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WO2024137697A1 - Polythérapies pour traiter le cancer - Google Patents

Polythérapies pour traiter le cancer Download PDF

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Publication number
WO2024137697A1
WO2024137697A1 PCT/US2023/084937 US2023084937W WO2024137697A1 WO 2024137697 A1 WO2024137697 A1 WO 2024137697A1 US 2023084937 W US2023084937 W US 2023084937W WO 2024137697 A1 WO2024137697 A1 WO 2024137697A1
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milligrams
immune checkpoint
checkpoint inhibitor
cancer
administered
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Gunnar Kaufmann
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Oncternal Therapeutics Inc
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Oncternal Therapeutics Inc
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Priority to AU2023409023A priority Critical patent/AU2023409023A1/en
Priority to CN202380094535.7A priority patent/CN120813602A/zh
Priority to EP23908368.6A priority patent/EP4638506A1/fr
Publication of WO2024137697A1 publication Critical patent/WO2024137697A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an evolutionarily - conserved type I membrane protein that belongs to the ROR subfamily and has extracellular domains that contain immunoglobulin (Ig)-like, Frizzled, and Kringle domains. Current data suggest that ROR1 may function in non-canonical WNT-signaling to promote the survival of malignant cells.
  • Checkpoint inhibitors act by blocking checkpoint proteins from binding partner proteins, thereby allowing T cells to kill cancer cells.
  • Checkpoint inhibitor drugs include drugs targeting PD-1, PD-L1, and PD-L2.
  • Described herein are methods of treating cancer that combine the use of an ROR1 antagonist and a checkpoint inhibitor antagonist. Surprisingly and unexpectedly, it is observed that the combination of a ROR1 antagonist and a checkpoint inhibitor provide a synergistic effect in the treatment of cancer in a subject in need thereof, which is superior to the effect of either the ROR1 antagonist or the checkpoint inhibitor acting alone.
  • Described herein in a certain aspect is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a tyrosine kinase-like orphan receptor 1 (ROR1) antagonist and a therapeutically effective amount of an immune checkpoint inhibitor to the subject.
  • the immune checkpoint inhibitor comprises a PD-1 inhibitor, or a PD-L1 inhibitor.
  • the immune checkpoint inhibitor is a small molecule drug.
  • the immune checkpoint inhibitor comprises an antibody, a peptide, or a protein.
  • the immune checkpoint inhibitor comprises a PD-1 inhibitor.
  • the PD-1 inhibitor is a PD-1 inhibitor antibody.
  • the PD-1 inhibitor antibody comprises nivolumab, pembrolizumab, cemiplimab, dorstarlimab, or combinations thereof.
  • the PD-1 inhibitor antibody comprises pembrolizumab.
  • the PD-1 inhibitor antibody comprises JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilmab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), Retifanlimab (INCMGA00012) (MGA012), AMP -224, AMP-514, or combinations thereof.
  • the immune checkpoint inhibitor comprises a PD-L1 inhibitor.
  • the PD-Ll inhibitor is a PD-Ll inhibitor antibody.
  • the PD-L1 inhibitor antibody comprises atezolizumab, avelumab, durvalumab, or combinations thereof. In certain embodiments, the PD-L1 inhibitor antibody comprises Envafolimab (KN035), Cosibelimab (CK-301), AUNP12, CA-170, BMS-986189, or combinations thereof. In certain embodiments, the ROR1 antagonist is an antibody or a small molecule. In certain embodiments, the antibody comprises a Fab, F(ab’)2, Fv, or an scFv. In certain embodiments, the ROR1 antagonist is an anti-RORl antibody. In certain embodiments, the antibody is zilovertamab.
  • the antibody binds to an ROR1 amino acid sequence as set forth in SEQ ID NO 30 or SEQ ID NO: 31.
  • the immune checkpoint inhibitor and the ROR1 antagonist are administered in a combined synergistic amount.
  • the method further comprises reducing the growth of a tumor. In certain embodiments, the method reduces the growth of a tumor by about 20% or more. In certain embodiments, the method reduces the growth of a tumor by from about 25% to about 45% when compared to administration of the immune checkpoint inhibitor and the ROR1 antagonist separately. In certain embodiments, the method further comprises reducing the mass or volume of a tumor.
  • the antibody comprises a humanized heavy chain variable region and a humanized light chain variable region, wherein said humanized heavy chain variable region comprises the sequences set forth in SEQ ID NO. 1, SEQ ID NO. 2, and SEQ ID NO. 3; and wherein said humanized light chain variable region comprises the sequences set forth in SEQ ID NO. 4, SEQ ID NO. 5, and SEQ ID NO. 6.
  • the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100 identical to that set forth in SEQ ID NO: 7; and wherein the light chain variable region comprises an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100 identical to that set forth in SEQ ID NO: 8.
  • an immune cell infiltrate of the cancer expresses PD-1.
  • the cancer expresses PD-L1.
  • the cancer over expresses PD-L1.
  • the immune checkpoint inhibitor and the ROR1 antagonist are administered substantially simultaneously. In certain embodiments, the immune checkpoint inhibitor and the ROR1 antagonist are administered separately. In certain embodiments, the immune checkpoint inhibitor and the ROR1 antagonist are administered sequentially. In certain embodiments, the immune checkpoint inhibitor and the ROR1 antagonist are co-formulated for administration by a single formulation. In certain embodiments, the immune checkpoint inhibitor and the ROR1 antagonist are administered in separate compositions. In certain embodiments, the immune checkpoint inhibitor and the ROR1 antagonist are admixed prior to administration. In certain embodiments, the immune checkpoint inhibitor is administered by intravenous infusion. In certain embodiments, the immune checkpoint inhibitor is administered once every two- weeks.
  • the immune checkpoint inhibitor is administered once every three-weeks. In certain embodiments, the immune checkpoint inhibitor is administered once every four-weeks. In certain embodiments, the immune checkpoint inhibitor is administered at a dosage from about 200 milligrams to about 2000 milligrams. In certain embodiments, the immune checkpoint inhibitor is administered at a dosage from about 200 milligrams to about 800 milligrams. In certain embodiments, the immune checkpoint inhibitor is administered at a dosage from about 300 milligrams to about 600 milligrams. In certain embodiments, the immune checkpoint inhibitor is administered at a dosage of about 300 milligrams. In certain embodiments, the immune checkpoint inhibitor is administered at a dosage of about 600 milligrams.
  • the immune checkpoint inhibitor is administered in an amount of 200 mg every six weeks; 300 mg every six weeks, or 400 mg every six weeks. In certain embodiments, the immune checkpoint inhibitor is administered in an amount of 100 mg every three weeks; or 300 mg every six weeks. In certain embodiments, the immune checkpoint inhibitor is administered in an amount of 2 mg/kg, or 1 mg/kg every 3 weeks. In certain embodiments, the immune checkpoint inhibitor is administered in an amount of 50 mg every three weeks; or 100 mg every six weeks. In certain embodiments, the immune checkpoint inhibitor is administered in an amount of about 50 mg to about 400 mg every three weeks. In certain embodiments, the immune checkpoint inhibitor is administered in a 25 mg/mL solution.
  • the immune checkpoint inhibitor is administered by injection, or intravenous infusion. In certain embodiments, the immune checkpoint inhibitor is administered at a dosage of about 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.0, 2.25, 2.50, 2.75, 3.00, 3.5, 4, 4.5, 5, 5.5, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14,
  • the ROR1 antagonist is administered at a dosage from about 200 milligrams to about 2000 milligrams. In certain embodiments, the ROR1 antagonist is administered at a dosage from about 200 milligrams to about 800 milligrams. In certain embodiments, the ROR1 antagonist is administered at a dosage from about 300 milligrams to about 600 milligrams. In certain embodiments, the ROR1 antagonist is administered at a dosage of about 300 milligrams. In certain embodiments, the ROR1 antagonist is administered at a dosage of about 600 milligrams.
  • the ROR1 antagonist is administered at a dosage of about 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.0, 2.25, 2.50, 2.75, 3.00, 3.5, 4, 4.5, 5, 5.5, 6.5, 7,
  • the ROR1 antagonist is administered in a 25 mg/mL solution. In certain embodiments, the ROR1 antagonist is administered once every two-weeks. In certain embodiments, the ROR1 antagonist is administered once every three-weeks. In certain embodiments, the ROR1 antagonist is administered once every four- weeks. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human.
  • the cancer is lymphoma, leukemia, myeloma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell cancer, melanoma, stomach cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, head and neck cancer, uterine cancer, adenocarcinoma, sarcoma, or adrenal cancer.
  • the cancer is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, mantle cell lymphoma (MCL), marginal cell B-Cell lymphoma, Burkitt's Lymphoma, myeloma, AML, B-ALL, T-ALL, or B cell leukemia.
  • CLL chronic lymphocytic leukemia
  • MCL mantle cell lymphoma
  • MCL mantle cell lymphoma
  • marginal cell B-Cell lymphoma Burkitt's Lymphoma
  • myeloma AML, B-ALL, T-ALL, or B cell leukemia.
  • a pharmaceutical composition comprising a therapeutically effective amount of a tyrosine kinase-like orphan receptor 1 (ROR1) antagonist and a therapeutically effective amount of an immune checkpoint inhibitor.
  • the immune checkpoint inhibitor comprises a PD-1 inhibitor, or a PD- L1 inhibitor.
  • the immune checkpoint inhibitor is a small molecule drug.
  • the immune checkpoint inhibitor is an antibody.
  • the immune checkpoint inhibitor comprises a PD-1 inhibitor.
  • the PD-1 inhibitor is a PD-1 inhibitor antibody.
  • the ROR1 antagonist is an anti-RORl antibody. In certain embodiments, the antibody is zilovertamab. In certain embodiments, the immune checkpoint inhibitor and the ROR1 antagonist are administered in a combined synergistic amount. In certain embodiments, the method further comprises reducing the growth of a tumor. In certain embodiments, the pharmaceutical composition reduces the growth of a tumor by about 20% or more. In certain embodiments, the pharmaceutical composition reduces the growth of a tumor by from about 25% to about 45% when compared to administration of the immune checkpoint inhibitor and the ROR1 antagonist separately. In certain embodiments, the pharmaceutical composition reduced the mass or volume of a tumor.
  • the antibody comprises a humanized heavy chain variable region and a humanized light chain variable region, wherein said humanized heavy chain variable region comprises the sequences set forth in SEQ ID NO. 1, SEQ ID NO. 2, and SEQ ID NO. 3; and wherein said humanized light chain variable region comprises the sequences set forth in SEQ ID NO. 4, SEQ ID NO. 5, and SEQ ID NO. 6.
  • the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100 identical to that set forth in SEQ ID NO: 7; and wherein the light chain variable region comprises an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100 identical to that set forth in SEQ ID NO: 8.
  • the immune checkpoint inhibitor is comprised in an amount of about 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.0, 2.25, 2.50, 2.75, 3.00, 3.5, 4, 4.5, 5, 5.5, 6.5, 7, 7.5, 8,
  • the composition comprises the ROR1 antagonist in an amount of about 200 milligrams to about 2000 milligrams. In certain embodiments, the composition comprises the ROR1 antagonist in an amount of about 200 milligrams to about 800 milligrams. In certain embodiments, the composition comprises the ROR1 antagonist in an amount of about 300 milligrams to about 600 milligrams. In certain embodiments, the composition comprises the ROR1 antagonist in an amount of about 300 milligrams to about 600 milligrams. In certain embodiments, the composition comprises the ROR1 antagonist in an amount of about 300 milligrams. In certain embodiments, the composition comprises the ROR1 antagonist in an amount of about 600 milligrams.
  • the composition comprises the ROR1 antagonist in an amount of about 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.0, 2.25, 2.50, 2.75, 3.00, 3.5, 4, 4.5, 5, 5.5, 6.5, 7, 7.5, 8, 8.5, 9,
  • the composition comprises the RORl antagonist in an amount of about 1, 2, 5, 10, 15, 20, 25, or 30 mg/mL.
  • the composition comprises the immune checkpoint inhibitor in an amount of about 200 milligrams to about 800 milligrams. In certain embodiments, the composition comprises the immune checkpoint inhibitor in an amount of about 300 milligrams to about 600 milligrams. In certain embodiments, the composition comprises the immune checkpoint inhibitor in an amount of about 300 milligrams to about 600 milligrams. In certain embodiments, the composition comprises the immune checkpoint inhibitor in an amount of about 300 milligrams. In certain embodiments, the composition comprises the immune checkpoint inhibitor in an amount of about 600 milligrams.
  • the composition comprises the immune checkpoint inhibitor in an amount of about 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.0, 2.25, 2.50, 2.75, 3.00, 3.5, 4, 4.5, 5, 5.5, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11,
  • the composition comprises the immune checkpoint inhibitor in an amount of about 10, 15, 20, 25, or 30 mg/mL.
  • the composition comprises the ROR1 antagonist and the immune checkpoint inhibitor in a combined synergistic amount.
  • the composition comprises the ROR1 antagonist and the immune checkpoint inhibitor in a combined synergistic amount effective to treat a cancer in a subject.
  • the cancer comprises a mutated PD-L1 gene.
  • the cancer expresses PD-L1.
  • the cancer over expresses PD-L1.
  • the cancer is lymphoma, leukemia, myeloma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell cancer, melanoma, stomach cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, head and neck cancer, uterine cancer, adenocarcinoma, sarcoma, or adrenal cancer.
  • the cancer is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, mantle cell lymphoma (MCL), marginal cell B-Cell lymphoma, Burkitt's Lymphoma, myeloma, AML, B-ALL, T-ALL, or B cell leukemia.
  • CLL chronic lymphocytic leukemia
  • MCL mantle cell lymphoma
  • MCL mantle cell lymphoma
  • marginal cell B-Cell lymphoma Burkitt's Lymphoma
  • myeloma AML, B-ALL, T-ALL, or B cell leukemia.
  • ROR1 tyrosine kinase-like orphan receptor 1
  • aspects disclosed herein include a use of a therapeutically effective amount of a tyrosine kinase-like orphan receptor 1 (ROR1) antagonist and a therapeutically effective amount of an immune checkpoint inhibitor in a method of treating a cancer in a subject in need thereof, comprising administering the pharmaceutical composition to the subject.
  • aspects disclosed herein include a use of a therapeutically effective amount of a tyrosine kinase-like orphan receptor 1 (ROR1) antagonist and a therapeutically effective amount of an immune checkpoint inhibitor for the manufacture of a medicament for treating cancer in a subject in need thereof.
  • the immune checkpoint inhibitor comprises a PD-1 inhibitor, or a PD-Ll inhibitor.
  • the immune checkpoint inhibitor is a small molecule drug. In some embodiments, the immune checkpoint inhibitor comprises an antibody, a peptide, or a protein. In some embodiments, the immune checkpoint inhibitor comprises a PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is a PD-1 inhibitor antibody. In some embodiments, the PD-1 inhibitor antibody comprises nivolumab, pembrolizumab, cemiplimab, dorstarlimab, or combinations thereof. In some embodiments, the PD-1 inhibitor antibody comprises pembrolizumab.
  • the PD-1 inhibitor antibody comprises JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilmab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), Retifanlimab (INCMGA00012) (MGA012), AMP -224, AMP-514, or combinations thereof.
  • the immune checkpoint inhibitor comprises a PD-L1 inhibitor.
  • the PD-L1 inhibitor is a PD-L1 inhibitor antibody.
  • the PD-L1 inhibitor antibody comprises atezolizumab, avelumab, durvalumab, or combinations thereof.
  • thePD-Ll inhibitor antibody comprises Envafolimab (KN035), Cosibelimab (CK-301), AUNP12, CA-170, BMS-986189, or combinations thereof.
  • theRORl antagonist is an antibody or a small molecule.
  • the antibody comprises a Fab, F(ab’)2, Fv, or an scFv.
  • the R0R1 antagonist is an anti-RORl antibody.
  • the antibody is zilovertamab.
  • the antibody binds to an R0R1 amino acid sequence as set forth in SEQ ID NO 30 or SEQ ID NO : 31.
  • the immune checkpoint inhibitor and the ROR1 antagonist are administered in a combined synergistic amount.
  • the use comprises reducing the growth of a tumor. In some embodiments, the use reduces the growth of a tumor by about 20% or more. In some embodiments, the use reduces the growth of a tumor by from about 25% to about 45% when compared to administration of the immune checkpoint inhibitor and the ROR1 antagonist separately. In some embodiments, the use comprise reducing the mass or volume of a tumor.
  • the antibody comprises a humanized heavy chain variable region and a humanized light chain variable region, wherein said humanized heavy chain variable region comprises the sequences set forth in SEQ ID NO. 1, SEQ ID NO. 2, and SEQ ID NO. 3; and wherein said humanized light chain variable region comprises the sequences set forth in SEQ ID NO. 4, SEQ ID NO. 5, and SEQ ID NO. 6.
  • the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100 identical to that set forth in SEQ ID NO: 7; and wherein the light chain variable region comprises an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100 identical to that set forth in SEQ ID NO: 8.
  • an immune cell infiltrate of the cancer expresses PD-1.
  • the cancer expresses PD-L1.
  • the cancer over expresses PD-Ll.
  • the immune checkpoint inhibitor and the ROR1 antagonist are administered substantially simultaneously.
  • the immune checkpoint inhibitor and the ROR1 antagonist are administered separately. In some embodiments, the immune checkpoint inhibitor and the ROR1 antagonist are administered sequentially. In some embodiments, theimmune checkpoint inhibitor and the ROR1 antagonist are co-formulated for administration by a single formulation. In some embodiments, the immune checkpoint inhibitor and the ROR1 antagonist are administered in separate compositions. In some embodiments, the immune checkpoint inhibitor and the R0R1 antagonist are admixed prior to administration. In some embodiments, the immune checkpoint inhibitor is administered by intravenous infusion.
  • the immune checkpoint inhibitor is administered once every t wo-weeks.In some embodiments, the immune checkpoint inhibitor is administered once every three-weeks.In some embodiments, the immune checkpoint inhibitor is administered once every four-weeks.In some embodiments, the immune checkpoint inhibitor is administered at a dosage from about 200 milligrams to about 2000 milligrams. In some embodiments, the immune checkpoint inhibitor is administered at a dosage from about 200 milligrams to about 800 milligrams. In some embodiments, the immune checkpoint inhibitor is administered at a dosage from about 300 milligrams to about 600 milligrams. In some embodiments, the immune checkpoint inhibitor is administered at a dosageof about300 milligrams.
  • the immune checkpoint inhibitor is administered at a dosage of about 600 milligrams. In some embodiments, the immune checkpoint inhibitor is administered in an amount of 200 mg every six weeks; 300 mg every six weeks, or 400 mg every six weeks. In some embodiments, the immune checkpoint inhibitor is administered in an amount of 100 mg every three weeks; or 300 mg every six weeks. In some embodiments, the immune checkpoint inhibitor is administered in an amount of 2 mg/kg, or 1 mg/kg every 3 weeks. In some embodiments, the immune checkpoint inhibitor is administered in an amount of 50 mg every three weeks; or 100 mg every six weeks. In some embodiments, the immune checkpoint inhibitor is administered in an amount of about 50 mg to about 400 mg every three weeks.
  • the immune checkpoint inhibitor is administered in a 25 mg/mL solution. In some embodiments, the immune checkpoint inhibitor is administered by injection, or intravenous infusion. In some embodiments, the immune checkpoint inhibitor is administered at a dosage of about 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.0, 2.25, 2.50, 2.75, 3.00, 3.5, 4, 4.5, 5, 5.5, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, or 20 mg/kg.
  • the ROR1 antagonist is administered at a dosage from about 200 milligrams to about 2000 milligrams. In some embodiments, theRORl antagonist is administered at a dosage from about 200 milligrams to about 800 milligrams.In some embodiments, the ROR1 antagonist is administered at a dosage from about 300 milligrams to about 600 milligrams.In some embodiments, theRORl antagonist is administered at a dosage of about 300 milligrams.In some embodiments, the ROR1 antagonist is administered at a dosage of about 600 milligrams. In some embodiments, theRORl antagonist is administered at a dosage of about 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.0, 2.25, 2.50, 2.75, 3.00, 3.5, 4, 4.5, 5, 5.5, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, or 20 mg/kg.
  • the ROR1 antagonist is administered in a 25 mg/mL solution. In some embodiments, the ROR1 antagonist is administered once every two-weeks. In some embodiments, the ROR1 antagonist is administered once every three-weeks.In some embodiments, the ROR1 antagonist is administered once every four-weeks.In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.
  • the cancer is lymphoma, leukemia, myeloma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell cancer, melanoma, stomach cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, head and neck cancer, uterine cancer, adenocarcinoma, sarcoma, or adrenal cancer.
  • the cancer is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, mantle cell lymphoma (MCL), marginal cell B-Cell lymphoma, Burkitt's Lymphoma, myeloma, AML, B-ALL, T-ALL, or B cell leukemia.
  • CLL chronic lymphocytic leukemia
  • MCL mantle cell lymphoma
  • MCL mantle cell lymphoma
  • marginal cell B-Cell lymphoma Burkitt's Lymphoma
  • myeloma AML, B-ALL, T-ALL, or B cell leukemia.
  • FIG. 1 depicts the percent of Jeko-1 cytotoxicity in a mixture of donor cells and Jeko-1 cells.
  • Fig. 2A depicts the tumor volume over time of Donor 451 cells treated with ant- ROR1 antibody, pembrolizumab, or a combination.
  • Fig. 2B depicts the tumor volume over time of Donor 244 cells treated with ant- ROR1 antibody, pembrolizumab, or a combination.
  • a tyrosine kinase-like orphan receptor 1 (ROR1) antagonist and a therapeutically effective amount of an immune checkpoint inhibitor.
  • ROR1 tyrosine kinase-like orphan receptor 1
  • the checkpoint inhibitor comprises a PD-1 inhibitor, a PD-11 inhibitor, a PD- L2 inhibitor, or a combination thereof.
  • the checkpoint inhibitor is a small molecule inhibitor.
  • the checkpoint inhibitor is an antibody, peptide or protein.
  • the checkpoint inhibitor is a PD-1 inhibitor. In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor antibody. In some embodiments, the PD-1 inhibitor antibody comprises nivolumab, pembrolizumab, cemiplimab, dorstarlimab, JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilmab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), RETIFANLIMAB (INCMGA00012) (MGA012), AMP -224, AMP-514, or combinations thereof.
  • the PD-1 inhibitor antibody comprises nivolumab, pembrolizumab, cemiplimab, dorstarlimab, or combinations thereof.
  • the PD-1 inhibitor antibody comprises JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilmab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), RETIFANLIMAB (INCMGA00012) (MGA012), AMP -224, AMP-514, or combinations thereof.
  • the PD-1 inhibitor antibody comprises nivolumab.
  • the PD-1 inhibitor antibody comprises pembrolizumab. In some embodiments, the PD-1 inhibitor antibody comprises cemiplimab. In some embodiments, the PD-1 inhibitor antibody comprises dorstarlimab. In some embodiments, the PD-1 inhibitor antibody comprises JTX- 4014. In some embodiments, the PD-1 inhibitor antibody comprises spartalizumab (PDR001. In some embodiments, the PD-1 inhibitor antibody comprises camrelizumab (SHR1210). In some embodiments, the PD-1 inhibitor antibody comprises sintilmab (IBI308). In some embodiments, the PD-1 inhibitor antibody comprises tislelizumab (BGB-A317).
  • the PD-1 inhibitor antibody comprises toripalimab (JS 001). In some embodiments, the PD-1 inhibitor antibody comprises RETIFANLIMAB (INCMGA00012) (MGA012). In some embodiments, the PD-1 inhibitor antibody comprises AMP -224. In some embodiments, the PD-1 inhibitor antibody comprises, AMP -514.
  • the immune checkpoint inhibitor comprises a PD-Ll inhibitor.
  • the PD-L1 inhibitor comprises a PD-Ll inhibitor antibody.
  • the PD-L1 inhibitor is a small molecule.
  • the PD-L1 inhibitor comprises atezolizumab, avelumab, durvalumab, Envafolimab (KN035), Cosibelimab (CK-301), AUNP12, CA-170, BMS-986189, or combinations thereof.
  • the PD-Ll inhibitor comprises atezolizumab, avelumab, durvalumab, or combinations thereof.
  • the PD-L1 inhibitor comprises Envafolimab (KN035), Cosibelimab (CK-301), AUNP12, CA-170, BMS-986189, or combinations thereof.
  • the PD-L1 inhibitor comprises atezolizumab.
  • the PD-Ll inhibitor comprises avelumab.
  • the PD-Ll inhibitor comprises durvalumab.
  • the PD-Ll inhibitor comprises KN035.
  • the PD-L1 inhibitor comprises CK-301.
  • the PD- L1 inhibitor comprises AUNP12.
  • the PD-L1 inhibitor comprises CA- 170.
  • the PD-L1 inhibitor comprises BMS-986189.
  • the immune checkpoint inhibitor comprises a PD-L2 inhibitor. In some embodiments, the immune checkpoint inhibitor comprises CA-170, rHIgM12B, or combinations thereof. In some embodiments, the immune checkpoint inhibitor comprises CA-170. In some embodiments, the immune checkpoint inhibitor comprises rHIgM12B.
  • anti-RORl antibodies are monoclonal anti-RORl antibodies and anti-RORl antibody fragments.
  • the anti-RORl antibodies include anti-RORl antibodyconjugates and molecules comprising the anti-RORl antibodies, such as chimeric molecules.
  • an anti-RORl antibody includes, but is not limited to, full-length and native anti-RORl antibodies, as well as fragments and portion thereof retaining the binding specificities thereof, such as any specific binding portion thereof including those having any number of, immunoglobulin classes and/or isotypes (e.g., IgGl, IgG2, IgG3, IgG4, IgM, IgA, IgD, IgE and IgM); and biologically relevant (antigen-binding) fragments or specific binding portions thereof, including but not limited to Fab, F(ab’)2, Fv, and scFv (single chain or related entity).
  • immunoglobulin classes and/or isotypes e.g., IgGl, IgG2, IgG3, IgG4, IgM, IgA, IgD, IgE and IgM
  • biologically relevant (antigen-binding) fragments or specific binding portions thereof including but not limited to Fab, F(ab’)2,
  • a monoclonal antibody is generally one within a composition of substantially homogeneous antibodies; thus, any individual antibodies comprised within the monoclonal antibody composition are identical except for possible naturally occurring mutations that may be present in minor amounts.
  • the monoclonal antibody can comprise a human IgGl constant region.
  • the monoclonal antibody can comprise a human IgG4 constant region.
  • antibody herein is used in the broadest sense and includes monoclonal antibodies, and includes intact antibodies and functional (antigen-binding) antibody fragments thereof, including fragment antigen binding (Fab) fragments, F(ab')2 fragments, Fab' fragments, Fv fragments, recombinant IgG (rlgG) fragments, single chain antibody fragments, including single chain variable fragments (sFv or scFv), and single domain antibodies (e.g., sdAb, sdFv, nanobody) fragments.
  • the term encompasses genetically engineered and/or otherwise modified forms of immunoglobulins, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, and heteroconjugate antibodies, multispecific, e.g., bispecific, antibodies, diabodies, triabodies, and tetrabodies, tandem di-scFv, tandem tri-scFv.
  • antibody should be understood to encompass functional antibody fragments thereof.
  • the term also encompasses intact or full- length antibodies, including antibodies of any class or sub-class, including IgG and sub-classes thereof, IgM, IgE, IgA, and IgD.
  • the antibody can comprise a human IgGl constant region.
  • the antibody can comprise a human IgG4 constant region.
  • CDR complementarity determining region
  • HVR hypervariable region
  • FR-Hl full-length heavy chain variable region
  • FR-H2, FR-H3, and FR-H4 full-length heavy chain variable region
  • FR-L1, FR- L2, FR-L3, and FR-L4 full-length light chain variable region
  • the precise amino acid sequence boundaries of a given CDR or FR can be readily determined using any of a number of well-known schemes, including those described by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (“Kabat” numbering scheme), Al-Lazikani et al., (1997) JMB 273,927-948 (“Chothia” numbering scheme);
  • the CDRs of the antibodies described herein can be defined by a method selected from Kabat, Chothia, IMGT, Aho, AbM, or combinations thereof.
  • the boundaries of a given CDR or FR may vary depending on the scheme used for identification.
  • the Kabat scheme is based on structural alignments
  • the Chothia scheme is based on structural information. Numbering for both the Kabat and Chothia schemes is based upon the most common antibody region sequence lengths, with insertions accommodated by insertion letters, for example, “30a,” and deletions appearing in some antibodies. The two schemes place certain insertions and deletions (“indels”) at different positions, resulting in differential numbering.
  • the Contact scheme is based on analysis of complex crystal structures and is similar in many respects to the Chothia numbering scheme.
  • variable region refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen.
  • the variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three CDRs (See e.g., Kindt et al. Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91(2007)).
  • FRs conserved framework regions
  • antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively See e.g, Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991)).
  • Specific binding of antibody molecules described herein refers to binding mediated by one or more CDR portions of the antibody. Not all CDRs may be required for specific binding. Specific binding can be demonstrated by an ELISA against a specific recited target or antigen that shows significant increase in binding compared to an isotype control antibody.
  • the anti-RORl antibody or antigen binding fragment thereof comprises Cirmtuzumab. In certain embodiments, the anti-RORl antibody or antigen binding fragment thereof is Cirmtuzumab. In some embodiments, the anti-RORl antibody comprises the variable heavy chain (VH) of Cirmtuzumab. In some embodiments, the anti- RORl antibody comprises a VH CDR1, VH CDR2, and VH CDR3 derived from Cirmtuzumab. In some embodiments, the anti-RORl antibody comprises the variable light chain (VL) of Cirmtuzumab. In some embodiments, the anti-RORl antibody comprises a VL CDR1, VL CDR2, and VL CDR3 derived from Cirmtuzumab.
  • the ROR1 binding molecule or ROR1 binding fragment thereof comprises: a) a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence set forth in SEQ ID NO: 1; b) a heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence set forth in SEQ ID NO: 2; c) a heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence set forth in SEQ ID NO: 3; d) a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence set forth in SEQ ID NO: 4; e) a light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence set forth in SEQ ID NO: 5; and/or f) a light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence set forth in SEQ ID NO: 6.
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 comprising the amino acid sequence set forth in SEQ
  • the R0R1 binding molecule or R0R1 binding fragment thereof comprises: a) a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence set forth in SEQ ID NO: 11; b) a heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence set forth in SEQ ID NO: 12) a heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence set forth in SEQ ID NO: 13) a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence set forth in SEQ ID NO: 14; e) a light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence set forth in SEQ ID NO: 15; and/or f) a light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence set forth in SEQ ID NO: 16.
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 heavy chain complementarity determining region 2
  • HCDR3
  • the R0R1 binding molecule or R0R1 binding fragment thereof comprises: a) a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence set forth in SEQ ID NO: 21; b) a heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence set forth in SEQ ID NO: 22; c) a heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence set forth in SEQ ID NO: 23; d) a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence set forth in SEQ ID NO: 24; e) a light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence set forth in SEQ ID NO: 25; and/or f) a light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence set forth in SEQ ID NO: 26.
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 comprising the amino acid sequence set forth
  • the ROR1 binding molecule or ROR1 binding fragment thereof comprises: a) an immunoglobulin heavy chain variable region comprising an amino acid sequence at least 85%, 90%, 95%, 97%, 98%, or 99% identical to SEQ ID NO: 7; and/or b) an immunoglobulin light chain variable region comprising an amino acid sequence at least 85%, 90%, 95%, 97%, 98%, or 99% identical to SEQ ID NO: 8.
  • the ROR1 binding molecule or ROR1 binding fragment thereof comprises: a) an immunoglobulin heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 7; and/or b) an immunoglobulin light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 8.
  • the ROR1 binding molecule or ROR1 binding fragment thereof comprises: a) an immunoglobulin heavy chain variable region comprising an amino acid sequence at least 85%, 90%, 95%, 97%, 98%, or 99% identical to SEQ ID NO: 17; and/or b) an immunoglobulin light chain variable region comprising an amino acid sequence at least 85%, 90%, 95%, 97%, 98%, or 99% identical to SEQ ID NO: 18.
  • the ROR1 binding molecule or ROR1 binding fragment thereof comprises: a) an immunoglobulin heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 17; and/or b) an immunoglobulin light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 18.
  • the ROR1 binding molecule or ROR1 binding fragment thereof comprises: a) an immunoglobulin heavy chain variable region comprising an amino acid sequence at least 85%, 90%, 95%, 97%, 98%, or 99% identical to SEQ ID NO: 27; and/or b) an immunoglobulin light chain variable region comprising an amino acid sequence at least 85%, 90%, 95%, 97%, 98%, or 99% identical to SEQ ID NO: 28.
  • the ROR1 binding molecule or ROR1 binding fragment thereof comprises: a) an immunoglobulin heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 27; and/or b) an immunoglobulin light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 28.
  • the ROR1 binding molecule or ROR1 binding fragment thereof comprises: a) an immunoglobulin heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 9; and/or b) an immunoglobulin light chain comprising the amino acid sequence set forth in SEQ ID. NO: 10.
  • anti-RORl antibodies are anti-RORl antibody fragments.
  • An “antibody fragment” refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds.
  • Examples of anti-RORl antibody fragments include, but are not limited to, Fv, Fab, Fab’, Fab’-SH, F(ab’)2; diabodies; linear antibodies; single-chain antibody molecules (e.g. scFv or sFv); and multispecific anti-RORl antibodies formed from anti-RORl antibody fragments.
  • the anti-RORl antibodies are single-chain antibody fragments comprising a variable heavy chain region and/or a variable light chain region, such as scFvs.
  • Anti-RORl antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact anti-RORl antibody as well as production by recombinant host cells.
  • the anti-RORl antibodies are recombinantly- produced fragments, such as fragments comprising arrangements that do not occur naturally, such as those with two or more antibody regions or chains joined by synthetic linkers, e.g., polypeptide linkers, and/or those that are not produced by enzyme digestion of a naturally- occurring intact antibody.
  • the anti-RORl antibody fragments are scFvs.
  • a “humanized” antibody is an antibody in which all or substantially all CDR amino acid residues are derived from non-human CDRs and all or substantially all FR amino acid residues are derived from human FRs.
  • a humanized antibody optionally may include at least a portion of an antibody constant region derived from a human antibody.
  • a “humanized form” of a non-human antibody refers to a variant of the non-human antibody that has undergone humanization, typically to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody.
  • some FR residues in a humanized antibody are substituted with corresponding residues from a non- human antibody (e.g., the antibody from which the CDR residues are derived), e.g., to restore or improve antibody specificity or affinity.
  • a non- human antibody e.g., the antibody from which the CDR residues are derived
  • anti-RORl human antibodies are anti-RORl human antibodies.
  • a “human antibody” is an antibody with an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences, including human antibody libraries.
  • the term excludes humanized forms of non-human antibodies comprising non- human antigen-binding regions, such as those in which all or substantially all CDRs are non- human.
  • Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge. Such animals typically contain all or a portion of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or which are present extrachromosomally or integrated randomly into the animal’s chromosomes. In such transgenic animals, the endogenous immunoglobulin loci have generally been inactivated. Human antibodies also may be derived from human antibody libraries, including phage display and cell-free libraries, containing antibody-encoding sequences derived from a human repertoire.
  • polypeptide and “protein” are used interchangeably to refer to a polymer of amino acid residues, and are not limited to a minimum length.
  • Polypeptides including the provided antibodies and antibody chains and other peptides, e.g., linkers and binding peptides, may include amino acid residues including natural and/or non-natural amino acid residues.
  • the terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like.
  • the polypeptides may contain modifications with respect to a native or natural sequence, as long as the protein maintains the desired activity.
  • amino acid sequence variants of the antibodies provided herein are contemplated.
  • a variant typically differs from a polypeptide specifically disclosed herein in one or more substitutions, deletions, additions and/or insertions.
  • Such variants can be naturally occurring or can be synthetically generated, for example, by modifying one or more of the above polypeptide sequences of the invention and evaluating one or more biological activities of the polypeptide as described herein and/or using any of a number of known techniques.
  • Amino acid sequence variants of an antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., antigen-binding.
  • Amino acid sequence insertions and deletions include amino- and/or carboxyl- terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions and deletions of single or multiple amino acid residues.
  • terminal insertions include an antibody with an N-terminal methionyl residue.
  • Other insertional variants of the antibody molecule include the fusion to the N- or C-terminus of the antibody to an enzyme (e.g., for ADEPT) or a polypeptide which increases the serum half-life of the antibody.
  • intrasequence insertion variants of the antibody molecules include an insertion of 3 amino acids in the light chain.
  • terminal deletions include an antibody with a deletion of 7 or less amino acids at an end of the light chain.
  • the antibodies are altered to increase or decrease their glycosylation (e.g., by altering the amino acid sequence such that one or more glycosylation sites are created or removed).
  • a carbohydrate attached to an Fc region of an antibody may be altered.
  • Native antibodies from mammalian cells typically comprise a branched, biantennary oligosaccharide attached by an N-linkage to Asn297 of the CH2 domain of the Fc region (See e.g., Wright et al. TIBTECH 15:26-32 (1997)).
  • the oligosaccharide can be various carbohydrates, e.g., mannose, N-acetyl glucosamine (GlcNAc), galactose, sialic acid, fucose attached to a GlcNAc in the stem of the biantennar oligosaccharide structure. Modifications of the oligosaccharide in an antibody can be made, for example, to create antibody variants with certain improved properties.
  • Antibody glycosylation variants can have improved ADCC and/or CDC function.
  • antibody variants are provided having a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region.
  • the amount of fucose in such antibody may be from 1% to 80%, from 1% to 65%, from 5% to 65% or from 20% to 40%.
  • the amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn297 (See e.g., WO 08/077546).
  • Asn297 refers to the asparagine residue located at about position 297 in the Fc region (EU numbering of Fc region residues; See e.g., Edelman et al. Proc Natl Acad Sci USA. 1969 May; 63(l):78-85).
  • Asn297 may also be located about ⁇ 3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies.
  • Such fucosylation variants can have improved ADCC function (See e.g., Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); and Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004)).
  • Cell lines e.g., knockout cell lines and methods of their use can be used to produce defucosylated antibodies, e.g., Lecl3 CHO cells deficient in protein fucosylation and alpha- 1,6-fucosyltransf erase gene (FUT8) knockout CHO cells (See e.g., Ripka et al. Arch.
  • an anti-RORl antibody provided herein has a dissociation constant (KD) of about 1 pM, 100 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM, 2 nM, 1 nM, 0.5 nM, 0.1 nM, 0.05 nM, 0.01 nM or less (e.g., 10 8 M or less, e.g., from 10 8 M to 10 13 M, e.g., from 10 9 M to 10 13 M) for the antibody target.
  • KD dissociation constant
  • an anti- RORl antibody provided herein has a dissociation constant (KD) of about 100 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM, 2 nM, 1 nM, 0.5 nM, 0.1 nM, 0.05 nM, 0.01 nM, or 0.001 nM or greater (e.g., 10 8 M or less, e.g., from 10 8 M to 10 13 M, e.g., from 10 9 M to 10 13 M) for the antibody target.
  • the antibody target can be a ROR1 target.
  • KD can be measured by any suitable assay.
  • KD can be measured using surface plasmon resonance assays (e.g., using a BIACORE®-2000, a BIACORE®-3000 or Octet).
  • one or more amino acid modifications may be introduced into the Fc region of an anti-RORl antibody provided herein, thereby generating an Fc region variant.
  • An Fc region herein is a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region.
  • An Fc region includes native sequence Fc regions and variant Fc regions.
  • the Fc region variant may comprise a human Fc region sequence (e.g., a human IgGl, IgG2, IgG3 or IgG4 Fc region) comprising an amino acid modification (e.g., a substitution) at one or more amino acid positions.
  • a human Fc region sequence e.g., a human IgGl, IgG2, IgG3 or IgG4 Fc region
  • an amino acid modification e.g., a substitution
  • the Fc region of an immunoglobulin is important for many important antibody functions (e.g. effector functions), such as antigen-dependent cellular cytotoxicity (ADCC), complement dependent cytotoxicity (CDC), and antibody-dependent cell-mediated phagocytosis (ADCP), result in killing of target cells, albeit by different mechanisms.
  • effector functions such as antigen-dependent cellular cytotoxicity (ADCC), complement dependent cytotoxicity (CDC), and antibody-dependent cell-mediated phagocytosis (ADCP)
  • ADCC antigen-dependent cellular cytotoxicity
  • CDC complement dependent cytotoxicity
  • ADCP antibody-dependent cell-mediated phagocytosis
  • the antibodies described herein comprise the variable domains of the invention combined with constant domains comprising different Fc regions, selected based on the biological activities of the antibody for the intended use.
  • Human IgGs for example, can be classified into four subclasses, IgGl, IgG2, IgG3, and IgG4, and each these of these comprises an Fc region having a unique profile for binding to one or more of Fey receptors (activating receptors FcyRI (CD 64), FcyRIIA, FcyRIIC (CD32); FcyRIIIA and FcyRIIIB (CD 16) and inhibiting receptor FcyRIIB), and for the first component of complement (Clq).
  • Fey receptors activating receptors FcyRI (CD 64), FcyRIIA, FcyRIIC (CD32); FcyRIIIA and FcyRIIIB (CD 16) and inhibiting receptor FcyRIIB
  • Human IgGl and IgG3 bind to all Fey receptors; IgG2 binds to FcyRIIAmsi, and with lower affinity to
  • FcyRIIARi3i FcyRIIIAviss IgG4 binds to FcyRI, FcyRIIA, FcyRIIB, FcyRIIC, and FcyRIIIAvi58; and the inhibitory receptor FcyRIIB has a lower affinity for IgGl, IgG2 and IgG3 than all other Fey receptors. Studies have shown that FcyRI does not bind to IgG2, and FcyRIIIB does not bind to IgG2 or IgG4. Id. In general, with regard to ADCC activity, human IgGl>IgG3»IgG4>IgG2.
  • the anti-RORl antibodies of this disclosure are variants that possess reduced effector functions, which make it a desirable candidate for applications in which certain effector functions (such as complement fixation and ADCC) are unnecessary or deleterious.
  • Such anti-RORl antibodies can have decreased complement -depend ent cytotoxicity (CDC), antibody-dependent cell cytotoxicity (ADCC), or antibody dependent cellular phagocytosis (ADCP).
  • CDC complement -depend ent cytotoxicity
  • ADCC antibody-dependent cell cytotoxicity
  • ADCP antibody dependent cellular phagocytosis
  • the anti-RORl antibodies of this disclosure are variants that possess increased effector functions for applications in which increased immunogenicity would be beneficial.
  • Such anti-RORl antibodies can have increased CDC, ADCC, or ADCP, or a combination thereof.
  • Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest is described in U.S. Pat. No. 5,500,362 and 5,821,337.
  • non-radioactive assays methods may be employed (e.g., ACTITM and CytoTox 96® non-radioactive cytotoxicity assays).
  • Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC), monocytes, macrophages, and Natural Killer (NK) cells.
  • Anti-RORl antibodies can have increased half-lives and improved binding to the neonatal Fc receptor (FcRn) (See e.g., US 2005/0014934).
  • Such anti-RORl antibodies can comprise an Fc region with one or more substitutions therein which improve binding of the Fc region to FcRn, and include those with substitutions at one or more of Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434 according to the EU numbering system (See e.g., U.S. Pat. No. 7,371,826).
  • Fc region variants are also contemplated (See e.g., Duncan & Winter, Nature 322:738-40 (1988); U.S. Pat. Nos. 5,648,260 and5,624,821; and WO94/29351).
  • cysteine engineered anti- RORl antibodies e.g., “thioMAbs”
  • one or more residues of an antibody are substituted with cysteine residues.
  • the substituted residues occur at accessible sites of the antibody.
  • Reactive thiol groups can be positioned at sites for conjugation to other moieties, such as drug moieties or linker drug moieties, to create an immunoconjugate.
  • any one or more of the following residues may be substituted with cysteine: V205 (Kabat numbering) of the light chain; Al 18 (EU numbering) of the heavy chain; and S400 (EU numbering) of the heavy chain Fc region.
  • an anti-RORl antibody provided herein may be further modified to contain additional nonproteinaceous moieties that are known and available.
  • the moieties suitable for derivatization of the antibody include but are not limited to water soluble polymers.
  • Non-limiting examples of water soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol/propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1, 3- dioxolane, poly-1, 3, 6-trioxane, ethylene/maleic anhydride copolymer, polyaminoacids (either homopolymers or random copolymers), and dextran or poly(n vinyl pyrrolidone)poly ethylene glycol, polypropylene glycol homopolymers, polypropylen oxide/ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof.
  • PEG polyethylene glycol
  • copolymers of ethylene glycol/propylene glycol carboxymethylcellulose
  • dextran polyvinyl alcohol
  • Polyethylene glycol propionaldehyde may have advantages in manufacturing due toits stability in water.
  • the polymer may be of any molecular weight, and may be branched or unbranched.
  • the number of polymers attached to the antibody may vary, and if two or more polymers are attached, they can be the same or different molecules.
  • an immunoconjugate is an antibody conjugated to one or more heterologous molecule(s).
  • an immunoconjugate can comprise an anti-RORl antibody conjugated to one or more cytotoxic agents, such as chemotherapeutic agents or drugs, growth inhibitory agents, protein domains, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof), or radioactive isotopes.
  • an immunoconjugate can comprise an anti-RORl antibody, or fragment thereof (e.g., an scFv).
  • the anti-RORl antibodies described herein can be encoded by a nucleic acid.
  • a nucleic acid is a type of polynucleotide comprising two or more nucleotide bases.
  • the nucleic acid is a component of a vector that can be used to transfer the polypeptide encoding polynucleotide into a cell.
  • the term “vector” refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked.
  • One type of vector is a genomic integrated vector, or “integrated vector,” which can become integrated into the chromosomal DNA of the host cell.
  • vectors capable of directing the expression of genes to which they are operatively linked are referred to herein as “expression vectors.”
  • Suitable vectors comprise plasmids, bacterial artificial chromosomes, yeast artificial chromosomes, viral vectors and the like.
  • regulatory elements such as promoters, enhancers, polyad enylation signals for use in controlling transcription can be derived from mammalian, microbial, viral or insect genes. The ability to replicate in a host, usually conferred by an origin of replication, and a selection gene to facilitate recognition of transformants may additionally be incorporated.
  • Vectors derived from viruses such as lentiviruses, retroviruses, adenoviruses, ad eno -associated viruses, and the like, may be employed. Plasmid vectors can be linearized for integration into a genome.
  • homology when used herein to describe to an amino acid sequence or a nucleic acid sequence, relative to a reference sequence, can be determined using the formula described by Karlin and Altschul (Proc. Natl. Acad. Sci. USA 87: 2264-2268, 1990, modified as in Proc. Natl. Acad. Sci. USA 90:5873-5877, 1993). Such a formula is incorporated into the basic local alignment search tool (BLAST) programs of Altschul et al. (J. Mol. Biol. 215: 403-410, 1990). Percent homology of sequences can be determined using the most recent version of BLAST, as of the filing date of this application.
  • BLAST basic local alignment search tool
  • Percent (%) sequence identity with respect to a reference polypeptide sequence is the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are known for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Appropriate parameters for aligning sequences are able to be determined, including algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
  • % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2.
  • the ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087.
  • the ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, Calif., or may be compiled from the source code.
  • the ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.
  • the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B is calculated as follows: 100 times the fraction X/Y, where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B.
  • the nucleic acids encoding the anti-RORl antibodies described herein can be used to infect, transfect, transform, or otherwise render a suitable cell transgenic for the nucleic acid, thus enabling the production of antibodies for commercial or therapeutic uses.
  • Standard cell lines and methods for the production of antibodies from a large scale cell culture are known in the art. See e.g., Li et al., “Cell culture processes for monoclonal antibody production.” Mabs. 2010 Sep-Oct; 2(5): 466-477.
  • the cell is a Eukaryotic cell.
  • the Eukaryotic cell is a mammalian cell.
  • the mammalian cell is a cell line useful for producing antibodies is a Chinese Hamster Ovary cell (CHO) cell, an NSO murine myeloma cell, or a PER.C6® cell.
  • the nucleic acid encoding the antibody is integrated into a genomic locus of a cell useful for producing antibodies.
  • described herein is a method of making an anti-RORl antibody comprising culturing a cell comprising a nucleic acid encoding an antibody under conditions in vitro sufficient to allow production and secretion of said antibody.
  • a master cell bank comprising: (a) a mammalian cell line comprising a nucleic acid encoding an antibody described herein integrated at a genomic location; and (b) a cryoprotectant.
  • the cryoprotectant comprises glycerol or DMSO.
  • the master cell bank comprises: (a) a CHO cell line comprising a nucleic acid encoding an antibody with (i) a heavy chain amino acid sequence set forth by any one of SEQ ID NOs: 9,19, or 29; and (ii) a light chain amino acid sequence set forth by any one of SEQ ID NOs: 10, 20, or 30 integrated at a genomic location; and (b) a cryoprotectant.
  • the cryoprotectant comprises glycerol or DMSO.
  • the master cell bank is contained in a suitable vial or container able to withstand freezing by liquid nitrogen.
  • the harvesting can further comprise one or more purification steps to remove live cells, cellular debris, non-antibody proteins or polypeptides, undesired salts, buffers, and medium components.
  • the additional purification step(s) include centrifugation, ultracentrifugation, protein A, protein G, protein A/G, or protein L purification, and/or ion exchange chromatography.
  • the immune checkpoint inhibitor and the ROR1 antagonist are administered at the same time. In some embodiments, the immune checkpoint inhibitor and the ROR1 antagonist are administered simultaneously. In some embodiments, the immune checkpoint inhibitor and the ROR1 antagonist are administered substantially simultaneously. In some embodiments, the immune checkpoint inhibitor and the ROR1 antagonist are administered sequentially. In some embodiments, the immune checkpoint inhibitor and the ROR1 antagonist are administered separately.
  • the immune checkpoint inhibitor and the ROR1 antagonist are administered in a combined synergistic amount. In some embodiments, the immune checkpoint inhibitor and the ROR1 antagonist are co-formulated for administration by a single formulation. In some embodiments, the immune checkpoint inhibitor and the ROR1 antagonist are admixed prior to administration. In some embodiments, the immune checkpoint inhibitor and the ROR1 antagonist are administered in separate compositions.
  • the immune checkpoint inhibitor and the ROR1 antagonist described herein may be administered through a variety of routes, including, without limitation, subcutaneous, intraperitoneal, intravenous, intramuscular, intratumoral, intracerebral, or orally.
  • the immune checkpoint inhibitor is administered by intravenous infusion.
  • the immune checkpoint inhibitor is administered orally.
  • the ROR1 antagonist is administered by intravenous infusion.
  • the methods described herein comprise reducing the growth of a tumor.
  • the method reduces the growth of a tumor by about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, about 50% or more, about 55% or more, about 60% or more, about 70% or more, about 80% or more, or about 90% or more.
  • the method reduces the growth of a tumor by about 10% or more.
  • the method reduces the growth of a tumor by about 20% or more.
  • the method reduces the growth of a tumor by about 30% or more.
  • the method reduces the growth of a tumor by about 40% or more. In some embodiments, the method reduces the growth of a tumor by about 50% or more. In certain embodiments, the growth of a tumor is reduced when compared to the administration of the immune checkpoint inhibitor and the ROR1 antagonist separately. In certain embodiments, the growth of a tumor is reduced when compared to the administration of either the immune checkpoint inhibitor or the ROR1 antagonist alone.
  • the method reduces the growth of a tumor by from about 25% to about 45%. In certain embodiments, the growth of the tumor is reduced from about 15% to about 55%. In certain embodiments, the growth of the tumor is reduced from about 5% to about 65%. In certain embodiments, the growth of the tumor is reduced from about 5% to about 25%. In certain embodiments, the growth of the tumor is reduced from about 15% to about 35%. In certain embodiments, the growth of the tumor is reduced from about 35% to about 55%. In certain embodiments, the growth of the tumor is reduced from about 45% to about 65%.
  • the method comprises reducing the mass or volume of a tumor. In certain embodiments, the method comprises reducing the mass of a tumor by at least about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, about 50% or more, about 55% or more, about 60% or more, about 70% or more, about 80% or more, or about 90% or more.
  • the method comprises reducing the volume of a tumor by at least about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, about 50% or more, about 55% or more, about 60% or more, about 70% or more, about 80% or more, or about 90% or more.
  • the mass or volume of a tumor is reduced when compared to the administration of the immune checkpoint inhibitor and the ROR1 antagonist separately.
  • the mass or volume of a tumor is reduced when compared to the administration of either the immune checkpoint inhibitor or the ROR1 antagonist alone.
  • the checkpoint inhibitors are administered on a suitable dosage schedule, for example, weekly, twice weekly, monthly, twice monthly, once every two weeks, once every three weeks, or once a month etc.
  • the checkpoint inhibitor is administered once over the course of at least two weeks.
  • the checkpoint inhibitor is administered once over the course of at least three weeks.
  • the checkpoint inhibitor is administered once over the course of at least four weeks.
  • the antibodies can be administered in any therapeutically effective amount. Therapeutically effective amounts include amounts are those sufficient to ameliorate one or more symptoms associated with the disease or affliction to be treated.
  • the checkpoint inhibitor is administered at a therapeutically acceptable amount.
  • the checkpoint inhibitor is administered at an amount of at least about 100 milligrams, about 200 milligrams, about 30 milligrams, about 400 milligrams, about 500 milligrams, about 600 milligrams, about 700 milligrams, about 800 milligrams, about 900 milligrams, about 1000 milligrams, about 1100 milligrams, about 1200 milligrams, about 1300 milligrams, bout 1400 milligrams, about 1500 milligrams, about 1600 milligrams, about 1700 milligrams, about 1800 milligrams, about 1900 milligrams or about 2000 milligrams.
  • the checkpoint inhibitor is administered at an amount of no more than about 100 milligrams, about 200 milligrams, about 30 milligrams, about 400 milligrams, about 500 milligrams, about 600 milligrams, about 700 milligrams, about 800 milligrams, about 900 milligrams, about 1000 milligrams, about 1100 milligrams, about 1200 milligrams, about 1300 milligrams, bout 1400 milligrams, about 1500 milligrams, about 1600 milligrams, about 1700 milligrams, about 1800 milligrams, about 1900 milligrams or about 2000 milligrams.
  • the checkpoint inhibitor is administered at an amount from about 100 milligrams to about 1000 milligrams, from about 200 milligrams to about 1000 milligrams, from about 300 milligrams to about 1000 milligrams, from about 400 milligrams to about 1000 milligrams, from about 500 milligrams to about 1000 milligrams, from about 600 milligrams to about 1000 milligrams, from about 700 milligrams to about 1000 milligrams, from about 800 milligrams to about 1000 milligrams, from about 900 milligrams to about 1000 milligrams, from about 100 milligrams to about 900 milligrams, from about 200 milligrams to about 900 milligrams, from about 300 milligrams to about 900 milligrams, from about 400 milligrams to about 900 milligrams, from about 500 milligrams to about 900 milligrams, from about 600 milligrams to about 900 milligrams, from about 700 milligrams to about
  • the checkpoint inhibitor is administered in an amount of about 100 milligrams, about 200 milligrams, about 300 milligrams, about 400 milligrams, about 500 milligrams, about 600 milligrams, about 700 milligrams, about 800 milligrams, about 900 milligrams, about 1000 milligrams, about 1100 milligrams, about 1200 milligrams, about 1300 milligrams, bout 1400 milligrams, about 1500 milligrams, about 1600 milligrams, about 1700 milligrams, about 1800 milligrams, about 1900 milligrams or about 2000 milligrams.
  • the checkpoint inhibitor is administered at an amount of about 600 milligrams.
  • the checkpoint inhibitor can be administered at a dose based on the bodyweight or mass of the individual to whom the checkpoint inhibitor is administered. In certain embodiments, the checkpoint inhibitor is administered at between about 0.1 mg/kg and about 50 mg/kg. In certain embodiments, the checkpoint inhibitor is administered at between about
  • the checkpoint inhibitor is administered at between about 5 mg/kg and about 30 mg/kg. In certain embodiments, the checkpoint inhibitor is administered at between about 2 mg/kg and about 20 mg/kg. In certain embodiments, the checkpoint inhibitor is administered at between about 2 mg/kg and about 10 mg/kg. In certain embodiments, the checkpoint inhibitor is administered at between about
  • the checkpoint inhibitor is administered at between about 3 mg/kg and about 10 mg/kg. In certain embodiments, the checkpoint inhibitor is administered at between about 3 mg/kg and about 5 mg/kg. In certain embodiments, the checkpoint inhibitor is administered at between about 4 mg/kg and about
  • the checkpoint inhibitor is administered at between about 5 mg/kg and about 10 mg/kg. In certain embodiments, the checkpoint inhibitor is administered at least about 0.5 mg/kg, about 0.75 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 1.75 mg/kg, about 2 mg/kg, about 2.25 mg.
  • the checkpoint inhibitor is administered in a 5 mg/ml solution, 10 mg/ml solution, 15 mg/ml solution, 20 mg/ml solution, 25 mg/ml solution, 30 mg/ml solution. 35 mg/ml solution, 40 mg/ml solution, 45 mg/ml solution, or 50 mg/ml solution. In some embodiments, the checkpoint inhibitor is administered in a 15 mg/ml solution.
  • the antibodies are administered on a suitable dosage schedule, for example, weekly, twice weekly, monthly, twice monthly, once every two weeks, once every three weeks, or once a month etc.
  • the ROR1 binding molecule or ROR1 binding fragment is administered once over the course of at least two weeks.
  • the ROR1 binding molecule or ROR1 binding fragment is administered once over the course of at least three weeks.
  • the ROR1 binding molecule or ROR1 binding fragment is administered once over the course of at least four weeks.
  • the antibodies can be administered in any therapeutically effective amount. Therapeutically effective amounts include amounts are those sufficient to ameliorate one or more symptoms associated with the disease or affliction to be treated.
  • the ROR1 binding molecule or ROR1 binding fragment is administered at a therapeutically acceptable amount.
  • the ROR1 binding molecule or ROR1 binding fragment is administered at an amount of at least about 100 milligrams, about 200 milligrams, about 30 milligrams, about 400 milligrams, about 500 milligrams, about 600 milligrams, about 700 milligrams, about 800 milligrams, about 900 milligrams, about 1000 milligrams, about 1100 milligrams, about 1200 milligrams, about 1300 milligrams, bout 1400 milligrams, about 1500 milligrams, about 1600 milligrams, about 1700 milligrams, about 1800 milligrams, about 1900 milligrams or about 2000 milligrams.
  • the R0R1 binding molecule or ROR1 binding fragment is administered at an amount of no more than about 100 milligrams, about 200 milligrams, about 30 milligrams, about 400 milligrams, about 500 milligrams, about 600 milligrams, about 700 milligrams, about 800 milligrams, about 900 milligrams, about 1000 milligrams, about 1100 milligrams, about 1200 milligrams, about 1300 milligrams, bout 1400 milligrams, about 1500 milligrams, about 1600 milligrams, about 1700 milligrams, about 1800 milligrams, about 1900 milligrams or about 2000 milligrams.
  • the ROR1 binding molecule or ROR1 binding fragment is administered at an amount from about 100 milligrams to about 1000 milligrams, from about 200 milligrams to about 1000 milligrams, from about 300 milligrams to about 1000 milligrams, from about 400 milligrams to about 1000 milligrams, from about 500 milligrams to about 1000 milligrams, from about 600 milligrams to about 1000 milligrams, from about 700 milligrams to about 1000 milligrams, from about 800 milligrams to about 1000 milligrams, from about 900 milligrams to about 1000 milligrams, from about 100 milligrams to about 900 milligrams, from about 200 milligrams to about 900 milligrams, from about 300 milligrams to about 900 milligrams, from about 400 milligrams to about 900 milligrams, from about 500 milligrams to about 900 milligrams, from about 600 milligrams to about 900 milligrams, from about 500 mill
  • the R0R1 binding molecule of ROR1 binding fragment is administered at an amount from about 200 milligrams to about 800 milligrams.
  • the ROR1 binding molecule or ROR1 binding fragment is administered in an amount of about 100 milligrams, about 200 milligrams, about 300 milligrams, about 400 milligrams, about 500 milligrams, about 600 milligrams, about 700 milligrams, about 800 milligrams, about 900 milligrams, about 1000 milligrams, about 1100 milligrams, about 1200 milligrams, about 1300 milligrams, bout 1400 milligrams, about 1500 milligrams, about 1600 milligrams, about 1700 milligrams, about 1800 milligrams, about 1900 milligrams or about 2000 milligrams.
  • the ROR1 binding molecule of ROR1 binding fragment is administered at an amount of about 600 milligrams.
  • the ROR1 binding molecule or ROR1 biding fragment can be administered at a dose based on the body weight or mass of the individual to whom the ROR1 binding molecule or ROR1 binding fragment is administered.
  • the ROR1 binding molecule or ROR1 binding fragment is administered at between about 0.1 mg/kg and about 50 mg/kg.
  • the ROR1 binding molecule or ROR1 binding fragment is administered at between about 1 mg/kg and about 40 mg/kg.
  • the ROR1 binding molecule or ROR1 binding fragment is administered at between about 5 mg/kg and about 30 mg/kg.
  • the ROR1 binding molecule or ROR1 binding fragment is administered at between about 2 mg/kg and about 20 mg/kg. In certain embodiments, the ROR1 binding molecule or ROR1 binding fragment is administered at least about 0.5 mg/kg, about 0.75 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 1.75 mg/kg, about 2 mg/kg, about 2.25 mg.
  • the ROR1 antagonist is administered in a 5 mg/mL solution, 10 mg/mL solution, 15 mg/mL solution, 20 mg/mL solution, 25 mg/mL solution, 30 mg/mL solution. 35 mg/mL solution, 40 mg/mL solution, 45 mg/ml solution, or 50 mg/ml solution. In some embodiments, the ROR1 antagonist is administered in a 25 mg/mL solution.
  • aspects disclosed herein include a use of a therapeutically effective amount of a tyrosine kinase-like orphan receptor 1 (ROR1) antagonist and a therapeutically effective amount of an immune checkpoint inhibitor in a method of treating a cancer in a subject in need thereof, comprising administering the pharmaceutical composition to the subject.
  • aspects disclosed herein include a use of a therapeutically effective amount of a tyrosine kinase-like orphan receptor 1 (ROR1) antagonist and a therapeutically effective amount of an immune checkpoint inhibitor for the manufacture of a medicament for treating cancer in a subject in need thereof.
  • the immune checkpoint inhibitor comprises a PD-1 inhibitor, or a PD-Ll inhibitor.
  • the immune checkpoint inhibitor is a small molecule drug. In some embodiments, the immune checkpoint inhibitor comprises an antibody, a peptide, or a protein. In some embodiments, the immune checkpoint inhibitor comprises a PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is a PD-1 inhibitor antibody. In some embodiments, the PD-1 inhibitor antibody comprises nivolumab, pembrolizumab, cemiplimab, dorstarlimab, or combinations thereof. In some embodiments, the PD-1 inhibitor antibody comprises pembrolizumab.
  • the PD-1 inhibitor antibody comprises JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilmab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), Retifanlimab (INCMGA00012) (MGA012), AMP -224, AMP-514, or combinations thereof.
  • the immune checkpoint inhibitor comprises a PD-L1 inhibitor.
  • the PD-L1 inhibitor is a PD-L1 inhibitor antibody.
  • the PD-L1 inhibitor antibody comprises atezolizumab, avelumab, durvalumab, or combinations thereof.
  • thePD-Ll inhibitor antibody comprises Envafolimab (KN035), Cosibelimab (CK-301), AUNP12, CA-170, BMS-986189, or combinations thereof.
  • theRORl antagonist is an antibody or a small molecule.
  • the antibody comprises a Fab, F(ab’)2, Fv, or an scFv.
  • the ROR1 antagonist is an anti-RORl antibody.
  • the antibody is zilovertamab.
  • the antibody binds to an R0R1 amino acid sequence as set forth in SEQ ID NO 30 or SEQ ID NO : 31.
  • the immune checkpoint inhibitor and the ROR1 antagonist are administered in a combined synergistic amount.
  • the use comprises reducing the growth of a tumor. In some embodiments, the use reduces the growth of a tumor by about 20% or more. In some embodiments, the use reduces the growth of a tumor by from about 25% to about 45% when compared to administration of the immune checkpoint inhibitor and the ROR1 antagonist separately. In some embodiments, the use comprise reducing the mass or volume of a tumor.
  • the antibody comprises a humanized heavy chain variable region and a humanized light chain variable region, wherein said humanized heavy chain variable region comprises the sequences set forth in SEQ ID NO. 1, SEQ ID NO. 2, and SEQ ID NO. 3; and wherein said humanized light chain variable region comprises the sequences set forth in SEQ ID NO. 4, SEQ ID NO. 5, and SEQ ID NO. 6.
  • the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100 identical to that set forth in SEQ ID NO: 7; and wherein the light chain variable region comprises an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100 identical to that set forth in SEQ ID NO: 8.
  • an immune cell infiltrate of the cancer expresses PD-1.
  • the cancer expresses PD-L1.
  • the cancer over expresses PD-Ll.
  • the immune checkpoint inhibitor and the ROR1 antagonist are administered substantially simultaneously.
  • the immune checkpoint inhibitor and the ROR1 antagonist are administered separately. In some embodiments, the immune checkpoint inhibitor and the ROR1 antagonist are administered sequentially. In some embodiments, the immune checkpoint inhibitor and theRORl antagonist are co-formulated for administration by a single formulation. In some embodiments, the immune checkpoint inhibitor and the ROR1 antagonist are administered in separate compositions. In some embodiments, the immune checkpoint inhibitor and the ROR1 antagonist are admixed prior to administration. In some embodiments, the immune checkpoint inhibitor is administered by intravenous infusion.
  • the immune checkpoint inhibitor is administered once every t wo-weeks.In some embodiments, the immune checkpoint inhibitor is administered once every three-weeks.In some embodiments, the immune checkpoint inhibitor is administered once every four-weeks.In some embodiments, the immune checkpoint inhibitor is administered at a dosage from about 200 milligrams to about 2000 milligrams. In some embodiments, the immune checkpoint inhibitor is administered at a dosage from about 200 milligrams to about 800 milligrams. In some embodiments, the immune checkpoint inhibitor is administered at a dosage from about 300 milligrams to about 600 milligrams. In some embodiments, the immune checkpoint inhibitor is administered at a dosageof about300 milligrams.
  • the immune checkpoint inhibitor is administered at a dosage of about 600 milligrams. In some embodiments, the immune checkpoint inhibitor is administered in an amount of 200 mg every six weeks; 300 mg every six weeks, or 400 mg every six weeks. In some embodiments, the immune checkpoint inhibitor is administered in an amount of 100 mg every three weeks; or 300 mg every six weeks. In some embodiments, the immune checkpoint inhibitor is administered in an amount of 2 mg/kg, or 1 mg/kg every 3 weeks. In some embodiments, the immune checkpoint inhibitor is administered in an amount of 50 mg every three weeks; or 100 mg every six weeks. In some embodiments, the immune checkpoint inhibitor is administered in an amount of about 50 mg to about 400 mg every three weeks.
  • the immune checkpoint inhibitor is administered in a 25 mg/mL solution. In some embodiments, the immune checkpoint inhibitor is administered by injection, or intravenous infusion. In some embodiments, the immune checkpoint inhibitor is administered at a dosage of about 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.0, 2.25, 2.50, 2.75, 3.00, 3.5, 4, 4.5, 5, 5.5, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, or 20 mg/kg.
  • the ROR1 antagonist is administered at a dosage from about 200 milligrams to about 2000 milligrams. In some embodiments, theRORl antagonist is administered at a dosage from about 200 milligrams to about 800 milligrams.In some embodiments, the ROR1 antagonist is administered at a dosage from about 300 milligrams to about 600 milligrams.In some embodiments, theRORl antagonist is administered at a dosage of about 300 milligrams.In some embodiments, the ROR1 antagonist is administered at a dosage of about 600 milligrams. In some embodiments, theRORl antagonist is administered at a dosage of about 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.0, 2.25, 2.50, 2.75, 3.00, 3.5, 4, 4.5, 5, 5.5, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, or 20 mg/kg.
  • the ROR1 antagonist is administered in a 25 mg/mL solution. In some embodiments, the ROR1 antagonist is administered once every two-weeks. In some embodiments, the ROR1 antagonist is administered once every three-weeks.In some embodiments, the ROR1 antagonist is administered once every four-weeks.In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.
  • the cancer is lymphoma, leukemia, myeloma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell cancer, melanoma, stomach cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, head and neck cancer, uterine cancer, adenocarcinoma, sarcoma, or adrenal cancer.
  • the cancer is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, mantle cell lymphoma (MCL), marginal cell B-Cell lymphoma, Burkitt's Lymphoma, myeloma, AML, B-ALL, T-ALL, or B cell leukemia.
  • CLL chronic lymphocytic leukemia
  • MCL mantle cell lymphoma
  • MCL mantle cell lymphoma
  • marginal cell B-Cell lymphoma Burkitt's Lymphoma
  • myeloma AML, B-ALL, T-ALL, or B cell leukemia.
  • tumor refers to a neoplastic cell growth, and includes pre-cancerous and cancerous cells and tissues. Tumors usually present as a lesion or lump.
  • “treating” a tumor means that one or more symptoms of the disease, such as the tumor itself, vascularization of the tumor, or other parameters by which the disease is characterized, are reduced, ameliorated, inhibited, placed in a state of remission, or maintained in a state of remission. “Treating” a tumor also means that one or more hallmarks of the tumor may be eliminated, reduced or prevented by the treatment. Non -limiting examples of such hallmarks include uncontrolled degradation of the basement membrane and proximal extracellular matrix, migration, division, and organization of the endothelial cells into new functioning capillaries, and the persistence of such functioning capillaries.
  • Cancers, precancerous, tumors and / or neoplastic diseases treated with the methods and compositions of the present disclosure are not limited to any particular cell or tumor type or particular cancer, It includes any such disease (eg, cancer) that is present in a cell, such as a cancerous cell.
  • the peptide component of the antigen / MHC / costimulatory molecule / nanoparticle complex is an antigen or antigenic epitope or expressed or present in tumor cells, cancerous cells, precancerous cells or neoplastic cells or Derived or designed from those mimetics.
  • Various such proteins or epitopes have been identified for a variety of cancers.
  • the cancer is lymphoma, leukemia, myeloma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell cancer, melanoma, stomach cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, head and neck cancer, uterine cancer, adenocarcinoma, sarcoma, or adrenal cancer.
  • the cancer is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, mantle cell lymphoma (MCL), marginal cell B-Cell lymphoma, Burkitt's Lymphoma, myeloma, AML, B-ALL, T-ALL, or B cell leukemia. In some embodiments, the cancer is mantle cell lymphoma.
  • the cancer comprises a mutated PD-L1 gene. In some embodiments the cancer expresses PD-L1. In some embodiments, the cancer over expresses PD-L1.
  • the anti-RORl antibodies and/or the checkpoint inhibitors of the current disclosure are included in a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients, carriers, and diluents.
  • the anti-RORl antibodies and/or the checkpoint inhibitors of the current disclosure are administered suspended in a sterile solution.
  • the solution comprises about 0.9% NaCl. In certain embodiments, the solution comprises about 5.0% dextrose.
  • the solution further comprises one or more of: buffers, for example, acetate, citrate, histidine, succinate, phosphate, bicarbonate and hydroxymethylaminomethane (Tris); surfactants, for example, polysorbate 80 (Tween 80), polysorbate 20 (Tween 20), and poloxamer 188; polyol/disaccharide/polysaccharides, for example, glucose, dextrose, mannose, mannitol, sorbitol, sucrose, trehalose, and dextran 40; amino acids, for example, glycine or arginine; antioxidants, for example, ascorbic acid, methionine; or chelating agents, for example, ED TA or EGTA.
  • buffers for example, acetate, citrate, histidine, succinate, phosphate, bicarbonate and hydroxymethylaminomethane (Tris)
  • surfactants for example, polysorbate 80 (Tween 80), polysorbate 20 (
  • the anti-RORl antibodies and/or the checkpoint inhibitors of the current disclosure can be shipped/stored lyophilized and reconstituted before administration.
  • lyophilized anti-RORl antibody and/or checkpoint inhibitors formulations comprise a bulking agent such as, mannitol, sorbitol, sucrose, trehalose, dextran 40, or combinations thereof.
  • the lyophilized formulation can be contained in a vial comprised of glass or other suitable non -reactive material.
  • the anti-RORl antibodies and/or the checkpoint inhibitors when formulated, whether reconstituted or not, can be buffered at a certain pH, generally less than 7.0.
  • kits comprising one or more of the anti-RORl antibodies and/or the checkpoint inhibitors described herein in a suitable container and one or more additional components selected from: instructions for use; a diluent, an excipient, a carrier, and a device for administration.
  • described herein is a method of preparing a plasma cell neoplasm treatment comprising admixing one or more pharmaceutically acceptable excipients, carriers, or diluents and an anti-RORl antibody and/or checkpoint inhibitor of the current disclosure.
  • described herein is a method of preparing a cancer treatment for storage or shipping comprising lyophilizing one or more anti-RORl antibodies and/or the checkpoint inhibitors of the current disclosure.
  • range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • a sample includes a plurality of samples, including mixtures thereof.
  • analyzing are often used interchangeably herein to refer to forms of measurement. The terms include determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of’ can include determining the amount of something present in addition to determining whether it is present or absent depending on the context.
  • the extracellular domain of ROR1 consists of amino acids 30-406.
  • the term "antibody against ROR1, anti-RORl antibody or ROR1 Mab” as used herein relates to an antibody specifically binding to human ROR1. The antibody binds specifically to the extracellular domain of ROR1.
  • the antibody binds specifically to fragments of the extracellular domain, which are the Ig-like C2-type domain, the frizzled domain, or the kringle domain. These fragments are mentioned in W02005100605. It is further disclosed that the antibody may bind specifically to the extracellular domain fragment WNISSELNKDSYLTL of ROR1. This fragment is disclosed in Daneshmanesh A H et al., Int. J. Cancer, 123 (2008) 1190-1195.
  • the term “individual,” “patient,” or “subject” refers to individuals diagnosed with, suspected of being afflicted with, or at-risk of developing at least one disease for which the described compositions and method are useful for treating.
  • the individual is a mammal.
  • the mammal is a mouse, rat, rabbit, dog, cat, horse, cow, sheep, pig, goat, llama, alpaca, or yak.
  • the individual is a human.
  • Treatment refers to, e.g., a deliberate intervention to a physiological disease state resulting in the reduction in severity of a disease or condition; the reduction in the duration of a condition course; the amelioration or elimination of one or more symptoms associated with a disease or condition; or the provision of beneficial effects to a subject with a disease or condition. Treatment does not require curing the underlying disease or condition.
  • a “therapeutically effective amount,” “effective dose,” “effective amount,” or “therapeutically effective dosage” of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a subject against the onset of a disease or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
  • the ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.
  • “pharmaceutically acceptable” with reference to a carrier” “excipient” or “diluent” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion).
  • the active compound i.e., antibody
  • the active compound i.e., antibody
  • the active compound i.e., antibody
  • the pharmaceutical compounds described herein can include one or more pharmaceutically acceptable salts.
  • a “pharmaceutically acceptable salt” refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see e.g., Berge, S.M., et al. (1977) J. Pharm. Sci. 66: 1 -19). Examples of such salts include acid addition salts and base addition salts.
  • Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl- substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like.
  • nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like
  • nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl- substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like.
  • Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like.
  • an “epitope” refers to the binding determinant of an antibody or fragment described herein minimally necessary for specific binding of the antibody or fragment thereof to a target antigen.
  • the target antigen is a polypeptide the epitope will be a continuous or discontinuous epitope.
  • a continuous epitope is formed by one region of the target antigen, while a discontinuous epitope may be formed from two or more separate regions.
  • a discontinuous epitope for example, may form when a target antigen adopts a tertiary structure that brings two amino acid sequences together and forms a three- dimensional structure bound by the antibody.
  • Example 1 Combination treatment of cancer with pembrolizumab and zilovertamab
  • Human donor cells were screened in vitro. Donor cells from two different donors were combined with Jeko-1 cells and either stimulated with anti-CD3/CD28 (5 ug/'inL each), pembrolizumab (1 ug/mL), zilovertamab (20 ug/mL), or a combination of pembrolizumab (1 ug/mL) and zilovertamab (20 ug/'inL), and incubated at the indicated effector to target ratios. As depicted in FIG.
  • zilovertamab modulates T cell activity in vitro and synergizes with pembrolizumab, which is more apparent at lower effector to target cell concentrations.
  • Donor lines 451 and 244 did not have high alloreactivity against Jeko-1 cells and were selected for in vivo studies.
  • Tumor Growth Inhibition is expressed as Mean% A Inhibition and was calculated by using the following formula: [(C-C0)-(T-T0)/(C-C0)]*100%, where C refers to the tumor volume of the vehicle on a specific day of dosing, CO to the tumor volume of the vehicle on the first day of dosing, T to the tumor volume of the treatment on a specific day of dosing and TO to the tumor volume of the treatment group on the first day of dosing.
  • the combination treatment resulted in a greater tumor growth inhibition of both donor cells. It is observed that the combination of the ROR1 antagonist and a checkpoint inhibitor provide a synergistic effect in the treatment of cancer in a subject in need thereof, which is superior to the effect of either the ROR1 antagonist or the checkpoint inhibitor acting alone.
  • A is the difference between the combination and the monotherapeutic
  • Example 2 A clinical trial to treat lymphoma with a combination of pembrolizumab and zilovertamab
  • Primary outcome measures include reduced tumor growth.
  • Secondary outcome measures will include reduced tumor mass, reduced tumor volume, and increased survival over time.

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Abstract

L'invention concerne des méthodes et des compositions pour le traitement du cancer, de telles méthodes comprenant l'utilisation combinée d'un antagoniste de ROR1 et d'un antagoniste d'inhibiteur de point de contrôle.
PCT/US2023/084937 2022-12-20 2023-12-19 Polythérapies pour traiter le cancer Ceased WO2024137697A1 (fr)

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CN202380094535.7A CN120813602A (zh) 2022-12-20 2023-12-19 用于治疗癌症的组合疗法
EP23908368.6A EP4638506A1 (fr) 2022-12-20 2023-12-19 Polythérapies pour traiter le cancer

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Citations (3)

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WO2019005639A2 (fr) * 2017-06-25 2019-01-03 Systimmune, Inc. Anticorps multispécifiques et procédés de préparation et d'utilisation associés
WO2019204564A1 (fr) * 2018-04-18 2019-10-24 Exelixis, Inc. Constructions d'anticorps anti-ror
WO2021159029A1 (fr) * 2020-02-07 2021-08-12 VelosBio Inc. Anticorps et compositions anti-ror1

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Publication number Priority date Publication date Assignee Title
WO2019005639A2 (fr) * 2017-06-25 2019-01-03 Systimmune, Inc. Anticorps multispécifiques et procédés de préparation et d'utilisation associés
WO2019204564A1 (fr) * 2018-04-18 2019-10-24 Exelixis, Inc. Constructions d'anticorps anti-ror
WO2021159029A1 (fr) * 2020-02-07 2021-08-12 VelosBio Inc. Anticorps et compositions anti-ror1

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Title
OU ZHENGLIN, DOU XIAOLIN, TANG NENG, LIU GUODONG: "Pressure increases PD-L1 expression in A549 lung adenocarcinoma cells and causes resistance to anti-ROR1 CAR T cell-mediated cytotoxicity", SCIENTIFIC REPORTS, vol. 12, no. 1, 1 January 2022 (2022-01-01), US , pages 1 - 10, XP093189836, ISSN: 2045-2322, DOI: 10.1038/s41598-022-10905-6 *

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