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JP-7856702-B2 - Immunomodulation and treatment of solid tumors using antibodies that specifically bind CD38

JP7856702B2JP 7856702 B2JP7856702 B2JP 7856702B2JP-7856702-B2

Inventors

  • アフマディ，タハムタン
  • カズナフ，タイネク
  • ロクホースト，ヘンク エム．
  • マティス，ツナ
  • サセール，エイミー

Assignees

  • ヤンセン バイオテツク，インコーポレーテツド

Dates

Publication Date
20260511
Application Date
20240730
Priority Date
20150624

Claims (20)

  1. A pharmaceutical composition for use in suppressing the activity of immune suppressor cells in patients with cancer, The pharmaceutical composition comprises an antibody that specifically binds to CD38. The aforementioned antibody is of the IgG1 isotype. The aforementioned antibody is a) the heavy chain variable region (VH) amino acid sequence of SEQ ID NO: 4, and b) the light chain variable region (VL) amino acid sequence of SEQ ID NO: 5.
  2. The pharmaceutical composition according to claim 1, wherein the cancer is multiple myeloma.
  3. The pharmaceutical composition according to claim 1 or 2 , wherein the immune suppressor cells include regulatory T cells (Treg).
  4. a) The Treg contains CD3 + CD4 + CD25 + CD127 dim T cells, b) The Treg expresses CD38, c) The function of the Treg is inhibited by killing the Treg, The pharmaceutical composition according to claim 3 , or any combination thereof.
  5. The pharmaceutical composition according to claim 4 , wherein the function of the Treg is inhibited by killing the Treg, and the killing of the Treg is mediated by antibody-dependent cell-mediated cytotoxicity (ADCC).
  6. The pharmaceutical composition according to claim 1 or 2 , wherein the immune suppressor cells include bone marrow-derived suppressor cells (MDSCs).
  7. a) The MDSC contains CD11b + HLADR - CD14 - CD33 + CD15 + cells, b) The MDSC expresses CD38, c) The function of the MDSC is inhibited by killing the MDSC, The pharmaceutical composition according to claim 6 , or any combination thereof.
  8. The pharmaceutical composition according to claim 7 , wherein the function of the MDSC is inhibited by killing the MDSC, and the killing of the MDSC is mediated by ADCC.
  9. The pharmaceutical composition according to claim 1 or 2 , wherein the immune suppressor cells include regulatory B cells (Breg).
  10. a) The Breg contains CD19 + CD24 + CD38 + cells, b) The function of the Breg is inhibited by killing the Breg, The pharmaceutical composition according to claim 9 , which is either a) and b).
  11. The pharmaceutical composition according to claim 10 , wherein the function of the Breg is inhibited by killing the Breg, and the killing of the Breg is mediated by ADCC.
  12. The pharmaceutical composition according to any one of claims 1 to 11 , wherein the immune suppressor cells are present in the bone marrow or peripheral blood.
  13. The pharmaceutical composition according to any one of claims 1 to 12 , wherein the pharmaceutical composition is formulated for intravenous administration.
  14. The pharmaceutical composition according to any one of claims 1 to 12 , further comprising hyaluronidase and formulated for subcutaneous administration.
  15. The pharmaceutical composition according to any one of claims 1 to 14 , wherein the patient is treated with an immune checkpoint inhibitor.
  16. The pharmaceutical composition according to claim 15 , wherein the immune checkpoint inhibitor comprises an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, an anti-LAG3 antibody, an anti-TIM3 antibody, or an anti-CTLA-4 antibody.
  17. The pharmaceutical composition according to claim 16 , wherein the immune checkpoint inhibitor comprises an anti-PD-1 antibody.
  18. The aforementioned anti-PD-1 antibody, a) VH of sequence number 22 and VL of sequence number 23, b) VH of sequence number 24 and VL of sequence number 25, c) VH of SEQ ID NO: 32 and VL of SEQ ID NO: 33, or d) VH of SEQ ID NO: 34 and VL of SEQ ID NO: 35, according to claim 17 .
  19. The pharmaceutical composition according to claim 16 , wherein the immune checkpoint inhibitor comprises an anti-PD-L1 antibody.
  20. The aforementioned anti-PD-L1 antibody, a) VH of sequence number 26 and VL of sequence number 27, b) VH of SEQ ID NO: 28 and VL of SEQ ID NO: 29, or c) VH of SEQ ID NO: 30 and VL of SEQ ID NO: 31, according to claim 19 .

Description

The present invention relates to immunomodulation and treatment methods for solid tumors using antibodies that specifically bind CD38. The immune system is tightly controlled by a network of co-stimulatory and co-inhibitory ligands and receptors. These molecules provide secondary signals to T cell activation, resulting in a balanced network of positive and negative signals that maximizes the immune response to infection and tumors while limiting self-immunity (Wang et al.). (Epub Mar. 7, 2011) J Exp Med 208(3):577-92 , Lepenies et al. , (2008) Endocr Metab Immu ne Disord Drug Targets 8:279-288). Immune checkpoint therapy for treating solid tumors targets co-inhibitory pathways in T cells that promote the antitumor immune response, and includes anti-CTLA-4 and anti-PD-1 antibodies, Y The approval of ERVOY® (ipilimumab), KEYTRUDA® (pembrolizumab), and OPDIVO® (nivolumab) is leading to advances in the clinical care of cancer patients. While anti-PD-1/PD-L1 antibodies have shown favorable clinical responses in patients with multiple solid tumors, their response rates remain considerably low. In patients who had received prior treatment, the rate was approximately 15% to 20% (Swaika et al.). (2015) Mol Immunol doi:10.1016/j. molimm. 2 015.02.009). Natural killer cells (NK), dendritic cells (DC), and effector T cells can elicit a strong antitumor response. However, tumor cells often possess an immunosuppressive microenvironment, which is conducive to the development of immunosuppressive populations of immune cells such as myeloid suppressor cells (MDSCs), regulatory T cells (Treg), or regulatory B cells (Breg). This contributes to tumor immune tolerance and the failure of immunotherapy regimens in cancer patients and experimental tumor models. The median lymphocyte count increased over time in patients treated with DARZALEX™ (daratumumab) at doses of 8 mg/kg (upper line) or 16 mg/kg (lower line), indicating that lymphocyte counts returned to normal after the end of treatment. Study name: SIRIUS. The X-axis represents the treatment cycle and the administration day within each treatment cycle (C1D1: Cycle 1, Day 1; C1D4: Cycle 1, Day 4, etc.). SCR: Normal value, EOT: End of treatment, WK: Week, POST-WK: Weeks after treatment, post-PDFU: Follow-up after exacerbation. The areas highlighted in gray shade indicate the 25-27% interquartile range (IQR) for each responder's data point at each outpatient visit.For individual patients (light gray line), the graph shows the percentage change (%) in the absolute number of CD3 + T cells in peripheral blood of patients treated with DARZALEX™ (daratumumab) relative to the normal range. Study name: SIRIUS (MMY2002). The X-axis represents the treatment cycle and the administration day within each treatment cycle (C1D1: Cycle 1, Day 1; C1D4: Cycle 1, Day 4, etc.). WK: Weeks, POST-WK: Weeks after treatment, POST-PDFU: Follow-up after exacerbation. The black line shows the median percentage change for all patients.For individual patients (light gray line), the graph shows the percentage change (%) in the absolute number of CD4 + T cells in peripheral blood of patients treated with DARZALEX™ (daratumumab) relative to the normal range. Study name: SIRIUS. The X-axis represents the treatment cycle and the administration day within each treatment cycle (C1D1: Cycle 1, Day 1; C1D4: Cycle 1, Day 4, etc.). WK: Weeks, POST-TMT: Post-treatment. The black line shows the median percentage change for all patients.For individual patients (light gray line), the graph shows the percentage change (%) in the absolute number of CD8 + T cells in peripheral blood of patients treated with DARZALEX™ (daratumumab) relative to the normal range. Study name: SIRIUS. The X-axis represents the treatment cycle and the administration day within each treatment cycle (C1D1: Cycle 1, Day 1; C1D4: Cycle 1, Day 4, etc.). WK: Weeks, Pre-PD FU: Follow-up before exacerbation, Post-PD FU: Follow-up after exacerbation. The black line shows the median percentage change for all patients.This graph shows that the number of CD45 + CD3 + cells (measured as a percentage of lymphocytes) in bone marrow aspirate increased over time during treatment with DARZALEX™ (daratumumab) at doses of 8 mg/kg or 16 mg/kg. As shown, this graph includes both responders and non-responders. Study name: SIRIUS. The X-axis represents the treatment cycle and the administration day within each treatment cycle (e.g., C2D22: cycle 2, day 22). SCR: normal value, Post-PD FU1: follow-up after exacerbation. The areas highlighted in gray shade indicate the 25–27 percent interquartile range (IQR) for the outpatient data points of non-responders at the 8 mg/kg dose, responders at the 16 mg/kg dose, or non-responders at the 16 mg/kg dose, respectively. NR: non-responder, R: responder.This graph shows that the number of CD45 + CD3 + CD8 + cells (measured as a percentage of lymphocytes) in bone marrow aspirate increased over time during treatment with DARZALEX™ (d