WO2024073716A2 - Thérapie combinatoire de protéines de fusion se liant à cd38 - Google Patents

Thérapie combinatoire de protéines de fusion se liant à cd38 Download PDF

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WO2024073716A2
WO2024073716A2 PCT/US2023/075591 US2023075591W WO2024073716A2 WO 2024073716 A2 WO2024073716 A2 WO 2024073716A2 US 2023075591 W US2023075591 W US 2023075591W WO 2024073716 A2 WO2024073716 A2 WO 2024073716A2
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Prior art keywords
fusion protein
subject
binding fusion
antibody
week
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PCT/US2023/075591
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English (en)
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WO2024073716A3 (fr
Inventor
Sarah Pogue
Sabrina Collins
Xavier PAROT
Shuang Wu LI
Laura THESILLAT-VERSMEE
Richard LABOTKA
Jim Sampson
Neeraj Gupta
Shining WANG
Kaveri SURYANARAYAN
David Wilson
Original Assignee
Takeda Pharmaceutical Company Limited
Cephalon Llc
Teva Pharmaceuticals Australia Pty Ltd
Arana Therapeutics, Inc.
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Publication of WO2024073716A2 publication Critical patent/WO2024073716A2/fr
Publication of WO2024073716A3 publication Critical patent/WO2024073716A3/fr

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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
    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/555—Interferons [IFN]
    • C07K14/56—IFN-alpha
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies

Definitions

  • CD38 is a 45 kDa type II transmembrane glycoprotein. It has a short N-terminal cytoplasmic tail of 20 amino acids, a single transmembrane helix and a long extracellular domain of 256 amino acids. It is expressed on the surface of many immune cells including CD4 and CD8 positive T cells, B cells, NK cells, monocytes, plasma cells, and on a significant proportion of normal bone marrow precursor cells.
  • CD38 is expressed at high levels on various types of cancer cells, e.g., multiple myeloma cells, in most cases of T- and B-lineage acute lymphoblastic leukemias, some acute myelocytic leukemias, follicular center cell lymphomas and T lymphoblastic lymphomas. CD38 is also expressed on B-lineage chronic lymphoblastic leukemia (B-CLL) cells. Antibodies that target CD38 have been used in the treatment of CD38-expressing cancers and hematological malignancies.
  • B-CLL B-lineage chronic lymphoblastic leukemia
  • Interferons and in particular IFN-alpha, are able to increase apoptosis and decrease proliferation of certain cancer cells.
  • IFN-alpha has been approved by the FDA for the treatment of several cancers including melanoma, renal cell carcinoma, B cell lymphoma, multiple myeloma, chronic myelogenous leukemia (CML) and hairy cell leukemia.
  • IFN may be targeted to cancer cells, for example, by linking it with a targeting antibody or targeting fragment thereof.
  • the present disclosure in some aspects, relates to methods of treating cancer (e.g., CD38-expressing cancer) using a CD38-binding fusion protein comprising an anti-CD38 binder, such as an-anti CD38 antibody or binding domain or fragment thereof, fused to one or more (e.g., one, two) attenuated interferon alpha-2b protein in combination with an additional anti-CD38 antibody (e.g., daratumumab), and optionally additional agents (e.g., immunomodulatory drugs such as lenalidomide or pomalidomide, or proteasome inhibitors such as bortezomib or carfilzomib), for treating the cancer.
  • additional anti-CD38 antibody e.g., daratumumab
  • additional agents e.g., immunomodulatory drugs such as lenalidomide or pomalidomide, or proteasome inhibitors such as bortezomib or carfilzomib
  • the CD38- expressing cancer is multiple myeloma.
  • the multiple myeloma is Relapsed or Refractory Multiple Myeloma (RRMM).
  • the methods described herein are effective in treating RRMM: (i) in subjects who have received 1-3 prior lines of therapy (e.g., one or more prior lines of therapy) for multiple myeloma, including at least one proteasome inhibitor, at least one CD38 monoclonal antibody (mAb) drug, and/or at least one immunomodulatory drug (e.g., an immunomodulatory imide drug ((IMiD)); (ii) in subjects who were refractory to an immunomodulatory drug (e.g., an IMiD (e.g., lenalidomide or pomalidomide)) and nonrefractory to anti-CD38 monoclonal antibodies (mAbs); and/or (iii) in subjects who are not refractory to the combination partners (e.
  • 1-3 prior lines of therapy e
  • Some aspects of the present disclosure provide methods of treating a CD38-expressing cancer, the method comprising administering to a subject in need thereof a CD38-binding fusion protein comprising a first anti-CD38 antibody fused to one or more attenuated interferon alpha-2b, and a second anti-CD38 antibody.
  • Some aspects of the present disclosure provide methods of treating a CD38-expressing cancer, the method comprising administering to a subject in need thereof a CD38-binding fusion protein comprising a first anti-CD38 antibody fused to one or more attenuated interferon alpha-2b, wherein the subject is receiving or has received treatment with a second anti-CD38 antibody.
  • Some aspects of the present disclosure provide methods of treating a CD38-expressing cancer, the method comprising administering to a subject in need thereof a second anti-CD38 antibody, wherein the subject is receiving or has received treatment with CD38-binding fusion protein comprising a first anti-CD38 antibody fused to one or more attenuated interferon alpha- 2b.
  • the first anti-CD38 antibody comprises a heavy chain complementarity determining region 1 (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain complementarity determining region 2 (CDR-H2) comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region 1 (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 4, a light chain complementarity determining region 2 (CDR-L2) comprising the amino acid sequence of SEQ ID NO: 5, a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of SEQ ID NO: 6.
  • the first anti-CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8.
  • the first anti-CD38 antibody is a full-length IgG antibody. In some embodiments, the first anti-CD38 antibody comprises a human IgG4 constant region. In some embodiments, the human IgG4 constant region comprises a proline at position 228 according to the EU numbering system.
  • the first anti-CD38 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
  • the attenuated interferon alpha-2b comprises T106A and A145D mutations relative to an interferon alpha- 2b comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the attenuated interferon alpha- 2b comprises the amino acid sequence of SEQ ID NO: 12.
  • the attenuated interferon alpha-2b is fused to the C-terminus of the heavy chain.
  • the CD38-binding fusion protein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
  • the second anti-CD38 antibody is daratumumab.
  • the CD38-binding fusion protein is administered once every 4 weeks during a period of administration. In some embodiments, the administrations are according to a 4-week treatment cycle during a period of administration. In some embodiments, the period of administration is up to 5 years.
  • the subject is administered 50-250 mg of the CD38-binding fusion protein each 4-week treatment cycle. In some embodiments, the subject is administered 60 mg, 80 mg, 120 mg, or 240 mg of the CD38-binding fusion protein each 4-week treatment cycle. In some embodiments, the subject is administered the CD38-binding fusion protein at a dose of 0.5-4 mg/kg each 4-week treatment cycle. In some embodiments, the subject is administered the CD38-binding fusion protein at a dose of 0.75 mg/kg, 1 mg/kg, 1.5 mg/kg, or 3 mg/kg each 4-week treatment cycle. In some embodiments, administration of the CD38- binding fusion protein occurs on day 1 of each 4-week treatment cycle. In some embodiments, the CD38-binding fusion protein is administered intravenously.
  • the subject is administered 1800 mg of the second anti-CD38 antibody once a week for two 4-week treatment cycles and once every two weeks for the next four 4-week treatment cycles, followed by administration of 1800 mg of the second anti-CD38 antibody once every four weeks thereafter.
  • the second anti-CD38 antibody is administered subcutaneously.
  • the method further comprises administering to subject a proteasome inhibitor.
  • the subject is receiving or has received treatment with a proteasome inhibitor.
  • the proteasome inhibitor is bortezomib.
  • bortezomib is administered at a dose of 1.3 mg/m 2 on days 1, 4, 8, and 11 for eight three- week treatment cycles. In some embodiments, bortezomib is administered subcutaneously.
  • the proteasome inhibitor is carfilzomib.
  • carfilzomib is administered at a dose of 20 mg/m 2 on day 1 of the first four- week treatment cycle, and at a dose of up to 70 mg/m 2 on days 8 and 15 for remaining 4-week treatment cycles during the period of administration.
  • the carfilzomib is administered intravenously.
  • the method further comprises administering to subject an immunomodulatory drug.
  • the subject is receiving or has received treatment with an immunomodulatory drug.
  • the immunomodulatory drug is pomalidomide.
  • pomalidomide is administered at a dose of 4 mg daily for the first 21 days of each 4-week treatment cycle during the period of administration. In some embodiments, pomalidomide is administered orally.
  • the subject is receiving or has received treatment with one or more of methylprednisolone, dexamethasone, acetaminophen, and diphenhydramine.
  • the CD38-binding fusion protein is in a composition that further comprises histidine, arginine, sucrose, and polysorbate 80 (PS 80).
  • the composition comprises histidine at a concentration of 50 nM, arginine at a concentration of 100 nM, sucrose at a concentration of 50 mg/ml, and PS80 at a concentration of 0.2 mg/ml.
  • the composition is at a pH of 6.6.
  • the CD38-expressing cancer is multiple myeloma.
  • multiple myeloma is refractory multiple myeloma.
  • the multiple myeloma is previously untreated multiple myeloma.
  • the administration results in tumor regression.
  • the subject is a human.
  • the subject is a rodent.
  • Some aspects of the present disclosure provide CD38-binding fusion proteins for use in a method of treating a CD38-expressing cancer, the method comprising administering to a subject in need thereof the CD38-binding fusion protein and a second anti-CD38 antibody, wherein the CD38-binding fusion protein comprises a first anti-CD38 antibody fused to one or more attenuated interferon alpha-2b.
  • Some aspects of the present disclosure provide CD38-binding fusion proteins for use in a method of treating a CD38-expressing cancer, the method comprising administering to a subject in need thereof the CD38-binding fusion protein, wherein the subject is receiving or has received treatment with a second anti-CD38 antibody, wherein the CD38-binding fusion protein comprises a first anti-CD38 antibody fused to one or more attenuated interferon alpha- 2b.
  • Some aspects of the present disclosure provide a second anti-CD38 antibody for use in a method of treating a CD38-expressing cancer, the method comprising administering to a subject in need thereof the second anti-CD38 antibody, wherein the subject is receiving or has received treatment with a CD38-binding fusion protein, wherein the CD38-binding fusion protein comprises a first anti-CD38 antibody fused to one or more attenuated interferon alpha- 2b.
  • the second anti-CD38 antibody is daratumumab.
  • the subject is receiving or has received treatment with a proteasome inhibitor.
  • the proteasome inhibitor is bortezomib or carfilzomib.
  • the subject is receiving or has received treatment with an immunomodulatory drug.
  • the immunomodulatory drug is pomalidomide.
  • Some aspects of the present disclosure provide a method of administering to a subject having multiple myeloma:
  • the CD38-binding fusion protein comprises: (a) a first anti-CD38 antibody comprising a heavy chain variable region of SEQ ID NO: 7 and a light chain variable region of SEQ ID NO: 8; and (b) an attenuated interferon alpha-2b comprising an amino acid sequence of SEQ ID NO: 12;
  • the method comprises administering 80 mg of the CD38-binding fusion protein once every 4-week cycle to the subject. In some embodiments, the method comprises administering 120 mg of the CD38-binding fusion protein once every 4-week cycle to the subject. In some embodiments, the method comprises administering 240 mg of the CD38-binding fusion protein once every 4-week cycle to the subject.
  • the CD38-binding fusion protein is administered intravenously to the subject.
  • daratumumab is administered subcutaneously to the subject.
  • the method comprises administering the CD38-binding fusion protein on day 1 of every 4-week cycle to the subject.
  • Some aspects of the present disclosure provide a method comprising administering daratumumab on days 1, 8, 15 and 22 during the first and the second 4-week cycle; administering daratumumab on days 1 and 15 during the third, the fourth, the fifth and the sixth 4-week cycle; and administering daratumumab on day 1 during the remaining 4-week cycle of treatment to the subject.
  • FIG. 1 shows the tumor inhibition activity of CD38-binding fusion protein combined with daratumumab in NCI-H929 multiple myeloma (MM) xenograft tumor model.
  • FIGs. 2A-2G show time profiles of clinical laboratory parameters of 3 patients in group 1, who received 80 mg of the CD38-binding fusion protein once per week for 4-week treatment cycle in combination with 1800 mg daratumumab administered once per week for treatment cycles 1-2, once per 2 weeks for treatment cycles 3-6, and once per 4 weeks for treatment cycles 7 and beyond.
  • ALT alanine transaminase
  • IU/L alanine transaminase
  • Time points are indicated as number of the cycle and day, e.g., C1D1 is cycle 1, day 1.
  • G1-G4 indicate the toxicity level grades 1 through 4.
  • FIGs. 3A-3G show time profiles of clinical laboratory parameters of 6 patients in group 2 who received 120 mg of the CD38-binding fusion once per week for 4-week treatment cycle in combination with 1800 mg daratumumab administered once per week for treatment cycles 1-2, once per 2 weeks for treatment cycles 3-6, and once per 4 weeks for treatment cycles 7 and beyond.
  • ALT alanine transaminase
  • IU/L alanine transaminase
  • Time points are indicated as number of the cycle and day, e.g., C1D1 is cycle 1, day 1.
  • G1-G4 indicate the toxicity level grades 1 through 4.
  • FIGs. 4A-4D show changes in CD38 receptor density after dosing in whole blood samples of patients from groups 1 and 2, who received of the CD38-binding fusion protein treatment in combination with daratumumab.
  • CD38 expression and receptor occupancy was evaluated from whole blood samples from all the patients in the study using flow cytometry.
  • CD38 receptor density was measured across the study time points in NK cells (FIG. 4A), monocytes (FIG. 4B), B cells (FIG. 4C) and T cells (FIG. 4D). Fold change was calculated from the baseline after dosing.
  • FIG. 5 shows total CD38 occupancy on lymphocytes in whole blood samples of patients from both groups 1 and 2 post-infusion of the CD38-binding fusion protein in the presence of daratumumab.
  • Total receptor occupancy was calculated as percentage using median fluorescent intensity. Average and median values are indicated on the x-axis.
  • the present disclosure in some aspects, relates to methods of treating cancer (e.g., CD38-expressing cancer) using a CD38-binding fusion protein comprising an anti-CD38 antibody fused to one or more (e.g., one, two) attenuated interferon alpha- 2b protein in combination with an additional anti-CD38 antibody (e.g., daratumumab), and optionally additional agents (e.g., immunomodulatory drugs such as lenalidomide or pomalidomide, or proteasome inhibitors such as bortezomib or carfilzomib), for treating the cancer.
  • the CD38-expressing cancer is multiple myeloma.
  • the multiple myeloma is relapsed or refractory multiple myeloma.
  • the methods described herein are effective in treating relapsed or refractory multiple myeloma: (i) in subjects who have received 1-3 prior lines of therapy (e.g., one or more prior lines of therapy) for multiple myeloma, including at least one proteasome inhibitor, at least one CD38 monoclonal antibody (mAb) drug, and/or at least one immunomodulatory drug (e.g., an IMiD); (ii) in subjects who were refractory to an immunomodulatory drug (e.g., an IMiD (e.g., lenalidomide)) and nonrefractory to anti-CD38 mAbs; and/or (iii) in subjects who are not refractory to the combination partners (e.g., for each combination tested).
  • 1-3 prior lines of therapy e.g., one or more prior lines of therapy
  • mAb mono
  • cancer e.g., CD38-expressing cancer such as multiple myeloma
  • a CD38-binding fusion protein comprising a first anti- CD38 antibody fused to one or more (e.g., one, two) attenuated interferon alpha- 2b protein in combination with a second anti-CD38 antibody (e.g., daratumumab), for treating the cancer.
  • a second anti-CD38 antibody e.g., daratumumab
  • a method described herein comprises administering to a subject in need thereof a CD38-binding fusion protein comprising a first anti-CD38 antibody fused to one or more (e.g., one, two) attenuated interferon alpha-2b, and a second anti-CD38 antibody (e.g., daratumumab).
  • a CD38-binding fusion protein comprising a first anti-CD38 antibody fused to one or more (e.g., one, two) attenuated interferon alpha-2b, and a second anti-CD38 antibody (e.g., daratumumab).
  • a method described herein comprises administering to a subject in need thereof a CD38-binding fusion protein comprising a first anti-CD38 antibody fused to one or more (e.g., one, two) attenuated interferon alpha- 2b, wherein the subject is receiving or has received treatment with a second anti-CD38 antibody (e.g., daratumumab).
  • a CD38-binding fusion protein comprising a first anti-CD38 antibody fused to one or more (e.g., one, two) attenuated interferon alpha- 2b, wherein the subject is receiving or has received treatment with a second anti-CD38 antibody (e.g., daratumumab).
  • a method described herein comprises administering to a subject in need thereof a second anti-CD38 antibody (e.g., daratumumab), wherein the subject is receiving or has received treatment with a CD38-binding fusion protein comprising a first anti-CD38 antibody fused to one or more (e.g., one, two) attenuated interferon alpha- 2b.
  • a proteasome inhibitor e.g., bortezomib or carfilzomib.
  • any one of the methods described herein is receiving or has received treatment with a proteasome inhibitor (e.g., bortezomib or carfilzomib). In some embodiments, any one of the methods described herein further comprises administering to the subject an immunomodulatory drug (e.g., pomalidomide or lenalidomide). In some embodiments, in any one of the methods described herein, the subject is receiving or has received treatment with an immunomodulatory drug (e.g., pomalidomide or lenalidomide).
  • an immunomodulatory drug e.g., pomalidomide or lenalidomide
  • CD38-binding fusion protein refers to a fusion protein comprising a CD38 binder, such as an anti-CD38 antibody or binding domain or fragment thereof fused to one or more (e.g., one, two) attenuated interferon alpha-2b proteins.
  • a “fusion protein” refers to a polypeptide comprising two or more proteinaceous components associated by at least one covalent bond which is a peptide bond, regardless of whether the peptide bond involves the participation of a carbon atom of a carboxyl acid group or involves another carbon atom.
  • fuse refers to the act of creating a fused molecule as described above, such as, e.g., a fusion protein generated from the recombinant fusion of genetic regions which when translated produces a single proteinaceous molecule.
  • CD38-binding fusion proteins that may be used in the compositions described herein are described in the art, e.g., in US Patent No. 10544199B2, incorporated herein by reference.
  • the amino acid sequences of an example of an anti-CD38 antibody are provided in Table 1 herein.
  • a CD38-binding fusion protein used in a method described herein comprises an anti- CD38 binder, such as an anti-CD38 antibody or binding domain or fragment thereof.
  • antibody includes, for example, an intact immunoglobulin or an antigen binding portion of an immunoglobulin or an antigen binding protein related or derived from an immunoglobulin. Intact antibody structural units often comprise a tetrameric protein. Each tetramer is typically composed of two identical pairs of polypeptide chains, each pair having one “light” chain (typically having a molecular weight of about 25 kDa) and one “heavy” chain (typically having a molecular weight of about 50- to 70 kDa).
  • Human immunoglobulin light chains may be classified as having kappa or lambda light chains.
  • the antibodies described herein comprise antigen binding domains (e.g., antibody heavy and/or light chains) that generally are based on the IgG class, which has several subclasses, including, but not limited to IgGl, IgG2, IgG3, and IgG4.
  • IgGl has different allotypes with polymorphisms at 356 (D or E), IgG2 and 358 (L or M).
  • the sequences depicted herein use the 356D/358M allotype; however any allotype is included herein and can be used in accordance with the present disclosure.
  • any sequence inclusive of an IgGl Fc domain included herein can have 356E/358L replacing the 356D/358M allotype.
  • the anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises a heavy chain comprising a heavy chain variable domain (VH) and a light chain comprising a light chain variable domain (VL).
  • VH heavy chain variable domain
  • VL light chain variable domain
  • VK(V.kappa), Vz. (V.lambda) VH genes that make up the kappa, lambda, and heavy chain immunoglobulin genetic loci respectively.
  • each of the loops is referred to as a complementarity-determining region (hereinafter referred to as a "CDR").
  • CDR complementarity-determining region
  • the variable domains also contain relatively invariant stretches called framework regions (FRs) of 15-30 amino acids separated by CDRs.
  • FRs framework regions
  • Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1-CDR1- FR2-CDR2-FR3-CDR3-FR4.
  • an “antibody molecule” refers to two- chain and multi-chain immunoglobulin proteins and glycoproteins.
  • an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein is an antibody fragment or antigen binding fragment of an antibody, including, for example, Fab, Fab', F(ab')2, and Fv fragments.
  • an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises a VH comprising a CDRH1 comprising the amino acid sequence of SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence of SEQ ID NO: 2, and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 3; and a VL comprising a CDRL1 comprising the amino acid sequence of SEQ ID NO: 4, a CDRL2 comprising the amino acid sequence of SEQ ID NO: 5, and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 6.
  • an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises a set of 6 CDRs that collectively contain up to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid modifications, relative to the 6 CDRs of the anti-CD38 antibody provided in Table 1.
  • the CDRs can be modified in any fashion, as long as the total number of changes in the set of 6 CDRs does not exceed 10 amino acid modifications, with any combination of CDRs being changed, e.g., there may be one change in CDRL1, two in CDRH2, none in CDRH3, etc.
  • each CDR has no more than a single amino acid substitution relative to the corresponding CDR of the anti-CD38 antibody provided in Table 1.
  • amino acid modifications in the CDRH3 are avoided.
  • an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 8.
  • an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises a VH comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 7 and a VL comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 8.
  • an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein is a full-length IgG antibody.
  • each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region.
  • Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region.
  • the Immunoglobulin molecules are IgG class IgG4, or a subclass thereof.
  • an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises an IgG4 constant region (e.g., a human IgG4 constant region comprising the amino acid sequence of SEQ ID NO: 14).
  • IgG4 constant region refers to a wild-type IgG4 constant region (e.g., a wild-type human IgG4 constant region) or an IgG4 constant region variant (e.g., a human IgG4 constant region variant) or fragment thereof.
  • IgG4 constant region variants (e.g., human IgG4 constant region variants) that may be used in the anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein may, in some embodiments, comprise one or more mutations, e.g., mutations that stabilize the hinge region and/or reduce the toxicity of the antibody.
  • a mutation at position 228 of the IgG4 according to the EU numbering system stabilizes the hinge of IgG4.
  • a mutation at position 228 of the IgG4 constant region according to the EU numbering system results in a proline at position 228.
  • modifications, such as mutations, in the IgG4 constant region decrease antibody dependent cell cytotoxicity (ADCC).
  • ADCC antibody dependent cell-mediated cytotoxicity
  • FcyRs Fc gamma receptors
  • modifications, such as mutations, in the IgG4 constant region decrease antibody dependent cell cytotoxicity (ADCC).
  • ADCC antibody dependent cell-mediated cytotoxicity
  • mutations include, without limitation, mutations at one or more of positions 252, 254, and 256 of the IgG4 constant region according to the EU numbering system.
  • a mutation at position 252 of the IgG4 constant region according to the EU numbering system results in a tyrosine at position 252.
  • a mutation at position 254 of the IgG4 constant region according to the EU numbering system results in a threonine at position 254.
  • a mutation at position 256 of the IgG4 constant region according to the EU numbering system results in a glutamic acid at position 256.
  • an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises an IgG4 constant region comprising a mutation at position 228 of the IgG4 constant region according to the EU numbering system.
  • an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises an IgG4 constant region comprising the amino acid sequence of SEQ ID NO: 15.
  • an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises a heavy chain comprising a VH and a human IgG4 constant region, wherein the VH comprises the amino acid sequence of SEQ ID NO: 7 and the IgG4 constant region comprises the amino acid sequence of SEQ ID NO: 15.
  • an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:
  • an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises a heavy chain comprising an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 9.
  • an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises a light chain comprising a VL and a kappa light constant region, wherein the VL comprises the amino acid sequence of SEQ ID NO: 8.
  • an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises a light chain comprising the amino acid sequence of SEQ ID NO:
  • an anti-CD38 antibody of the CD38-binding fusion protein used in a method described herein comprises a light chain comprising an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 10.
  • a CD38-binding fusion protein used in a method described herein further comprises an anti-CD38 antibody (e.g., the anti-CD38 antibody provided in Table 1) fused to one or more (e.g., one, two) attenuated interferon alpha- 2b protein (e.g., the attenuated interferon alpha- 2b protein is fused to the heavy chain of the anti-CD38 antibody).
  • an anti-CD38 antibody e.g., the anti-CD38 antibody provided in Table 1
  • one or more (e.g., one, two) attenuated interferon alpha- 2b protein e.g., the attenuated interferon alpha- 2b protein is fused to the heavy chain of the anti-CD38 antibody.
  • an attenuated interferon alpha- 2b protein comprises mutations that reduce its potency (e.g., A145D) and/or eliminate O-linked glycosylation of the interferon alpha- 2b protein (e.g., T106A) (in both instances, numbering is relative to the wild type sequence of human interferon-alpha-2b).
  • the potency (e.g., anti-proliferative activity) of attenuated interferon alpha-2b fused to a CD38 binding protein can be determined relative to a non-attenuated IFN- alpha2b (e.g., a wildtype IFN-alpha2b) using an on target (Daudi) assay, as described in USP 11,319,356.
  • a non-attenuated IFN- alpha2b e.g., a wildtype IFN-alpha2b
  • an on target (Daudi) assay as described in USP 11,319,356.
  • An attenuated interferon molecule can be fused to antibodies that specifically bind to CD38 (e.g., an anti-CD38 antibody), as described herein, such that the anti-CD38 antibody may serve as a delivery vehicle for the attenuated interferon to CD38-positive cells with a resulting diminution of off target interferon activity caused by the attenuated interferon molecule.
  • an anti-CD38 antibody e.g., an anti-CD38 antibody
  • the attenuated interferon alpha-2b protein is fused to the heavy chain of the anti-CD38 antibody. In some embodiments, the attenuated interferon alpha-2b protein is fused to the C-terminus of the heavy chain of the anti-CD38 antibody.
  • the CD38-binding fusion protein used in a method described herein comprises a heavy chain and a light chain, wherein the heavy chain comprises the heavy chain of an anti-CD38 antibody fused to an attenuated interferon alpha- 2b protein and wherein the light chain is the light chain of the anti-CD38 antibody.
  • the CD38- binding fusion protein used in a method described herein comprises two heavy chains and two light chains, wherein each heavy chain comprises the heavy chain of an anti-CD38 antibody fused to an attenuated interferon alpha- 2b protein and wherein each light chain is the light chain of the anti-CD38 antibody.
  • the attenuated interferon alpha-2b comprises T106A and A145D mutations relative to a wild type human interferon alpha-2b (e.g., a human interferon alpha- 2b comprising the amino acid sequence of SEQ ID NO: 11).
  • the attenuated interferon alpha- 2b comprises the amino acid of SEQ ID NO: 12.
  • the attenuated interferon alpha- 2b comprises an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical to the amino acid of SEQ ID NO: 12.
  • a CD38-binding fusion protein used in a method described herein comprises a heavy chain comprising an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical to the amino acid of SEQ ID NO: 13 and a light chain comprising an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical to the amino acid of SEQ ID NO: 10.
  • a CD38-binding fusion protein used in a method described herein comprises the amino acid of SEQ ID NO: 13 and a light chain comprising the amino acid of SEQ ID NO: 10.
  • a CD38-binding fusion protein used in a method described herein comprises two heavy chains and two light chains, wherein each heavy comprises the amino acid sequence of SEQ ID NO: 13 and each light chain comprises the amino acid sequence of SEQ ID NO: 10.
  • “Pomalidomide” refers to a thalidomide analog with immunomodulatory, antiangiogenic, and antineoplastic properties. Cellular activities of pomalidomide are mediated through its target cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex. Pomalidomide inhibits the proliferation of lenalidomide-resistant MM cell lines. Pomalidomide has been shown to enhance T cell- and NK cell-mediated immunity and inhibit production of pro-inflammatory cytokines by monocytes (POMALYST® (pomalidomide) Capsules).
  • Pomalidomide is approved in combination with dexamethasone for patients with multiple myeloma who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor, and had demonstrated disease progression on or within 60 days of completion of the last therapy.
  • Lenalidomide refers to a thalidomide analog which inhibits tumor angiogenesis, tumor- secreted cytokines, and tumor proliferation through inhibition of proteasome activity and induction of apoptosis.
  • Lenalidomide (REVLAMID®) has been shown to have direct antitumor effect, activity in inhibition of angiogenesis, and immunomodulation activity.
  • Lenalidomide induces tumor cell apoptosis directly and indirectly by inhibition of bone marrow stromal cell support, by anti- angiogenic and anti-osteoclastogenic effects, and by immunomodulatory activity.
  • Lenalidomide has a broad range of activities that can be exploited to treat many hematologic and solid cancers.
  • proteasome inhibitor refers to a compound that blocks the action of proteasomes, cellular complexes that break down proteins. Proteasome inhibitors have been used in the treatment of cancer. Examples of approved proteasome inhibitors for use in treating multiple myeloma include bortezomib and carfilzomib, which are used as the standard of care treatment for multiple myeloma.
  • Bortezomib has been described, e.g., in US Patent Nos. 6,713,446 and 6,958,319.
  • Bortezomib (VELCADE®) is a proteasome inhibitor that is cytotoxic to a variety of cancer cell types in vitro. Bortezomib causes a delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma. Bortezomib is indicated for treatment of adult patients with multiple myeloma and in combination with other antimyeloma agents.
  • Carfilzomib has been described, e.g., in US Patent No. 7,232,818.
  • Carfilzomib (KYPROLIS®) covalently irreversibly binds to and inhibits the chymotrypsin-like activity of the 20S proteasome.
  • Carfilzomib displays minimal interactions with non-proteasomal targets, thereby improving safety profiles over bortezomib.
  • Inhibition of proteasome-mediated proteolysis results in a build-up of polyubiquitinated proteins, which may cause cell cycle arrest, apoptosis, and inhibition of tumor growth.
  • Daratumumab is an anti-cancer medication marketed under the trade name DARZALEX®.
  • the daratumumab structure comprises a 145 kDa protein comprising an immunoglobulin G1 kappa (IgGl K) human monoclonal antibody (mAb).
  • mAb immunoglobulin G1 kappa
  • MM multiple myeloma
  • RMM relapsed refractory multiple myeloma
  • daratumumab is approved in the US and EU as a monotherapy and in combination with a variety of other agents (see, e.g., Palumbo et al. (2016). The New England Journal of Medicine, 375: 754-766).
  • Daratumumab binds to CD38 antigens and inhibits the growth of CD38 expressing tumor cells.
  • the mechanism of daratumumab for inhibiting growth of CD38+ tumor cells involves inducing apoptosis directly through Fc (fragment crystallizable) mediated cross linking as well as by immune-mediated tumor cell lysis through complement dependent cytotoxicity (CDC), antibody dependent cell mediated cytotoxicity (ADCC), and antibody dependent cellular phagocytosis (ADCP), e.g., as described in De Weers et al., The Journal of Immunology, 186: 1840-1848, 2011. Multiple myeloma cells with higher expression levels of CD38 show greater daratumumab-dependent lysis.
  • CDC complement dependent cytotoxicity
  • ADCC antibody dependent cell mediated cytotoxicity
  • ADCP antibody dependent cellular phagocytosis
  • the CD38-binding fusion protein described herein is administered once every four weeks.
  • agents e.g., the CD38-binding fusion protein described herein, the immunomodulatory drug (e.g., pomalidomide) and/or the proteasome inhibitor (e.g., bortezomib or carfilzomib)
  • treatment cycles e.g., one or more treatment cycles
  • a treatment cycle is 4 weeks (i.e., 28 days).
  • a treatment cycle is 3 weeks (i.e., 21 days).
  • certain agents are administered according to a 4-week treatment cycle, and other agents are administered according to a 3-week treatment cycle.
  • an agent is administered according to a 4-week treatment cycle, followed by administration according to different treatment cycles (e.g., a 3-week treatment cycle).
  • a period of administration is up to five years (e.g., up to 5 years, up to 4 years, up to 3 years, up to 2 years, up to 23 months, up to 22 months, up to 21 months, up to 20 months, up to 19 months, up to 18 months, up to 17 months, up to 16 months, up to 15 months, up to 14 months, up to 13 months, up to 12 months, up to 11 months, up to 10 months, up to 9 months, up to 8 months, up to 7 months, up to 6 months, up to 5 months, up to 4 months, up to 3 months, up to 2 months, or up to 1 month).
  • a period of administration is more than 2 years (e.g., 2-5 years).
  • a period of administration is until the subject exhibits disease progression. In some embodiments, a period of administration lasts until an event meeting the criteria for discontinuing the treatment is met (e.g., unacceptable toxicity is observed) for the subject. In some embodiments, a period of administration ends when no cancer cells are detected in the subject (e.g., when the subject is minimal residual disease (MRD)-negative). In some embodiments, a period of administration lasts the remainder of the subject’s lifetime.
  • MRD minimal residual disease
  • the CD38-binding fusion protein is administered at 0.5-4 mg/kg (e.g., 0.5-4, 0.5-3.5, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1, 1-4, 1- 3.5, 1-3, 1-2.5, 1-2, 1-1.5, 1.5-4, 1.4-3.5, 1.5-3, 1.5-2.5, 1.5-2, 2-4, 2-3.5, 2-3, 2-2.5, 2.5-4, 2.5- 3.5, 2.5-3, 3-4, 3-3.5, or 3.5-4 mg/kg) of the subject.
  • 0.5-4 mg/kg e.g., 0.5-4, 0.5-3.5, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1, 1-4, 1- 3.5, 1-3, 1-2.5, 1-2, 1-1.5, 1.5-4, 1.4-3.5, 1.5-3, 1.5-2.5, 1.5-2, 2-4, 2-3.5, 2-3, 2-2.5, 2.5-4, 2.5- 3.5, 2.5-3, 3-4, 3-3.5, or 3.5-4 mg/kg
  • the CD38-binding fusion protein in a method described herein, is administered at 0.75-3 mg/kg (e.g., 0.75- 3, 1-3, 1.2-2.8, 1.4-2.6, 1.6-2.4, 1.8-2.2, or 1.9-2.1 mg/kg) of the subject. In some embodiments, in a method described herein, the CD38-binding fusion protein is administered at about 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, or 4 mg/kg of the subject. In some embodiments, in a method described herein, the CD38-binding fusion protein is administered at about 1 mg/kg of the subject.
  • the CD38-binding fusion protein is administered at a dose of 50-250 mg (e.g., 50-250, 50-200, 50-150, 50-100, 60-250, 60-200, 60-150, 60-100, 100-250, 100-200, 100-150, 150-250, 150-200, or 200-250 mg) to the subject regardless of the subject’s weight.
  • the CD38-binding fusion protein is administered at a dose of 60-240 mg (e.g., 60-240, 80-240, 100-200, or 120-160 mg) to the subject regardless of the subject’s weight.
  • the CD38-binding fusion protein in a method described herein, is administered at a dose of about 60 mg, 80 mg, 120 mg, or 240 mg to the subject regardless of the subject’s weight. In some embodiments, in a method described herein, the CD38-binding fusion protein is administered at a dose of about 80 mg to the subject regardless of the subject’s weight.
  • the CD38-binding fusion protein is administered at 0.75-3 mg/kg (e.g., about 0.75, 1, 1.5, 2, 2.5, or 3 mg/kg) of the subject or at a dose of 60-240 mg (e.g., about 60 80, 120, or 240 mg regardless of the subject’s weight) according to treatment cycles (e.g., 4-week (i.e., 28-day) treatment cycles) during a period of administration (e.g., any one of the period of administration described herein).
  • treatment cycles e.g., 4-week (i.e., 28-day) treatment cycles
  • the CD38-binding fusion protein is administered at 0.75-3 mg/kg (e.g., about 0.751, 1.5, 2, 2.5, or 3 mg/kg) of the subject or at a dose of 60-240 mg (e.g., about 60, 80, 120, or 240 mg regardless of the subject’s weight) once in each 4-week treatment cycle (e.g., on day 1 of each treatment cycle).
  • the CD38-binding fusion protein is administered intravenously (e.g., via intravenous injection or infusion).
  • the subject is administered the second anti-CD38 antibody (e.g., daratumumab, e.g., according to any known dose and dosing regimen for daratumumab).
  • the second anti-CD38 antibody e.g., daratumumab
  • the second anti-CD38 antibody is administered according to 4-week or 3-week treatment cycles.
  • the subject in a method described herein, is administered 1500-2000 mg (e.g., 1500-2000, 1500-1900, 1500-1800, 1500-1700, 1500-1600, 1600-2000, 1600-1900, 1600-1800, 1600-1700, 1700-2000, 1700-1900, 1700-1800, 1800- 2000, 1800-1900, or 1900-2000 mg) of the second anti-CD38 antibody (e.g., daratumumab) regardless of the subject’s weight according to 4-week or 3-week treatment cycles.
  • the second anti-CD38 antibody e.g., daratumumab
  • the subject in a method described herein, is administered about 1800 mg of the second anti-CD38 antibody (e.g., daratumumab) regardless of the subject’s weight once a week for two 4-week treatment cycles (cycles 1-2) and once every two weeks for the next four 4-week treatment cycles (cycles 3-6).
  • the subject following the 4- week treatment cycles, is administered about 1800 mg of the second anti-CD38 antibody (e.g., daratumumab) regardless of the subject’s weight once every 4 weeks thereafter during a period of administration.
  • the subject in a method described herein, is administered about 1800 mg of the second anti-CD38 antibody (e.g., daratumumab) regardless of the subject’s weight once a week for three 4-week treatment cycles (cycles 1-3) and once every three weeks for the next five 4-week treatment cycles (cycles 4-8).
  • the subject following the 4- week treatment cycles, is administered about 1800 mg of the second anti-CD38 antibody (e.g., daratumumab) regardless of the subject’s weight once every 4 weeks for eight
  • the subject is administered about 1800 mg of the second anti-CD38 antibody (e.g., daratumumab) regardless of the subject’s weight once every 4 weeks thereafter during a period of administration.
  • the second anti-CD38 antibody e.g., daratumumab
  • the methods described herein comprise administering to a subject having multiple myeloma (i) 60-240 mg of the CD38-binding fusion protein once every
  • the CD38-binding fusion protein comprises: a first anti-CD38 antibody comprising a heavy chain variable region of SEQ ID NO: 7 and a light chain variable region of SEQ ID NO: 8; and an attenuated interferon alpha- 2b comprising an amino acid sequence of SEQ ID NO: 12.
  • the methods described herein comprise administering to a subject having multiple myeloma (i) 60-240 mg of the CD38-binding fusion once every 4- week cycle; (ii) 1800 mg of daratumumab once a week during a first and a second 4- week cycle; (iii) 1800 mg of daratumumab once every two weeks during a third, a fourth, a fifth and a sixth 4- week cycle; and (iv) 1800 mg of daratumumab once every four weeks during the remaining 4-week cycles of treatment.
  • the CD38-binding fusion protein comprises: a first anti-CD38 antibody comprising a heavy chain variable region of SEQ ID NO: 7 and a light chain variable region of SEQ ID NO: 8; and an attenuated interferon alpha-2b comprising an amino acid sequence of SEQ ID NO: 12.
  • the methods described herein comprise administering to a subject having multiple myeloma (i) 60 mg of the CD38-binding fusion protein once every 4- week cycle; (ii) 1800 mg of daratumumab once a week during a first and a second 4-week cycle; (iii) 1800 mg of daratumumab once every two weeks during a third, a fourth, a fifth and a sixth 4-week cycle; and (iv) 1800 mg of daratumumab once every four weeks during the remaining 4-week cycles of treatment.
  • the methods described herein comprise administering to a subject having multiple myeloma (i) 80 mg of the CD38-binding fusion protein once every 4- week cycle; (ii) 1800 mg of daratumumab once a week during a first and a second 4-week cycle; (iii) 1800 mg of daratumumab once every two weeks during a third, a fourth, a fifth and a sixth 4-week cycle; and (iv) 1800 mg of daratumumab once every four weeks during the remaining 4-week cycles of treatment.
  • the methods described herein comprise administering to a subject having multiple myeloma (i) 120 mg of the CD38-binding fusion protein once every 4- week cycle; (ii) 1800 mg of daratumumab once a week during a first and a second 4-week cycle; (iii) 1800 mg of daratumumab once every two weeks during a third, a fourth, a fifth and a sixth 4-week cycle; and (iv) 1800 mg of daratumumab once every four weeks during the remaining 4-week cycles of treatment.
  • the methods described herein comprise administering to a subject having multiple myeloma: (i) 240 mg of the CD38-binding fusion protein once every 4- week cycle; (ii) 1800 mg of daratumumab once a week during a first and a second 4-week cycle; (iii) 1800 mg of daratumumab once every two weeks during a third, a fourth, a fifth and a sixth 4- week cycle; and (iv) 1800 mg of daratumumab once every four weeks during the remaining 4-week cycles of treatment.
  • the method comprises administering to the subject the CD38- binding fusion protein on day 1 of every 4-week cycle. In some embodiments, the method comprises administering daratumumab to the subject on days 1, 8, 15 and 22 during the first and the second 4-week cycle; on days 1 and 15 during the third, the fourth, the fifth and the sixth 4-week cycle; and day 1 during the remaining 4-week cycle of treatment.
  • the second anti-CD38 antibody e.g., daratumumab
  • the second anti-CD38 antibody is administered subcutaneously (e.g., via subcutaneous injection).
  • a method described herein comprises administering to the subject the CD38-binding fusion protein, the second anti-CD38 antibody (e.g., daratumumab), and additionally a proteasome inhibitor (e.g., bortezomib or carfilzomib).
  • a method described herein comprises administering to the subject the CD38- binding fusion protein and the second anti-CD38 antibody (e.g., daratumumab), wherein the subject is receiving or has received treatment with a proteasome inhibitor (e.g., bortezomib or carfilzomib).
  • the proteasome inhibitor administered to the subject is carfilzomib.
  • carfilzomib is administered according to any known dose and dosing regimen for carfilzomib.
  • carfilzomib is administered at a dose based on the subject’s body surface area.
  • bortezomib is administered at a dose of 10-30 mg/m 2 (e.g., 10-30, 10-25, 10-20, 10-15, 15-30, 15-25, 15-20, 20-30, 20-25, or 25-30 mg/m 2 ).
  • carfilzomib in a method described herein, is administered at a dose of about 10, 15, 20, 25, 30 mg/m 2 . In some embodiments, in a method described herein, carfilzomib is administered at a dose of up to 70 mg/m 2 (e.g., up to 70, up to 60, or up to 50 mg/m 2 ). In some embodiments, in a method described herein, carfilzomib is administered at a dose of about 70 mg/m 2 .
  • carfilzomib in a method described herein, is administered at a dose of about 20 mg/m 2 on day 1 of cycle 1 (i.e., the first 4-week treatment cycle during a period of administration), and at a dose of up to 70 mg/m 2 on days 8 and 15 for remaining 4-week treatment cycles during a period of administration.
  • carfilzomib in a method described herein, is administered intravenously (e.g., intravenous injection or infusion).
  • the proteasome inhibitor administered to the subject is bortezomib.
  • bortezomib is administered according to any known dose and dosing regimen for bortezomib.
  • bortezomib is administered at a dose based on the subject’s body surface area.
  • bortezomib is administered at a dose of 1-1.5 mg/m 2 (e.g., 1-1.5, 1-1.4, 1-1.3, 1-1.2, 1-1.1, 1.1-1.5, 1.1-1.4, 1.1-1.3, 1.1- 1.2, 1.2-1.5, 1.2-1.4, 1.2-1.3, 1.3-1.5, 1.3-1.4, or 1.4-1.5 mg/m 2 ). In some embodiments, in a method described herein, bortezomib is administered at a dose of about 1, 1.1, 1.2, 1.3, 1.4, or 1.5 mg/m 2 .
  • bortezomib in a method described herein, is administered at a dose of about 1.3 mg/m 2 on days 1, 4, 8, and 11 for eight 3-week (i.e., 21 days) treatment cycles during a period of administration. In some embodiments, in a method described herein, bortezomib is administered subcutaneously (e.g., via subcutaneous injection).
  • a method described herein comprises administering to the subject the CD38-binding fusion protein, the second anti-CD38 antibody (e.g., daratumumab), and additionally an immunomodulatory drug (e.g., pomalidomide or lenalidomide).
  • a method described herein comprises administering to the subject the CD38- binding fusion protein and the second anti-CD38 antibody (e.g., daratumumab), wherein the subject is receiving or has received treatment with an immunomodulatory drug (e.g., pomalidomide or lenalidomide).
  • the immunomodulatory drug administered to the subject is pomalidomide (e.g., according to any known dose and dosing regimen for pomalidomide).
  • the subject in a method described herein, is administered 2-6 mg (e.g., 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, or 5-6 mg) of pomalidomide daily.
  • the subject in a method described herein, the subject is administered 2, 3, 4, 5, or 6 mg of pomalidomide daily.
  • the subject is administered 4 mg of pomalidomide daily for the first 21 days of each 4-week treatment cycle during a period of administration.
  • pomalidomide is administered orally (e.g., as a capsule).
  • the immunomodulatory drug administered to the subject is lenalidomide (e.g., according to any known dose and dosing regimen for lenalidomide).
  • the subject is administered 5-15 mg (e.g., 5-15, 5-12, 5-9, 5-6, 8-15, 8-12, 8-9, 9-15, 9-12, or 12-15 mg) of lenalidomide daily.
  • the subject is administered about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mg of lenalidomide daily.
  • the subject in a method described herein, is administered 10 mg of lenalidomide daily for 28 days of each 4-week treatment cycle during a period of administration (i.e., lenalidomide is administered every day of each 4-week treatment cycle).
  • lenalidomide in a method described herein, lenalidomide is administered orally (e.g., as a capsule).
  • a method of treating a CD38-expressing cancer described herein comprises administering, during a period of administration, to a subject in need thereof a CD38-binding fusion protein described herein, daratumumab, and pomalidomide, wherein the CD38-binding fusion protein is administered (e.g., via intravenous infusion) at a dose of 60- 240 mg (e.g., about 60, 80, 120, or 240 mg) on day 1 of each 4-week treatment cycle, wherein daratumumab is administered (e.g., via subcutaneous injection) at a dose of about 1800 mg once a week for two 4-week treatment cycles and once every two weeks for the next four 4- week treatment cycles, followed by administration of 1800 mg of daratumumab once every four weeks thereafter, and wherein pomalidomide is administered (e.g., orally as a capsule) at a dose of 4 mg daily for the first 21 days of each 4-week treatment cycle.
  • the CD38-binding fusion protein is administered (
  • a method of treating a CD38-expressing cancer described herein comprises administering to a subject in need thereof a CD38-binding fusion protein described herein, daratumumab, and pomalidomide, wherein the CD38-binding fusion protein is administered (e.g., via intravenous infusion) at a dose of 60-240 mg (e.g., about 60, 80, 120, or 240 mg) on day 1 of each 4-week treatment cycle, wherein daratumumab is administered (e.g., via subcutaneous injection) at a dose of about 1800 mg once a week for two 4-week treatment cycles, once every two weeks for the next four 4-week treatment cycles, followed by once every four weeks thereafter, and wherein pomalidomide is administered (e.g., orally as a capsule) at a dose of 2-4 mg daily for the first 21 days of each 4-week treatment cycle.
  • the CD38-binding fusion protein is administered (e.g., via intravenous infusion) at a dose of 60-
  • a method of treating a CD38-expressing cancer described herein comprises administering to a subject in need thereof a CD38-binding fusion protein described herein, daratumumab, and pomalidomide, wherein the CD38-binding fusion protein is administered (e.g., via intravenous infusion) at a dose of 60-240 mg (e.g., about 60, 80, 120, or 240 mg) on day 1 of each 4-week treatment cycle, wherein daratumumab is administered (e.g., via subcutaneous injection) at a dose of about 1800 mg once a week for two 4-week treatment cycles, once every two weeks for the next four 4-week treatment cycles, followed by once every four weeks thereafter, and wherein pomalidomide is administered (e.g., orally as a capsule) at a dose of 2 mg daily for the first 21 days of each 4-week treatment cycle.
  • the CD38-binding fusion protein is administered (e.g., via intravenous infusion) at a dose of 60-240
  • a method of treating a CD38-expressing cancer described herein comprises administering to a subject in need thereof a CD38-binding fusion protein described herein, daratumumab, and pomalidomide, wherein the CD38-binding fusion protein is administered (e.g., via intravenous infusion) at a dose of 60-240 mg (e.g., about 60, 80, 120, or 240 mg) on day 1 of each 4- week treatment cycle, wherein daratumumab is administered (e.g., via subcutaneous injection) at a dose of about 1800 mg once a week for two 4-week treatment cycles, once every two weeks for the next four 4-week treatment cycles, followed by once every four weeks thereafter, and wherein pomalidomide is administered (e.g., orally as a capsule) at a dose of 3 mg daily for the first 21 days of each 4-week treatment cycle.
  • the CD38-binding fusion protein is administered (e.g., via intravenous infusion) at a dose of 60-240
  • the method comprising administering 2-4 mg of pomalidomide for up to the first 21 days of each 4-week treatment cycle depending on patient response (e.g., patient adverse side effects).
  • administration of pomalidomide may be discontinued (e.g., for that cycle) or adjusted (e.g., decrease in dosing amount or frequency) at a day earlier than day 21 in response to adverse side effects.
  • a method of treating a CD38-expressing cancer described herein comprises administeringto a subject in need thereof a CD38-binding fusion protein described herein, daratumumab, and carfilzomib, wherein the CD38-binding fusion protein is administered (e.g., via intravenous infusion) at a dose of 80-240 mg (e.g., about 80, 120, or 240 mg) on day 1 of each 4-week treatment cycle, wherein daratumumab is administered (e.g., via subcutaneous injection) at a dose of about 1800 mg once a week for two 4-week treatment cycles and once every two weeks for the next four 4-week treatment cycles, followed by administration of 1800 mg of daratumumab once every four weeks thereafter, and wherein carfilzomib is administered is administered intravenously (e.g., intravenous injection or infusion) at a dose of 20 mg/m2 on day 1 of the first four- week treatment cycle, and at a dose of up to 70
  • the subject in any one of the methods described herein, is receiving or has received treatment with one or more of methylprednisolone, dexamethasone, acetaminophen, and diphenhydramine.
  • the CD38-binding fusion protein is formulated in a composition for administration.
  • a composition comprising the CD38-binding fusion protein used in a method described herein comprises a buffer (e.g., a histidine/histidine-HCl buffer), a tonicity agent (e.g., arginine- HCL), a stabilizer (e.g., sucrose), and a surfactant (e.g., polysorbate such as polysorbate 80).
  • a buffer e.g., a histidine/histidine-HCl buffer
  • a tonicity agent e.g., arginine- HCL
  • a stabilizer e.g., sucrose
  • a surfactant e.g., polysorbate such as polysorbate 80.
  • a composition described herein has a pH between 6.1-7.1 (e.g., 6.6) and comprises a CD38-binding fusion protein at a concentration of 8-12 mg/mL (e.g., 10 mg/ml), histidine/histidine-HCl at a concentration of 40-60 mM (e.g., 50 mM), arginine-HCL at a concentration of 75-125 mM (e.g., 100 mM), sucrose at a concentration of 30-80 mg/ml (e.g., 50 mg/ml), and polysorbate 80 at a 0.1-0.3 mg/ml (e.g., 0.2 mg/ml).
  • a CD38-binding fusion protein at a concentration of 8-12 mg/mL (e.g., 10 mg/ml)
  • histidine/histidine-HCl at a concentration of 40-60 mM (e.g., 50 mM)
  • arginine-HCL at a concentration
  • a composition comprising the CD38-binding fusion protein used in a method described herein comprises a CD38-binding fusion protein at a concentration that does not exceed 100 mg/ml. In some embodiments, a composition comprising the CD38- binding fusion protein used in a method described herein comprises a CD38-binding fusion protein at a concentration of 8-12 mg/ml.
  • a composition comprising the CD38- binding fusion protein used in a method described herein may comprise a CD38-binding fusion protein at a concentration of 8-12 mg/ml, 8-11.5 mg/ml, 8-11 mg/ml, 8-10.5 mg/ml, 8-10 mg/ml, 8-9.5 mg/ml, 8-9 mg/ml, 8-8.5 mg/ml, 8.5-12 mg/ml, 8.5-11.5 mg/ml, 8.5-11 mg/ml,
  • 9.5-10.5 mg/ml 9.5-10 mg/ml, 10-12 mg/ml, 10-11.5 mg/ml, 10-11 mg/ml, 10-10.5 mg/ml,
  • a composition comprising the CD38-binding fusion protein used in a method described herein comprises a CD38-binding fusion protein at a concentration of about 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, or 12 mg/ml.
  • a composition comprising the CD38- binding fusion protein used in a method described herein comprises a CD38-binding fusion protein at a concentration of about 10 mg/ml.
  • a composition comprising the CD38-binding fusion protein used in a method described herein has a pH of 5.5-7.5.
  • a composition comprising the CD38-binding fusion protein used in a method described herein may have a pH of 5.5-7.5, 5.5- 7, 5.5-6.5, 5.5-6, 6-7.5, 6-7, 6-6.5, 6.5-7.5, 6.5-7, or 7-7.5.
  • a composition described herein has a pH of about 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, or 7.5.
  • a composition comprising the CD38-binding fusion protein used in a method described herein has a pH of about 6.1-7.1 (e.g., 6.1-7.1, 6.2-7, 6.3-6.9, 6.4-6.8, or 6.5-6.7). In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein has a pH of about 6.6.
  • a composition comprising the CD38-binding fusion protein used in a method as described herein further comprises a buffer (e.g., a histidine/histidine-HCl buffer), a tonicity agent (e.g., arginine-HCL), a stabilizer (e.g., sucrose), and a surfactant (e.g., polysorbate such as polysorbate 80).
  • a buffer e.g., a histidine/histidine-HCl buffer
  • a tonicity agent e.g., arginine-HCL
  • a stabilizer e.g., sucrose
  • a surfactant e.g., polysorbate such as polysorbate 80.
  • a composition comprising the CD38-binding fusion protein used in a method described herein comprises a buffer comprising histidine and histidine-HCL.
  • the histidine and histidine-HCL balance results in a final histidine concentration in the composition of 10-120 mM (e.g., 10-120 mM, 20-110 mM, 30-100 mM, 40-90 mM, 50-80 mM, or 60-70 mM).
  • the histidine and histidine-HCL balance results in a final histidine concentration in the composition of 12.5-107.5 mM.
  • the histidine and histidine-HCL balance results in a final histidine concentration in the composition of 15-50 mM (e.g., about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, or about 50 mM).
  • 15-50 mM e.g., about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, or about 50 mM.
  • the histidine and histidine-HCL balance results in a final histidine concentration in the composition of about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,
  • the relative amount of histidine and histidine-HCL may be adjusted, e.g., to achieve a desired pH, while maintaining the histidine concentration in the composition, as described herein.
  • the histidine and histidine-HCL balance results in a final histidine concentration in the composition of about 15 mM (e.g., when the composition comprises a buffer comprising histidine at a concentration of 7.5 mM and histidine-HCL at a concentration of 7.5 mM).
  • the histidine and histidine-HCL balance results in a final histidine concentration in the composition of about 50 mM (e.g., when the composition comprises a buffer comprising histidine at a concentration of 40 mM and histidine-HCL at a concentration of 10 mM).
  • a composition comprising the CD38-binding fusion protein used in a method described herein comprises a tonicity agent comprising arginine-HCL.
  • a composition comprising the CD38-binding fusion protein used in a method described herein comprises arginine-HCL at a concentration of 50-125 mM (e.g., 50-125 mM, 60-120 mM, 70-110 mM, or 80-100 mM, 75-125 mM, 95-105 mM, or 97.5-102.5 mM).
  • a composition comprising the CD38-binding fusion protein used in a method described herein comprises arginine-HCL at a concentration of about 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, 115 mM, or 120 mM.
  • a composition comprising the CD38- binding fusion protein used in a method described herein comprises arginine-HCL at a concentration of about 100 mM.
  • a composition comprising the CD38-binding fusion protein used in a method described herein comprises a stabilizer.
  • the stabilizer is a sugar.
  • the stabilizer is sucrose.
  • a composition comprising the CD38-binding fusion protein used in a method described herein comprises sucrose at a concentration of 3-10 % w/v (equivalent to 30-100 mg/ml).
  • a composition described herein may comprise sucrose at a concentration of 3-10 % w/v, 3-9 % w/v, 3-8 % w/v, 3-7 % w/v, 3-6 % w/v, 3-5 % w/v, 3-4 % w/v, 3-10 % w/v, 3-9 % w/v, 3-8 % w/v, 3-7 % w/v, 3-6 % w/v, 3-5 % w/v, 3-4 % w/v, 4-10 % w/v, 4-9 % w/v, 4-8 % w/v, 4-7 % w/v, 4-6 % w/v, 4-5 % w/v, 5-10 % w/v, 5-9 % w/v, 5-8 % w/v, 5-7 % w/v, 5-6 % w/v, 6-10 % w/v, 6-9 w/
  • a composition comprising the CD38-binding fusion protein used in a method described herein comprises sucrose at a concentration of about 3% w/v (equivalent to 30 mg/mL), 3.5% w/v (equivalent to 35 mg/mL), 4% w/v (equivalent to 40 mg/mL), 4.5% w/v (equivalent to 45 mg/mL), 5% w/v (equivalent to 50 mg/mL), 5.5% w/v (equivalent to 55 mg/mL), 6% w/v (equivalent to 60 mg/mL), 6.5% w/v (equivalent to 65 mg/mL), 7% w/v (equivalent to 70 mg/mL), 7.5% w/v (equivalent to 75 mg/mL), 8% w/v (equivalent to 80 mg/mL), 8.5% w/v (equivalent to 85 mg/mL), 9w/v (equivalent to 90 mg/mL),
  • a composition comprising the CD38-binding fusion protein used in a method described herein comprises sucrose at a concentration of about 4%-8% w/v (equivalent to 40-80 mg/mL). In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises sucrose at a concentration of about 4%-7% w/v (equivalent to 40-70 mg/mL). In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises sucrose at a concentration of about 4%- 6% w/v (equivalent to 40-60 mg/mL).
  • a composition comprising the CD38-binding fusion protein used in a method described herein comprises sucrose at a concentration of about 4.5%-5.5% w/v (equivalent to 45-55 mg/mL). In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises sucrose at a concentration of about 4% w/v, 5% w/v, 6% w/v, 7% w/v, or 8 % w/v (equivalent to 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml or 80 mg/ml, respectively). In some embodiments, a composition comprising the CD38-binding fusion protein used in a method described herein comprises sucrose at a concentration of about 5% w/v (equivalent to 50 mg/ml).
  • a composition comprising the CD38-binding fusion protein used in a method described herein comprises a surfactant.
  • the surfactant is a polysorbate.
  • the surfactant is a polysorbate 80 (PS80).
  • a composition comprising the CD38-binding fusion protein used in a method described herein comprises PS80 at a concentration of 0.005-0.03 % w/v (equivalent to 0.05- 0.3 mg/ml).
  • a composition comprising the CD38-binding fusion protein used in a method described herein may comprise PS80 at a concentration of 0.005-0.03 % w/v, 0.005- 0.025 % w/v, 0.005-0.02 % w/v, 0.005-0.015 % w/v, 0.005-0.01% w/v, 0.01-0.03 % w/v, 0.01- 0.025 % w/v, 0.01-0.02 % w/v, 0.01-0.015 % w/v, 0.015-0.03 % w/v, 0.015-0.025 % w/v, 0.015-0.02 % w/v, 0.02-0.03 % w/v, 0.02-0.025 % w/v, 0.02-0.03 % w/v, 0.02-0.025 % w/v, 0.02-0.03 % w/v, 0.02-0.025 % w/v, 0.0
  • a composition comprising the CD38-binding fusion protein used in a method described herein comprises PS 80 at a concentration of about 0.007% w/v (equivalent to 0.07 mg/mL), 0.008% w/v (equivalent to 0.08 mg/mL), 0.009% w/v (equivalent to 0.09 mg/mL), 0.01% w/v (equivalent to 0.1 mg/mL), 0.011% w/v (equivalent to 0.11 mg/mL), 0.012% w/v (equivalent to 0.12 mg/mL), 0.013% w/v (equivalent to 0.13 mg/mL), 0.014% w/v (equivalent to 0.14 mg/mL), 0.015% w/v (equivalent to 0.15 mg/mL), 0.016% w/v (equivalent to 0.16 mg/mL), 0.017% w/v (equivalent to 0.17 mg/mL), 0.018% w/v (equi
  • a composition described herein comprises PS 80 at a concentration of about 0.01%-0.03% w/v (equivalent to 0.1-0.3 mg/mL).
  • a composition comprising the CD38-binding fusion protein used in a method described herein comprises PS80 at a concentration of about 0.015%-0.025% w/v (equivalent to 0.15-0.25 mg/mL).
  • a composition comprising the CD38-binding fusion protein used in a method described herein comprises PS 80 at a concentration of about 0.02% w/v (equivalent to 0.2 mg/ml).
  • a composition comprising the CD38-binding fusion protein used in a method described herein comprises a CD38-binding fusion protein (e.g., a CD38-binding fusion protein as provided in Table 1) at a concentration of 8.5-11.5 mg/ml (e.g., 10 mg/ml), histidine (e.g., composed of histidine and histidine-HCL) at a concentration of 15-60 mM (e.g., 15 mM, 20 mM, 30 mM, 40 mM, or 50 mM), arginine-HCL at a concentration of 80-120 mM (e.g., 100 mM), sucrose at a concentration of 3-8% w/v (e.g., 5% w/v), and PS80 at a concentration of 0.01-0.03% w/v (e.g., 0.02% w/v), and wherein the composition is at a pH of 5.5-7.5 (e.g.,
  • a composition comprising the CD38-binding fusion protein used in a method described herein comprises a CD38-binding fusion protein (e.g., a CD38-binding fusion protein as provided in Table 1) at a concentration of 10 mg/ml, histidine (e.g., composed of histidine and histidine-HCL) at a concentration of 50 mM, arginine-HCL at a concentration of 100 mM, sucrose at a concentration of 5% w/v, and PS80 at a concentration of 0.02% w/v, and wherein the composition is at a pH of 6.6.
  • the CD38-binding fusion protein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
  • a composition comprising the CD38-binding fusion protein used in a method described herein comprises a CD38-binding fusion protein (e.g., a CD38-binding fusion protein as provided in Table 1) at a concentration of 10 mg/ml, histidine (e.g., composed of histidine and histidine-HCL) at a concentration of 15 mM, arginine-HCL at a concentration of 100 mM, sucrose at a concentration of 5% w/v, and PS80 at a concentration of 0.02% w/v, and wherein the composition is at a pH of 6.
  • the CD38-binding fusion protein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
  • a composition comprising the CD38-binding fusion protein used in a method described herein is an aqueous solution.
  • a composition described herein (e.g., in a form of aqueous solution or in lyophilized form) is stored in dosage unit form.
  • a lyophilized form of a composition described herein is stored for at least 2 months, at least 4 months, at least 6 months, at least 1 year, at least 2 years, or at least 3 years.
  • a composition described herein (e.g., in a form of aqueous solution or in lyophilized form) is stored frozen.
  • a method described herein is effective in treating a cancer in a patient. Treating may include, for example, inhibiting or reducing proliferation of CD38- positive cells in the cancer and/or inducing apoptosis of CD38-positive cells in the cancer.
  • the terms “subject” and “patient” are used interchangeably and include any mammals, including companion and farm mammals, as well as rodents, including mice, rabbits, and rats, and other rodents. Non-human primates, such as Cynomolgus monkeys, are more preferred, and human beings are highly preferred.
  • the subject is a human.
  • the subject is a human adult (e.g., more than 18 years old, including 18 years old).
  • the subject is a non-adult human (e.g., less than 18 years old).
  • treatment refers to obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof or reducing the likelihood of a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse effect attributable to the disease.
  • Treatment covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development or progression; and (c) relieving the disease, i.e., causing regression of the disease and/or relieving one or more disease symptoms. “Treatment” is also meant to encompass delivery of an agent in order to provide for a pharmacologic effect, even in the absence of a disease or condition.
  • the cancer is a CD38-expressing cancer. In some embodiments, the cancer is not a CD38-expressing cancer. In some embodiments, the cancer is multiple myeloma (MM). In some embodiments, the subject has not received any prior lines of MM therapy. In some embodiments, the subject has not received any prior anti-CD38-based therapies.
  • MM multiple myeloma
  • the subject has undergone standard of care (SOC) treatment for MM.
  • subject has undergone autologous stem cell transplant (ASCT) and is responsive to such treatment.
  • SOC standard of care
  • ASCT autologous stem cell transplant
  • the subject suffers from Relapsed or Refractory Multiple Myeloma (RRMM).
  • RRMM Refractory Multiple Myeloma
  • the subject with RRMM has failed treatment with, is intolerant to, or is not a candidate for available therapies that are known to confer clinical benefit in RRMM patients.
  • the RRMM subject has received at least three prior lines of MM therapy and is refractory or intolerant to at least one proteasome inhibitor (PI) based therapy, at least one immunomodulatory drug (e.g., an IMiD) based therapy, and optionally at least one steroid-based therapy.
  • the prior lines of MM therapy can include one or more anti-CD38 therapy, including but not limited to daratumumab.
  • the RRMM subject has received at least three prior lines of MM therapy including daratumumab, and is relapsed or refractory to daratumumab, at least one proteasome inhibitor (PI) based therapy, at least one immunomodulatory drug (e.g., an IMiD) based therapy, and optionally at least one steroid-based therapy.
  • MM therapy including daratumumab, and is relapsed or refractory to daratumumab, at least one proteasome inhibitor (PI) based therapy, at least one immunomodulatory drug (e.g., an IMiD) based therapy, and optionally at least one steroid-based therapy.
  • PI proteasome inhibitor
  • IMiD immunomodulatory drug
  • the RRMM subject has received at least three prior lines of MM therapy, and is refractory to at least one proteasome inhibitor (PI) based therapy, at least one immunomodulatory drug (e.g., an IMiD) based therapy, and optionally at least one steroid- based therapy.
  • the prior lines of MM therapy do not include any anti-CD38 therapy.
  • the RRMM subject has received at least two prior lines of MM therapy wherein one of these two lines includes a combination of a PI based therapy and an immunomodulatory drug (e.g., an IMiD) based therapy, and the subject is refractory to at least one PI based therapy, at least one immunomodulatory (e.g., IMiD) based therapy, and optionally at least one steroid-based therapy.
  • a PI based therapy e.g., an IMiD
  • One or more of the prior lines of MM therapy can include an anti-CD38 therapy, including but not limited to daratumumab.
  • the RRMM subject has received at least two prior lines of MM therapy, wherein one of these two lines includes a combination of a PI based therapy and an immunomodulatory drug (e.g., IMiD) based therapy, and the other line includes daratumumab, and the subject is relapsed or refractory to daratumumab, at least one PI based therapy, at least one immunomodulatory drug (e.g., IMiD) based therapy, and optionally at least one steroid- based therapy.
  • IMiD immunomodulatory drug
  • the RRMM subject has received at least two prior lines of MM therapy wherein one of these two lines includes a combination of a PI based therapy and an immunomodulatory drug (e.g., IMiD) based therapy, and the subject is refractory to at least one PI based therapy, at least one immunomodulatory drug (e.g., IMiD) based therapy, and optionally at least one steroid-based therapy.
  • the prior lines of MM therapy do not include any anti-CD38 therapy.
  • the RRMM subject has received prior lines of anti-CD38 therapy, including but not limited to daratumumab, and the subject is relapsed or refractory to the anti-CD38 therapy at any time during treatment with the methods described herein.
  • the RRMM subject has received 1-3 (e.g., 1, 2, 3) prior lines of therapy, including at least 1 proteasome inhibitor (PI), 1 immunomodulatory imide drug (e.g., IMiD), and 1 anti-CD38 monoclonal antibody (mAb) drug.
  • PI proteasome inhibitor
  • IMiD immunomodulatory imide drug
  • mAb monoclonal antibody
  • the RRMM subject is refractory to lenalidomide and nonrefractory to anti-CD38 mAbs.
  • the RRMM subject is not refractory to the drugs used in the combination therapy (e.g., but may be refractory to antimyeloma drugs not included in the combination therapy).
  • Example 1 Synergistic effect in tumor inhibition with a combination of CD38-binding fusion protein and daratumumab in mouse model
  • This study aims at evaluating the efficacy of a CD38-binding fusion protein (heavy chain of SEQ ID NO: 13 and light of SEQ ID NO: 10 as set forth in Table 1) alone and in combination with daratumumab in a human multiple myeloma xenograft model using CB.17 SCID female mice.
  • mice Female severe combined immunodeficient mice (Fox Chase SCID®, CB17/Icr- Prkdcscid/IcrlcoCrl, Charles River) were eight weeks old on Day 1 of the study and had a body weight (BW) range of 14.0 to 22.1 g.
  • the animals were fed ad libitum water (reverse osmosis, 1 ppm Cl) and NIH 31 Modified and Irradiated Lab Diet® consisting of 18.0% crude protein, 5.0% crude fat, and 5.0% crude fiber.
  • the mice were housed on irradiated Enrich-o’cobsTM bedding in static microisolators on a 12-hour light cycle at 20-22 °C (68-72 °F) and 40-60% humidity. All studies were performed in compliance with the recommendations of the Guide for Care and Use of Laboratory Animals with respect to restraint, husbandry, surgical procedures, feed and fluid regulation, and veterinary care.
  • NCI-H929 is a differentiated, highly secretory human plasma cell line established from a malignant effusion obtained from a patient with IgAK myeloma. The cells possess a translocated MYC allele, and an activated NRAS allele.
  • NCI-H929 (ATCC® CRL-9068TM) plasma cell myeloma cells were obtained from the American Type Culture Collection, and were maintained at CR Discovery Services as exponentially growing suspension cultures in RPMI-1640 medium supplemented with 20% fetal bovine serum, 2 mM glutamine, 100 units/mL penicillin G sodium, 100 pg/mL streptomycin sulfate, 25 pg/mL gentamicin, and 50 pM P-mercaptoethanol.
  • the tumor cells were grown in tissue culture flasks in a humidified incubator at 37 °C, in an atmosphere of 5% CO2 and 95% air.
  • NCI-H929 tumor cells used for implantation were harvested during log phase growth and resuspended at a concentration of 1 x 10 8 cells/mL in 50% Matrigel (BDBiosciences). Each mouse was injected subcutaneously in the right flank with 1 x 10 7 tumor cells (0.1 mL cell suspension). The tumors were measured with a caliper in two dimensions to monitor size as the mean volume approached the desired 130 to 170 mm 3 range. Tumor size was calculated using the formula:
  • Tumor weight may be estimated with the assumption that 1 mg is equivalent to 1 mm 3 of tumor volume.
  • CD38-binding-attenuated IFN a2b fusion protein CD38-binding-attenuated IFN a2b fusion protein
  • daratumumab a combined solution of CD38-binding fusion protein and daratumumab were stored at 4 °C, protected from light.
  • Group 1 received the PBS vehicle twice weekly for four weeks and served as the benchmark group for tumor engraftment and progression, as well as the control.
  • Group 2 received the CD38-binding fusion protein at 6 pg/animal twice weekly for four weeks.
  • Group 3 received daratumumab at 50 pg/animal twice weekly for four weeks.
  • Group 4 received daratumumab at 100 pg/animal twice weekly for four weeks.
  • Group 5 received daratumumab at 200 pg/animal twice weekly for four weeks.
  • Group 6 received a combined dose of CD38- binding fusion protein at 6 pg/animal and daratumumab at 50 pg/animal twice weekly for four weeks.
  • Group 7 received a combined dose of CD38-binding fusion protein at 6 pg/animal and daratumumab at 100 pg/animal twice weekly for four weeks.
  • Group 8 received a combined dose of CD38-binding fusion protein at 6 pg/animal and daratumumab at 200 pg/animal twice weekly for four weeks.
  • Tumor Growth Delay Endpoint The study endpoint was a tumor volume of 2000 mm 3 or Day 60, whichever came first. The study was ended on Day 59. Each animal was euthanized for tumor progression (TP) when its tumor reached the volume endpoint. The time to endpoint (TTE) for each mouse was calculated with the following equation:
  • TTE (days) [logio (endpoint volume, mm 3 ) - b] / m
  • b is the intercept and m is the slope of the line obtained by linear regression of log- transformed tumor growth data set.
  • the data set is comprised of the first observation that exceeded the study endpoint volume and the three consecutive observations that immediately preceded the attainment of the endpoint volume. Any animal that did not reach endpoint was euthanized at the end of the study and assigned a TTE value equal to the last day of the study (Day 59). In instances in which the log-transformed calculated TTE preceded the day prior to reaching endpoint or exceeded the day of reaching tumor volume endpoint, a linear interpolation was performed to approximate the TTE. Any animal determined to have died from treatment-related (TR) causes was assigned a TTE value equal to the day of death. Any animal that died from non-treatment-related (NTR) causes was excluded from the analysis.
  • TR treatment-related
  • NTR non-treatment-related
  • TTD tumor growth delay
  • MTV Median Tumor Volume
  • Treatment efficacy may also be determined from the tumor volumes of animals remaining in the study on the last day and from the number and magnitude of regression responses.
  • the MTV(n) is defined as the median tumor volume on the final day (Day 60) in the number of evaluable animals remaining, n, whose tumors have not attained the volume endpoint.
  • Treatment may cause partial regression (PR) or complete regression (CR) of the tumor in an animal.
  • PR partial regression
  • CR complete regression
  • the tumor volume is 50% or less of its Day 1 volume for three consecutive measurements during the course of the study, and equal to or greater than 13.5 mm 3 for one or more of these three measurements.
  • CR complete regression
  • the tumor volume is less than 13.5 mm 3 for three consecutive measurements during the study.
  • Any animal with a complete regression (CR) response at the end of the study was additionally classified as a tumor free survivor (TFS). Animals were scored only once during the study for a partial regression (PR) or CR event and only as CR if both PR and CR criteria were satisfied.
  • PR partial regression
  • CR complete regression
  • mice were observed frequently for health and overt signs of any adverse treatment-related (TR) side effects, and noteworthy clinical observations were recorded.
  • Individual body weight loss was monitored per protocol, and any animal whose weight exceeded the limits for acceptable body weight loss was euthanized.
  • Acceptable toxicity was defined as a group mean body weight (BW) loss of less than 20% during the study and not more than one TR death among ten treated animals, or 10%. Any dosing regimen resulting in greater toxicity is considered above the maximum tolerated dose (MTD).
  • a death was to be classified as TR if it was attributable to treatment side effects as evidenced by clinical signs and/or necropsy, or may also be classified as TR if due to unknown causes during the dosing period or within 14 days of the last dose.
  • NTR deaths are further categorized as NTRa (due to accident or human error), NTRm (due to necropsy-confirmed tumor dissemination by invasion or metastasis), and NTRu (due to unknown causes).
  • Prism reports results as non-significant (ns) at P > 0.05, significant (symbolized by “*”) at 0.01 ⁇ P ⁇ 0.05, very significant (“**”) at 0.001 ⁇ P ⁇ 0.01 and extremely significant (“***”) at P ⁇ 0.001. Because statistical tests are tests of significance and do not provide an estimate of the size of the difference between groups, all levels of significance were described as either significant or non-significant.
  • mice models The treatment effects on mice models are summarized in Table 2 below.
  • Table 2 The data shows that, surprisingly, the combination of the CD38-binding fusion protein (6 pg/animal) and daratumumab (50, 100, or 200 pg/animal) achieved synergistic effects in tumor inhibition.
  • Example 2 Efficacy of a combination of CD 38 -binding fusion protein and daratumumab in human subjects with relapsed or refractory multiple myeloma
  • the safety, tolerability, and efficacy of a combination of a CD38-binding fusion protein (heavy chain of SEQ ID NO: 13 and light of SEQ ID NO: 10 as set forth in Table 1) in combination with daratumumab are evaluated in human subjects with Relapsed or Refractory Multiple Myeloma (RRMM) with at least 2 prior lines of therapy, including at least 1 proteasome inhibitor (PI), 1 immunomodulatory imide drug (e.g., IMiD), and 1 anti-CD38 monoclonal antibody (mAb) drug.
  • PI proteasome inhibitor
  • IMiD immunomodulatory imide drug
  • mAb monoclonal antibody
  • the initial dose level that is evaluated for the CD38-binding fusion protein is 80 mg once every 4 weeks (administered intravenously) based on 4-week treatment cycles (i.e., administered once per 4-week treatment cycle).
  • CD38-binding fusion protein dose of 60 mg, 120 mg, or 240 mg once every 4 weeks can be evaluated depending on the observed toxicity at the initial dose of 120 mg.
  • Daratumumab is also administered via subcutaneous injection according the 4-week treatment cycles at a dose of 1800 mg every week in Cycles 1 and 2, once every 2 weeks in Cycles 3 to 6, and once every 4 weeks thereafter when in combination with the CD38-binding fusion protein.
  • Safety, tolerability, and efficacy of the combination therapy are evaluated and a dose of the CD38-binding fusion protein is selected for further studies.
  • the efficacy of the combination of the CD38-binding fusion protein and daratumumab is compared with treatment with daratumumab alone, a combination of daratumumab SC, bortezomib, and dexamethasone, or a combination of daratumumab, pomalidomide, and dexamethasone.
  • Example 3 Efficacy of triple combinations of CD38-binding fusion protein, daratumumab, and a proteasome inhibitor or an immunomodulatory drug in human subjects with relapsed or refractory multiple myeloma
  • RRMM Relapsed or Refractory Multiple Myeloma
  • Group 1 is administered CD38-binding fusion protein (heavy chain of SEQ ID NO: 13 and light of SEQ ID NO: 10 as set forth in Table 1) in combination with daratumumab, and carfilzomib according to 4-week treatment cycles.
  • CD38-binding fusion protein is administered at a dose of 80, 120, or 240 mg via IV infusion on Day 1 every 28 days.
  • Daratumumab is administered at a dose of 1800 mg via subcutaneous injection on Days 1, 8, 15, and 22 of Cycles 1 and 2 followed by on Days 1 and 15 of Cycles 3-6 and on Day 1 every 28 days thereafter.
  • Carfilzomib is administered intravenously at an initial dose of 20 mg/m 2 on Day 1 of Cycle 1 followed by a target dose of 70 mg/m 2 on Days 8 and 15 of remaining treatment cycle.
  • Group 2 is administered CD38-binding fusion protein (heavy chain of SEQ ID NO: 13 and light of SEQ ID NO: 10 as set forth in Table 1) in combination with daratumumab, and pomalidomide.
  • CD38-binding fusion protein is administered at a dose of 80, 120, or 240 mg via IV infusion on Day 1 every 28 days.
  • Daratumumab is administered at a dose of 1800 mg via subcutaneous injection on Days 1, 8, 15, and 22 of Cycles 1 and 2 followed by on Days 1 and 15 of Cycles 3-6 and on Day 1 every 28 days thereafter.
  • Pomalidomide is administered orally (as capsules) at a dose of 4 mg once daily on Days 1 to 21 in a 28-day (4-week) treatment cycle.
  • Example 4 Efficacy of a combination of CD38-binding fusion protein and daratumumab in human subjects with relapsed or refractory multiple myeloma
  • the CD38-binding fusion protein was evaluated at 80 mg dose administered intravenously once every 4 weeks based on 4-week treatment cycles (i.e., administered once per 4-week treatment cycle).
  • daratumumab was evaluated at 1800 mg dose administered subcutaneously once every week for treatment cycles 1-2, once every 2 weeks for treatment cycles 3-6, and once every 4 weeks for treatment cycles 7 and beyond.
  • the CD38-binding fusion protein was evaluated at 120 mg dose administered intravenously once every 4 weeks based on 4-week treatment cycles (i.e., administered once per 4-week treatment cycle).
  • daratumumab was evaluated at 1800 mg dose administered subcutaneously once every week for treatment cycles 1-2, once every 2 weeks for treatment cycles 3-6, and once every 4 weeks for treatment cycles 7 and beyond.
  • the toxicity endpoint in patients in both groups was defined as follows: patients who experienced dose limiting toxicity (DLT) in cycle 1 in the treatment phase of the study, or patients who completed the cycle 1 dose of the CD38-binding fusion protein and received at least 75% of the planned dose of daratumumab.
  • DLT dose limiting toxicity
  • DLT was defined as any of the following events that was considered by the investigator to be related to the CD38-binding fusion protein administration: Grade 5 adverse event (results in death), hematologic toxicity unrelated to the underlying disease (nonfebrile Grade 4 neutropenia, Grade 4 thrombocytopenia, Grade 3 or more thrombocytopenia with clinically significant bleeding, any other Grade 4 or more hematologic toxicity with the exception of Grade 4 lymphopenia), non-hematologic toxicity of Grade 3 or more unrelated to the underlying disease, and delay in the initiation of Cycle 2 by more than 14 days due to a lack of adequate recovery of treatment-related hematological or nonhematologic toxicities.
  • DLT dose limiting toxicity
  • Cl Cycle 1
  • MR minor response
  • SD stable disease
  • PD progressive disease
  • CD38 is expressed on multiple myeloma cells, as well as a variety of immune cells, particularly upon activation. Activation pathways may be triggered by the attenuated interferon delivery of the CD38-binding fusion protein and the FcyR engagement of daratumumab.
  • NK cells, monocytes, B cells and T cells in whole blood from groups 1 and 2 were sorted and CD38 receptor density was measured across the study time points.
  • CD38 Receptor Density was increased on T cells after dosing (FIG. 4D).
  • One patient in the 120 mg dose group exhibited a robust increase in CD38 receptor density through Day 2.
  • the remaining patients with available data exhibited modest increases immediately after dosing. Data show that receptor density levels returned to baseline on Day 1 of Cycle 2.
  • Percent occupancy of the CD38 receptors was calculated in whole blood lymphocytes post- infusion in the presence of daratumumab. The results demonstrated that nearly all CD38 receptors are occupied by the CD38-binding fusion protein after infusion (FIG. 5). Maximal occupancy was observed in the immediate hours post-dose at both levels of the CD38-binding fusion protein tested, and it stayed bound to available lymphocytic CD38 receptors through day 2. The CD38-binding fusion protein was minimally detected on Day 8 of treatment cycles in peripheral blood.
  • CD38 receptor density does not markedly decrease across all cell types after treatment with the CD38-binding fusion protein and daratumumab. Nearly all available CD38 receptors on peripheral lymphocytes are occupied by the CD38-binding fusion protein through day 2 of evaluated treatment cycles.
  • Example 5 Clinical effects of prior Daratumumab treatment on response to CD38-binding fusion protein treatment

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Abstract

L'invention concerne des méthodes de traitement du cancer (p. ex., un cancer exprimant CD38 tel qu'un myélome multiple) à l'aide d'une protéine de fusion se liant à CD38 comprenant un anticorps anti-CD38 fusionné à une ou plusieurs protéines d'interféron alpha-2b atténuées en combinaison avec un anticorps anti-CD38 supplémentaire (p. ex., du daratumumab), et éventuellement des agents supplémentaires (p. ex., des médicaments immunomodulateurs tels que le lénalidomide ou le pomalidomide, ou des inhibiteurs de protéasome tels que le bortézomib ou le carfilzomib), pour traiter le cancer. Dans certains modes de réalisation, le cancer est un myélome multiple.
PCT/US2023/075591 2022-09-29 2023-09-29 Thérapie combinatoire de protéines de fusion se liant à cd38 WO2024073716A2 (fr)

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