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JP-7855634-B2 - Combination immunotherapy and chemotherapy for the treatment of hematological malignancies

JP7855634B2JP 7855634 B2JP7855634 B2JP 7855634B2JP-7855634-B2

Inventors

  • バーガー マーク

Assignees

  • アクティニウム ファーマシューティカルズ インコーポレイテッド

Dates

Publication Date
20260508
Application Date
20240516
Priority Date
20180108

Claims (11)

  1. A pharmaceutical composition for inhibiting the growth and/or proliferation of CD33-expressing cells in a human subject, which is combined with a combination of four individual chemotherapeutic agents, wherein the pharmaceutical composition comprises an anti-CD33 targeting agent. The four individual chemotherapeutic agents mentioned above are as follows: 3-7 mg of cladribine / body surface area of 1 m² of the subject / 1 day 1-3 g of cytarabine / body surface area of 1 m² of the subject / 1 day, 5-15 mg of mitoxantrone / body surface area of 1 m² of the subject / 1 day, and 100-500 μg of filgrastim or granulocyte colony-stimulating factor / 1 day. Includes, The anti-CD33 targeting agent comprises HuM195 labeled with an effective amount of an alpha-emitting isotope, The cells expressing CD33 include blast cells, and The pharmaceutical composition is characterized in that it is for treating a hematological disease or disorder selected from the group consisting of multiple myeloma, acute myeloid leukemia, myelodysplastic syndrome, and myeloproliferative neoplasm.
  2. The four individual chemotherapeutic agents mentioned above, 5 mg cladribine / body surface area of the subject per 1 m² / 1 day, 2 g cytarabine / body surface area of the subject in 1 m² / 1 day, 10 mg of mitoxantrone / 1 m² of body surface area of the subject / 1 day, and 300 μg of filgrastim / 1 day, The pharmaceutical composition according to claim 1, which is administered as such.
  3. The four individual chemotherapeutic agents mentioned above, Cladribine was administered on days 1, 2, 3, 4, and 5 of the treatment period. Cytarabine was administered on days 1, 2, 3, 4, and 5 of the treatment period. The pharmaceutical composition according to claim 1 or 2, wherein mitoxantrone is administered to the subject on the first, second, and third days of the treatment period, and filgrastim is administered on the zero, first, second, third, fourth, and fifth days of the treatment period.
  4. The pharmaceutical composition according to claim 1, wherein the anti-CD33 targeting agent is administered on any of the following days of the treatment period: days 5 to 30, days 9 to 20, or day 14.
  5. The pharmaceutical composition according to claim 1, wherein the anti-CD33 targeting agent is administered in a protein dose of less than 16 mg/kg of body weight of the target, or less than 10 mg/kg of body weight of the target, or less than 6 mg/kg of body weight of the target, or less than 50 μg/kg of body weight of the target, or less than 20 μg/kg of body weight of the target.
  6. The pharmaceutical composition according to claim 1, wherein the anti-CD33 targeting agent is labeled with 225Ac and administered at a radiation dose of 0.7 to 0.8 μCi/kg of body weight of the target, 0.8 to 0.9 μCi/kg of body weight of the target, or 0.9 to 1.0 μCi/kg of body weight of the target.
  7. A pharmaceutical composition according to claim 1 for treating a hematological disorder or condition selected from the group consisting of acute myeloid leukemia, myelodysplastic syndrome, and myeloproliferative neoplasm.
  8. The pharmaceutical composition according to claim 7, wherein the anti-CD33 targeting agent is labeled with 225Ac and administered at a radiation dose of 0.7 to 0.8 μCi/kg of body weight of the target, 0.8 to 0.9 μCi/kg of body weight of the target, or 0.9 to 1.0 μCi/kg of body weight of the target.
  9. The pharmaceutical composition according to claim 8 for treating relapsed/refractory acute myeloid leukemia in the subject mentioned above.
  10. The pharmaceutical composition according to claim 9, wherein the anti-CD33 targeting agent is labeled with 225Ac and administered at a radiation dose of 0.7 to 0.8 μCi/kg of body weight of the target, 0.8 to 0.9 μCi/kg of body weight of the target, or 0.9 to 1.0 μCi/kg of body weight of the target.
  11. The pharmaceutical composition according to claim 1, wherein the anti-CD33 targeting agent is administered in a single dose.

Description

Cross-reference of related applications This application claims the benefit of the prior U.S. Provisional Application No. 62/614,658, filed on 8 January 2017 under Section 119(e) of the U.S. Patent Act, which is incorporated herein by reference in its entirety. Sequence Listing This application includes a computer-readable sequence listing incorporated herein by reference. 37 The text file “Sequencelisting17046_ST25” submitted via EFS in accordance with CFR 1.52(e)(5) and Rule 13 ter. 1(a) is identical to the sequence listing forming part of this international application. The present invention relates to a method for treating subjects with proliferative disorders by administering immunotherapeutic agents and chemotherapeutic agents against the CD33 epitope, and more specifically, to the administration of anti-CD33 antibodies and CLAG-M chemotherapeutic agents for the treatment of hematological diseases or disorders. Hematological malignancies have historically been treated with high-dose chemotherapy and/or radiation. Current treatment protocols generally include combinations of chemotherapy agents such as vincristine, carmustine, cytarabine, melphalan, cyclophosphamide, daunorubicin, and steroids such as prednisone or dexamethasone. However, such treatments result in low remission rates and poor overall survival for hematological disorders such as acute myeloid leukemia (AML). For example, recent advances using autologous bone marrow transplantation or peripheral blood mononuclear cell transplantation following high-dose chemotherapy have increased the complete remission rate and duration of remission in multiple myeloma (MM). However, evidence of a cure has not been obtained. The effectiveness of these available chemotherapy regimens for MM is limited because MM exhibits a low proliferation rate, acquires multidrug resistance, and has high resistance to apoptosis. MM can account for approximately 1% of all cancers and over 10% of all hematological malignancies. The majority of MM patients relapse within a few years, and in many cases, relapsed patients do not respond to salvage therapy. For more than 90% of MM patients, the disease eventually becomes chemotherapy-resistant. Relapsed/refractory acute myeloid leukemia (RR-AML) in adults presents a particularly challenging treatment challenge. Treatment responses vary due to the use of different salvage chemotherapy regimens aimed at achieving disease remission in order to proceed to stem cell transplantation. While no universally accepted regimen has been established, various regimens such as CLAG-M (cladribine, cytarabine, mitoxantrone, and filgrastim), FLAG (fludarabine, cytarabine, idarubicin, and filgrastim), or MEC (mitoxantrone, etoposide, and cytarabine) have been used. CLAG-M has been shown to achieve a 58% morphological complete response rate in prospective clinical trials for the treatment of RR-AML. A recent retrospective study compared two commonly used regimens for RR-AML: CLAG (cladribine, cytarabine, and filgrastim) and MEC (mitoxantrone, etoposide, and cytarabine). See Price et al., Leukemia Research, vol. 35, issue 3, pages 301-304. The complete response rate was 37.9% for CLAG (n=97) and 23.8% for MEC (n=65) (P=0.048), and the median overall survival was 7.3 months and 4.5 months, respectively (P=0.05). In primary refractory disease, the complete response rate was 45.5% for CLAG and 22.2% for MEC (P=0.09), and the median overall survival was 11 months and 4.5 months, respectively (P=0.07). In patients with relapsed AML, the complete response rate was 36.8% for CLAG and 25.9% for MEC (P=0.35), and the median overall survival was 6.7 months and 6.7 months, respectively (P=0.87). The combination of a purine nucleoside analog (cladribine) and cytarabine increases the intracellular accumulation of Ara-C-5' triphosphate (ara-C TP), which causes cytotoxicity in leukemic blasts. The addition of granulocyte colony-stimulating factor (G-CSF) further enhances the effect of purine nucleoside analogs combined with Ara-C by activating leukemia cells and making them more receptive to chemotherapy. Phenotypic changes that distinguish cancer cells from normal cells originating from the same tissue or cell type are often associated with one or more changes in the expression of specific gene products, including the loss of normal cell surface components or the acquisition of other components (i.e., antigens undetectable in corresponding normal non-cancerous cells). Antigens expressed by cancer cells (i.e., within or on cancer cells) but not by normal cells, or antigens expressed by cancer cells at substantially higher levels than those found in normal cells, are often referred to as “tumor-specific antigens” or “tumor-associated antigens.” Such tumor-specific antigens can serve as markers of tumor phenotype and have been used as targets in cancer immunotherapy. Therefore, a key strategy that can enhance the effectiveness of killing leukemic blasts when adde