

24. The method of claim 23, wherein the glue is Trametiglue.

25. The method of any one of claims 1-24, wherein the hematological cancer is a CD123- positive hematological cancer.

26. The method of claim 25, wherein the subject has previously been identified or diagnosed as having a CD 123 -positive hematological cancer.

27. The method of any one of claims 1-24, wherein the hematological cancer is a CD123- negative hematological cancer.

28. The method of claim 27, wherein the subject has previously been identified or diagnosed as having a CD 123 -negative hematological cancer.

29. The method of any one of claims 1-28, wherein the hematological cancer is a lymphoma or a leukemia.

30. The method of claim 29, wherein the leukemia is acute myeloid leukemia (AML) or B cell lymphoblastic leukemia (B-ALL).

31. The method of any one of claims 1-28, wherein the hematological cancer is blastic plasmacytoid dendritic cell neoplasm (BPDCN).

32. A pharmaceutical composition comprising an effective amount of a MEK1 / 2 inhibitor and an effective amount of a CD 123 -targeted therapeutic agent.

33. The pharmaceutical composition of claim 32, wherein the CD 123 -targeted therapeutic agent is an antibody or an antigen-binding antibody fragment.

34. The pharmaceutical composition of claim 33, wherein the antibody is talacotuzumab.

35. The pharmaceutical composition of claim 32, wherein the CD 123 -targeted therapeutic agent is an antibody drug conjugate (ADC).

36. The pharmaceutical composition of claim 35, wherein the ADC is selected from the group of pivekimab sunirine, SGN-CD123A, BYON4413, and VIP943.

37. The pharmaceutical composition of claim 32, wherein the CD 123 -targeted therapeutic agent is a fusion protein.

38. The pharmaceutical composition of claim 37, wherein the fusion protein is tagraxofusp.

39. The pharmaceutical composition of claim 32, wherein the CD 123 -targeted therapeutic agent is a T cell engager or an NK cell engager.

40. The pharmaceutical composition of claim 39, wherein the T cell engager or the NK cell engager is selected from the group consisting of: APVO436, flotetuzumab, vibecotamab, SAR443579, IGM-2537, and AFM28.

41. The pharmaceutical composition of claim 32, wherein the CD 123 -targeted therapeutic agent is a darpin.

42. The pharmaceutical composition of claim 42, wherein the darpin is MP0533.

43. The pharmaceutical composition of claim 32, wherein the CD 123 -targeted therapeutic agent is a CAR T cell or a CAR NK cell.

44. The pharmaceutical composition of claim 43, wherein the CAR T cell is ACLX-002 or AUTO 1.

45. The pharmaceutical composition of any one of claims 32-44, wherein the MEK1 / 2 inhibitor is an allosteric inhibitor.

46. The pharmaceutical composition of claim 45, wherein the MEK1 / 2 inhibitor is selected from the group consisting of: trametinib, cobimetinib, selumetinib, binimetinib, mirdametinib, pimasertib, avutometinib, and GDC-0623.

47. The pharmaceutical composition of any one of claims 32-44, wherein the MEK1 / 2 inhibitor is an ATP-competitive inhibitor.

48. The pharmaceutical composition of claim 47, wherein the ATP-competitive inhibitor is MAP855.

49. The pharmaceutical composition of any one of claims 32-44, wherein the MEK1 / 2 inhibitor is a proteolysis targeted chimera (PROTAC).

50. The pharmaceutical composition of claim 49, wherein the PROTAC is MS432.

51. The pharmaceutical composition of any one of claims 32-44, wherein the MEK1 / 2 inhibitor is a glue.

52. The pharmaceutical composition of claim 51, wherein the glue is Trametiglue.

53. A method of increasing expression of CD123 in a hematological cancer cell, the method comprising contacting the hematological cancer cell with a MEK1 / 2 inhibitor.

54. The method of claim 53, wherein the MEK1 / 2 inhibitor is an allosteric inhibitor.

55. The method of claim 54, wherein the MEK1 / 2 inhibitor is selected from the group consisting of: trametinib, cobimetinib, selumetinib, binimetinib, mirdametinib, pimasertib, avutometinib, and GDC-0623.

56. The method of claim 53, wherein the MEK1 / 2 inhibitor is an ATP-competitive inhibitor.

57. The method of claim 56, wherein the ATP-competitive inhibitor is MAP855.

58. The method of claim 53, wherein the MEK1 / 2 inhibitor is a proteolysis targeted chimera (PROTAC).

59. The method of claim 58, wherein the PROTAC is MS432.

60. The method of claim 53, wherein the MEK1 / 2 inhibitor is a glue.

61. The method of claim 60, wherein the glue is Trametiglue.

62. The method of any one of claims 53-61, wherein the hematological cancer cell is in vitro.

63. The method of any one of claims 53-61, wherein the hematological cancer cell is in a subject.

64. The method of any one of claims 53-62, wherein the hematological cancer cell is a leukemia cell, a lymphoma cell, or a blastic plasmacytoid dendritic cell neoplasm (BPDCN).

65. The method of claim 64, wherein the leukemia cell is an acute myeloid leukemia cell or B cell lymphoblastic leukemia cell.

66. A method of sensitizing a subject having a hematological cancer for treatment with a CD 123 -targeted therapeutic agent, the method comprising administering an effective amount of a MEK1 / 2 inhibitor to the subject.

67. A method of increasing the therapeutic effect of a CD 123 -targeted therapeutic agent in a subject having a hematological cancer, the method comprising administering an effective amount of a MEK1 / 2 inhibitor to the subject.

68. The method of claim 67, wherein the increased therapeutic effect is an increase in hematological cancer cell death.

69. The method of any one of claims 66-68, wherein the MEK1 / 2 inhibitor is an allosteric inhibitor.

70. The method of any one of claims 66-69, wherein the MEK1 / 2 inhibitor is selected from the group consisting of: trametinib, cobimetinib, selumetinib, binimetinib, mirdametinib, pimasertib, avutometinib, and GDC-0623.

71. The method of any one of claims 66-68, wherein the MEK1 / 2 inhibitor is an ATP- competitive inhibitor.

72. The method of claim 71, wherein the ATP-competitive inhibitor is MAP855.

73. The method of any one of claims 66-68, wherein the MEK1 / 2 inhibitor is a proteolysis targeted chimera (PROTAC).

74. The method of claim 73, wherein the PROTAC is MS432.

75. The method of any one of claims 66-68, wherein the MEK1 / 2 inhibitor is a glue.

76. The method of claim 75, wherein the glue is Trametiglue.

77. The method of any one of claims 66-76, wherein the hematological cancer is a CD 123 -positive hematological cancer.

78. The method of any one of claims 66-76, wherein the hematological cancer is a CD 123 -negative hematological cancer.

79. The method of any one of claims 66-78, wherein the hematological cancer is a leukemia or a lymphoma.

80. The method of claim 79, wherein the leukemia is acute myeloid leukemia or B cell acute lymphoblastic leukemia (B-ALL).

81. The method of claim 79, wherein the hematological cancer is blastic plasmacytoid dendritic cell neoplasm (BPDCN).

82. A method of treating a hematological cancer in a subject, the method comprising administering to the subject an effective amount of a SHP2 inhibitor and an effective amount of a CD 123 -targeted therapeutic agent.

83. The method of claim 82, wherein the method comprises administering the SHP2 inhibitor to the subject prior to administering the CD 123 -targeted therapeutic agent to the subject.

84. The method of claim 82, wherein the method comprises administering the SHP2 inhibitor to the subject at substantially the same time as administering the CD 123 -targeted therapeutic agent to the subject.

85. The method of any one of claims 82-84, wherein the subject was previously administered a CD 123 -targeted therapeutic agent without a SHP2 inhibitor, and the subject was not responsive to treatment with the CD 123 -targeted therapeutic agent without the SHP2 inhibitor.

86. The method of any one of claims 82-85, wherein the CD 123 -targeted therapeutic agent is an antibody or an antigen-binding antibody fragment.

87. The method of claim 86, wherein the antibody is talacotuzumab.

88. The method of any one of claims 82-85, wherein the CD 123 -targeted therapeutic agent is an antibody drug conjugate (ADC).

89. The method of claim 88, wherein the ADC is selected from the group of pivekimab sunirine, SGN-CD123A, BYON4413, and VIP943.

90. The method of any one of claims 82-85, wherein the CD 123 -targeted therapeutic agent is a fusion protein.

91. The method of claim 90, wherein the fusion protein is tagraxofusp.

92. The method of any one of claims 82-85, wherein the CD 123 -targeted therapeutic agent is a T cell engager or an NK cell engager.

93. The method of claim 92, wherein the T cell engager or the NK cell engager is selected from the group consisting of: APVO436, flotetuzumab, vibecotamab, SAR443579, IGM-2537, and AFM28.

94. The method of any one of claims 82-85, wherein the CD 123 -targeted therapeutic agent is a darpin.

95. The method of claim 94, wherein the darpin is MP0533.

96. The method of any one of claims 82-85, wherein the CD 123 -targeted therapeutic agent is a CAR T cell or a CAR NK cell.

97. The method of claim 96, wherein the CAR T cell is ACLX-002 or AUT01 .

98. The method of any one of claims 82-97, wherein the SHP2 inhibitor is an allosteric inhibitor.

99. The method of claim 98, wherein the SHP2 inhibitor is selected from the group consisting of: batoprotafib, RMC-4550, SHP099, RMC-4630, GDC-1971 (RLY-1971), PF- 07284892, BBP-398 (IACS-13909), and JAB-3068.

100. The method of any one of claims 82-99, wherein the hematological cancer is a CD 123 -positive hematological cancer.

101. The method of claim 100, wherein the subject has previously been identified or diagnosed as having a CD 123 -positive hematological cancer.

102. The method of any one of claims 82-99, wherein the hematological cancer is a CD 123 -negative hematological cancer.

103. The method of claim 102, wherein the subject has previously been identified or diagnosed as having a CD 123 -negative hematological cancer.

104. The method of any one of claims 82-103, wherein the hematological cancer is a lymphoma or a leukemia.

105. The method of claim 104, wherein the leukemia is acute myeloid leukemia (AML) or B cell lymphoblastic leukemia (B-ALL).

106. The method of any one of claims 82-103, wherein the hematological cancer is blastic plasmacytoid dendritic cell neoplasm (BPDCN).

107. A pharmaceutical composition comprising an effective amount of a SHP2 inhibitor and an effective amount of a CD 123 -targeted therapeutic agent.

108. The pharmaceutical composition of claim 107, wherein the CD 123 -targeted therapeutic agent is an antibody or an antigen-binding antibody fragment.

109. The pharmaceutical composition of claim 108, wherein the antibody is talacotuzumab.

110. The pharmaceutical composition of claim 107, wherein the CD 123 -targeted therapeutic agent is an antibody drug conjugate (ADC).

111. The pharmaceutical composition of claim 110, wherein the ADC is selected from the group of pivekimab sunirine, SGN-CD123A, BYON4413, and VIP943.

112. The pharmaceutical composition of claim 107, wherein the CD 123 -targeted therapeutic agent is a fusion protein.

113. The pharmaceutical composition of claim 112, wherein the fusion protein is tagraxofusp.

114. The pharmaceutical composition of claim 107, wherein the CD 123 -targeted therapeutic agent is a T cell engager or an NK cell engager.

115. The pharmaceutical composition of claim 114, wherein the T cell engager or the NK cell engager is selected from the group consisting of: APVO436, flotetuzumab, vibecotamab, SAR443579, IGM-2537, and AFM28.

116. The pharmaceutical composition of claim 107, wherein the CD 123 -targeted therapeutic agent is a darpin.

117. The pharmaceutical composition of claim 116, wherein the darpin is MP0533.

118. The pharmaceutical composition of claim 107, wherein the CD 123 -targeted therapeutic agent is a CAR T cell or a CAR NK cell.

119. The pharmaceutical composition of claim 118, wherein the CAR T cell is ACLX- 002 or AUTO 1.

120. The pharmaceutical composition of any one of claims 107-119, wherein the SHP2 inhibitor is an allosteric inhibitor.

121. The pharmaceutical composition of claim 120, wherein the SHP2 inhibitor is selected from the group consisting of: batoprotafib, RMC-4550, SHP099, RMC-4630, GDC- 1971 (RLY-1971), PF-07284892, BBP-398 (IACS-13909), and JAB-3068.

122. A method of increasing expression of CD123 in a hematological cancer cell, the method comprising contacting the hematological cancer cell with a SHP2 inhibitor.

123. The method of claim 122, wherein the SHP2 inhibitor is an allosteric inhibitor.

124. The method of claim 123, wherein the SHP2 inhibitor is selected from the group consisting of: batoprotafib, RMC-4550, SHP099, RMC-4630, GDC-1971 (RLY-1971), PF- 07284892, BBP-398 (IACS-13909), and JAB-3068.

125. The method of any one of claims 122-124, wherein the hematological cancer cell is in vitro.

126. The method of any one of claims 122-124, wherein the hematological cancer cell is in a subject.

127. The method of any one of claims 122-126, wherein the hematological cancer cell is a leukemia cell or a lymphoma cell.

128. The method of claim 127, wherein the leukemia cell is an acute myeloid leukemia cell or B cell lymphoblastic leukemia cell.

129. The method of claim 128, wherein the hematological cancer cell is a blastic plasmacytoid dendritic cell neoplasm (BPDCN) cell.

130. A method of sensitizing a subject having a hematological cancer for treatment with a CD 123 -targeted therapeutic agent, the method comprising administering an effective amount of a SHP2 inhibitor to the subject.

131. A method of increasing the therapeutic effect of a CD 123 -targeted therapeutic agent in a subject having a hematological cancer, the method comprising administering an effective amount of a SHP2 inhibitor to the subject.

132. The method of claim 131, wherein the increased therapeutic effect is an increase in hematological cancer cell death.

133. The method of any one of claims 130-132, wherein the SHP2 inhibitor is an allosteric inhibitor.

134. The method of any one of claims 130-133, wherein the SHP2 inhibitor is selected from the group consisting of: batoprotafib, RMC-4550, SHP099, RMC-4630, GDC-1971 (RLY- 1971), PF-07284892, BBP-398 (IACS-13909), and JAB-3068.

135. The method of any one of claims 130-134, wherein the hematological cancer is a CD 123 -positive hematological cancer.

136. The method of any one of claims 130-134, wherein the hematological cancer is a CD 123 -negative hematological cancer.

137. The method of any one of claims 130-136, wherein the hematological cancer is a leukemia or a lymphoma.

138. The method of claim 137, wherein the leukemia is acute myeloid leukemia or B cell acute lymphoblastic leukemia (B-ALL).

139. The method of claim 137, wherein the hematological cancer is blastic plasmacytoid dendritic cell neoplasm (BPDCN).

140. A method of treating a hematological cancer in a subject, the method comprising administering to the subject an effective amount of a RAS inhibitor and an effective amount of a CD 123 -targeted therapeutic agent.

141. The method of claim 140, wherein the method comprises administering the RAS inhibitor to the subject prior to administering the CD 123 -targeted therapeutic agent to the subject.

142. The method of claim 140, wherein the method comprises administering the RAS inhibitor to the subject at substantially the same time as administering the CD 123 -targeted therapeutic agent to the subject.

143. The method of any one of claims 140-143, wherein the subject was previously administered a CD 123 -targeted therapeutic agent without a RAS inhibitor, and the subject was not responsive to treatment with the CD 123 -targeted therapeutic agent without the RAS inhibitor.

144. The method of any one of claims 140-143, wherein the CD 123 -targeted therapeutic agent is an antibody or an antigen-binding antibody fragment.

145. The method of claim 144, wherein the antibody is talacotuzumab.

146. The method of any one of claims 140-143, wherein the CD 123 -targeted therapeutic agent is an antibody drug conjugate (ADC).

147. The method of claim 146, wherein the ADC is selected from the group of pivekimab sunirine, SGN-CD123A, BYON4413, and VIP943.

148. The method of any one of claims 140-143, wherein the CD 123 -targeted therapeutic agent is a fusion protein.

149. The method of claim 148, wherein the fusion protein is tagraxofusp.

150. The method of any one of claims 140-143, wherein the CD 123 -targeted therapeutic agent is a T cell engager or an NK cell engager.

151. The method of claim 150, wherein the T cell engager or the NK cell engager is selected from the group consisting of: APVO436, flotetuzumab, vibecotamab, SAR443579, IGM-2537, and AFM28.

152. The method of any one of claims 140-143, wherein the CD 123 -targeted therapeutic agent is a darpin.

153. The method of claim 152, wherein the darpin is MP0533.

154. The method of any one of claims 140-143, wherein the CD 123 -targeted therapeutic agent is a CAR T cell or a CAR NK cell.

155. The method of claim 154, wherein the CAR T cell is ACLX-002 or AUTO1.

156. The method of any one of claims 140-155, wherein the RAS inhibitor is an allosteric inhibitor.

157. The method of claim 156, wherein the RAS inhibitor is RMC-6236 and / or RMC- 7977.

158. The method of any one of claims 140-157, wherein the hematological cancer is a CD 123 -positive hematological cancer.

159. The method of claim 158, wherein the subject has previously been identified or diagnosed as having a CD 123 -positive hematological cancer.

160. The method of any one of claims 140-157, wherein the hematological cancer is a CD 123 -negative hematological cancer.

161. The method of claim 160, wherein the subject has previously been identified or diagnosed as having a CD 123 -negative hematological cancer.

162. The method of any one of claims 140-161, wherein the hematological cancer is a lymphoma or a leukemia.

163. The method of claim 162, wherein the leukemia is acute myeloid leukemia (AML) or B cell lymphoblastic leukemia (B-ALL).

164. The method of any one of claims 140-161, wherein the hematological cancer is blastic plasmacytoid dendritic cell neoplasm (BPDCN).

165. A pharmaceutical composition comprising an effective amount of a RAS inhibitor and an effective amount of a CD 123 -targeted therapeutic agent.

166. The pharmaceutical composition of claim 165, wherein the CD 123 -targeted therapeutic agent is an antibody or an antigen-binding antibody fragment.

167. The pharmaceutical composition of claim 166, wherein the antibody is talacotuzumab.

168. The pharmaceutical composition of claim 165, wherein the CD 123 -targeted therapeutic agent is an antibody drug conjugate (ADC).

169. The pharmaceutical composition of claim 168, wherein the ADC is selected from the group of pivekimab sunirine, SGN-CD123A, BYON4413, and VIP943.

170. The pharmaceutical composition of claim 165, wherein the CD 123 -targeted therapeutic agent is a fusion protein.

171. The pharmaceutical composition of claim 170, wherein the fusion protein is tagraxofusp.

172. The pharmaceutical composition of claim 165, wherein the CD 123 -targeted therapeutic agent is a T cell engager or an NK cell engager.

173. The pharmaceutical composition of claim 172, wherein the T cell engager or the NK cell engager is selected from the group consisting of: APVO436, flotetuzumab, vibecotamab, SAR443579, IGM-2537, and AFM28.

174. The pharmaceutical composition of claim 165, wherein the CD 123 -targeted therapeutic agent is a darpin.

175. The pharmaceutical composition of claim 174, wherein the darpin is MP0533.

176. The pharmaceutical composition of claim 165, wherein the CD 123 -targeted therapeutic agent is a CAR T cell or a CAR NK cell.

177. The pharmaceutical composition of claim 176, wherein the CAR T cell is ACLX- 002 or AUTO 1.

178. The pharmaceutical composition of any one of claims 165-177, wherein the RAS inhibitor is an allosteric inhibitor.

179. The pharmaceutical composition of claim 178, wherein the RAS inhibitor is RMC- 6236 and / or RMC-7977.

180. A method of increasing expression of CD 123 in a hematological cancer cell, the method comprising contacting the hematological cancer cell with a RAS inhibitor.

181. The method of claim 180, wherein the RAS inhibitor is an allosteric inhibitor.

182. The method of claim 181, wherein the RAS inhibitor is RMC-6236 and / or RMC- 7977.

183. The method of any one of claims 180-182, wherein the hematological cancer cell is in vitro.

184. The method of any one of claims 180-182, wherein the hematological cancer cell is in a subject.

185. The method of any one of claims 180-184, wherein the hematological cancer cell is a leukemia cell or a lymphoma cell.

186. The method of claim 185, wherein the leukemia cell is an acute myeloid leukemia cell or B cell lymphoblastic leukemia cell.

187. The method of claim 186, wherein the hematological cancer cell is a blastic plasmacytoid dendritic cell neoplasm (BPDCN) cell.

188. A method of sensitizing a subject having a hematological cancer for treatment with a CD 123 -targeted therapeutic agent, the method comprising administering an effective amount of a RAS inhibitor to the subject.

189. A method of increasing the therapeutic effect of a CD 123 -targeted therapeutic agent in a subject having a hematological cancer, the method comprising administering an effective amount of a RAS inhibitor to the subject.

190. The method of claim 189, wherein the increased therapeutic effect is an increase in hematological cancer cell death.

191. The method of any one of claims 188-190, wherein the RAS inhibitor is an allosteric inhibitor.

192. The method of any one of claims 188-191, wherein the RAS inhibitor is RMC-6236 and / or RMC-7977.

193. The method of any one of claims 188-192, wherein the hematological cancer is a CD 123 -positive hematological cancer.

194. The method of any one of claims 188-192, wherein the hematological cancer is a CD 123 -negative hematological cancer.

195. The method of any one of claims 188-194, wherein the hematological cancer is a leukemia or a lymphoma.

196. The method of claim 195, wherein the leukemia is acute myeloid leukemia or B cell acute lymphoblastic leukemia (B-ALL).

197. The method of claim 195, wherein the hematological cancer is blastic plasmacytoid dendritic cell neoplasm (BPDCN).

198. An antibody drug conjugate comprising:(i) an antibody that specifically binds to CD 123; and(ii) a MEK1 / 2 inhibitor conjugated to the antibody.

199. An antibody drug conjugate comprising:(i) an antibody that specifically binds to CD 123; and(ii) a SHP2 inhibitor conjugated to the antibody.

200. An antibody drug conjugate comprising:(i) an antibody that specifically binds to CD 123; and(ii) a RAS inhibitor conjugated to the antibody.

201. The antibody drug conjugate of any one of claims 198-200, wherein the antibody drug conjugate further comprises a toxin conjugated to the antibody.

202. A pharmaceutical composition comprising the antibody drug conjugate of any one of claims 198-201.

203. A kit comprising the antibody drug conjugate of any one of claims 198-201 or the pharmaceutical composition of claim 202.

204. A method of treating a hematological cancer in a subject, the method comprising administering to the subject an effective amount of an antibody drug conjugate of any one of claims 198-201 or the pharmaceutical composition of claim 202.

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