EP4398889A1 - Kombinationstherapie - Google Patents

Kombinationstherapie

Info

Publication number
EP4398889A1
EP4398889A1 EP22786605.0A EP22786605A EP4398889A1 EP 4398889 A1 EP4398889 A1 EP 4398889A1 EP 22786605 A EP22786605 A EP 22786605A EP 4398889 A1 EP4398889 A1 EP 4398889A1
Authority
EP
European Patent Office
Prior art keywords
seq
amino acid
day
acid sequence
dkk1
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22786605.0A
Other languages
English (en)
French (fr)
Inventor
Michael H. KAGEY
Cynthia SIRARD
Yong BEN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beigene Switzerland GmbH
Leap Therapeutics Inc
Original Assignee
Beigene Switzerland GmbH
Leap Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beigene Switzerland GmbH, Leap Therapeutics Inc filed Critical Beigene Switzerland GmbH
Publication of EP4398889A1 publication Critical patent/EP4398889A1/de
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • Cancer is a cellular disorder characterized by uncontrolled or disregulated cellular proliferation, decreased cellular differentiation, inappropriate ability to invade surrounding tissue, and/or ability to establish new growth at ectopic sites.
  • the treatment for cancer may involve surgery, radiotherapy, chemotherapy, immunotherapy or a combination of these treatments. It is estimated that in 2020 in the United States 1,806,590 new cases of cancer will be diagnosed and 606,520 people will die from cancer. As such, despite significant advancements in the treatment of cancer, there is a continuing need for new and improved treatments for patients with cancer.
  • the invention described herein relates to a method of treating an esophagogastric cancer in a subject in need of treatment.
  • the method comprises administering to the subject suffering from esophagogastric cancer an effective amount of the combination of a DKK1 antibody, or antigen binding-fragment thereof; tislelizumab; and one or more chemotherapeutic agents or a pharmaceutically acceptable salt of any of the foregoing, wherein the subject is determined to have a DKK-1 H-score of 35 or more or a DKK1 Tumor Percentage Score (TPS) of 20% or more.
  • TPS Tumor Percentage Score
  • the subject is determined to have a Combined Positive Score (CPS) of less than 5 for PD-L1.
  • CPS Combined Positive Score
  • the method comprises administering to the subject suffering from esophagogastric cancer an effective amount of the combination of a DKK1 antibody, or antigen binding-fragment thereof; tislelizumab; and one or more chemotherapeutic agents or a pharmaceutically acceptable salt of any of the foregoing, wherein the subject is determined to have Combined Positive Score (CPS) of less than 5 for PD-L1.
  • CPS Combined Positive Score
  • the subject is determined to have a DKK-1 H-score of 35 or more or a DKK1 Tumor Percentage Score of 20% or more.
  • the subject has not received prior systemic therapy for the esophagogastric cancer.
  • the subject has received only one prior systemic therapy for the esophagogastric cancer.
  • any particular aspect thereof or the first and second aspects thereof the esophagogastric cancer is gastric cancer.
  • any particular aspect thereof or the first and second aspects thereof the esophagogastric cancer is gastroesophageal junction cancer.
  • any particular aspect thereof or the first, second, third or fourth aspect thereof the cancer is an adenocarcinoma.
  • any particular aspect thereof or the first, second, third, fourth or fifth aspect thereof the cancer is metastatic.
  • any particular aspect thereof or the first, second, third, fourth, fifth or sixth aspect thereof is advanced.
  • any particular aspect thereof or the first, second, third, fourth, fifth, sixth or seventh aspect thereof has received neoadjuvant therapy prior to administering an effective amount of the combination.
  • any particular aspect thereof or the first, second, third, fourth, fifth, sixth, seventh or eighth aspect thereof is administered in the course of one or more 21 -day cycles.
  • any particular aspect thereof or the first, second, third, fourth, fifth, sixth, seventh, eighth or ninth aspect thereof is administered in the course of one or more 21 -day cycles, wherein 300 mg of the DKK1 antibody, or antigen binding-fragment thereof is administered on day 1 and day 15 of the 21 -day cycle.
  • any particular aspect thereof or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth aspect thereof is administered in the course of one or more 21 -day cycles, wherein 200 mg of tislelizumab is administered on day 1 of the 21 -day cycle.
  • any particular aspect thereof or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh aspect thereof is selected from: 5-FU (fluorouracil), leucovorin (folinic acid); Capecitabine; Carboplatin; Cisplatin; Docetaxel; Epirubicin; Irinotecan; Oxaliplatin; Paclitaxel; andTrifluridine and Tipiracil.
  • the one or more chemotherapeutics agent is a combination selected from: Oxaliplatin, 5-FU and leucovorin (FOLFOX); oxaliplatin and capecitabine (CAPOX); 5-FU, leucovorin, oxaliplatin, and docetaxel (FLOT); Docetaxel and 5-FU; Docetaxel and capecitabine; paclitaxel and 5-FU; paclitaxel and capecitabine; Cisplatin and 5-FU; cisplatin and capecitabine; Paclitaxel and carboplatin; Irinotecan, 5-FU and leucovorin (FOLFIRI); Paclitaxel and cisplatin; paclitaxel and carboplatin; Docetaxel and cisplatin; Epi
  • the one or more chemotherapeutics agent is a combination of oxaliplatin and capecitabine (CAPOX).
  • the capecitabine is orally administered at 1000 mg/m2 twice daily on days 1-15 of each 21 day cycle and the oxaliplatin is administered at 130 mg/m2 on day 1 of each 21-day cycle.
  • the effective amount of the combination is administered in the course of one or more 21-day cycles or one or more 14-day cycles in some instances. In other words, the 21-day cycle can be repeated.
  • any particular aspect thereof or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth or fourteenth aspect thereof comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises complementarity determining regions (CDRs) LCDR1, LCDR2, and LCDR3 and the HCVR comprises CDRs HCDR1, HCDR2 and HCDR3, wherein LCDR1 has the amino sequence of SEQ ID NO: 1, LCDR2 has the amino sequence of SEQ ID NO:2, LCDR3 has the amino sequence of SEQ ID NO:3, HCDR1 has the amino sequence of SEQ ID NON, HCDR2 has the amino sequence of SEQ ID NO:5, and an HCDR3 has the amino sequence of SEQ ID NO:6.
  • LCVR light chain variable region
  • HCVR heavy chain variable region
  • the LCVR comprises complementarity determining regions (CDRs) LCDR1, LCDR2, and LCDR3
  • the LCVR comprises the amino acid sequence of SEQ ID NO: 7 and the HCVR comprises the amino acid sequence of SEQ ID NO: 8.
  • the LCVR and HCVR comprise amino acid sequences selected from the group consisting of: (i) a LCVR comprising the amino acid sequence of SEQ ID NO: 9 and a HCVR comprising the amino acid sequence of SEQ ID NO: 10; (ii) a LCVR comprising the amino acid sequence of SEQ ID NO: 11 and a HCVR comprising the amino acid sequence of SEQ ID NO: 12; (iii) a LCVR comprising the amino acid sequence of SEQ ID NO: 13 and a HCVR comprising the amino acid sequence of SEQ ID NO: 10; (iv) a LCVR comprising the amino acid sequence of SEQ ID NO: 14 and a HCVR comprising the amino acid sequence of SEQ ID NO: 10.
  • the LCVR and HCVR comprise amino acid sequences selected from the group consisting of: (i) a LCVR
  • the DKK1 antibody comprises a heavy chain and a light chain amino acid sequence selected from the group consisting of a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and light chain comprising the amino acid sequence of SEQ ID NO: 16, b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 17 and a light chain comprising the amino acid sequence of SEQ ID NO: 18, c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and a light chain comprising the amino acid sequence of SEQ ID NO: 20, and d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and a light chain comprising the amino acid sequence of SEQ ID NO: 21.
  • the DKK1 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 17 and a light chain comprising the amino acid sequence of SEQ ID NO: 18.
  • any particular aspect thereof or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth or seventeenth aspect thereof the DKK1 antibody comprises DKN-01.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising: a DKK1 antibody, or antigen binding-fragment thereof; tislelizumab; and one or more chemotherapeutic agents or a pharmaceutically acceptable salt of any of the foregoing.
  • FIG. l is a graph showing best overall response in the response evaluable (RE) mITT patient population (21 patients) rated by the DKK1 expression (first cutoff of data).
  • FIG. 2 shows the results depicted as durable response by DKK1 expression (25 patients; first cutoff of data).
  • FIG. 3 shows the results of duration on trial by DKK1 expression (25 patients; first cutoff of data).
  • FIG. 4 is a graph showing that tumoral DKK1 expression predicts response to DKN-01 Therapy (first cutoff of data).
  • FIG. 5 is a graph showing best overall response by PD-L1 and DKK1 expression (first cutoff of data).
  • FIG. 6 is a graph showing that durable response in the trial is independent of PD-L1 expression (first cutoff of data).
  • FIG. 7 is a plot showing that PD-L1 expression and DKK1 expression are not correlated in mITT population of 19 patients.
  • FIG. 8 is a graph showing best overall response in the response evaluable (RE) mITT patient population (21 patients; second cutoff of data).
  • FIG. 9 is a graph showing best overall response by PD-L1 and DKK1 expression in mITT population (21 patients; second cutoff of data).
  • FIG. 10 shows the results depicted as durable response by DKK1 expression in mITT population (21 patients; second cutoff of data).
  • FIG. 11 is a graph showing the duration of response (responders 15; second cutoff of data).
  • FIG. 13 is an analysis showing that patient response in Part A is associated with elevated DKK1 expression.
  • DKK1 expression was measured by RNAscope. Using either an H-score cutoff of ⁇ 35 or a DKK1 Percent Positive (i.e., TPS) cutoff of ⁇ 20% provides a similar result.
  • FIG. 14 is a plot comparing DKK1 H-score and DKK1 TPS for Part A tumor specimens. There is a significant Spearman correlation between DKK1 H-score and DKK1 TPS. The concordance between DKK1 high and low binning using an H-score cutoff of 35 or greater and a TPS cutoff of 20% or greater is 96%.
  • FIG. 15 shows the Best Overall Response based on DKK1 Expression for response evaluable mITT population (third cutoff of data).
  • FIG. 17 is a graph showing best overall response by PD-L1 and DKK1 expression in mITT population (21 patients, third cutoff of data).
  • Esophagogastric cancer refers to esophageal cancer and gastric (stomach) cancer (GC).
  • Esophageal cancer refers to cancer of the esophagus as well as the gastro-esophageal junction (GEJ).
  • GEJ gastro-esophageal junction
  • esophageal cancer comprises esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC).
  • ESCC refers to cancer that originates in squamous cells, which cells line the esophagus in approximately upper 2/3 of the organ.
  • EAC refers to cancer that originates in gland cells, which replace an area of squamous cells (e.g., in Barrett’s esophagus), typically in the lower 1/3 of the esophagus.
  • esophageal adenocarcinoma refers to adenocarcinoma of the esophagus as well as the gastro-esophageal junction.
  • the esophagogastric cancer is esophageal cancer.
  • the esophageal cancer is locally advanced or metastatic.
  • the locally advanced or metastatic esophageal cancer is inoperable.
  • the esophageal cancer is an adenocarcinoma.
  • the subject being treated for the locally advanced or metastatic esophageal cancer has not had prior systemic therapy for the esophageal cancer.
  • the subject has not had prior systemic therapy, but has received neoadjuvant or adjuvant therapy.
  • the esophagogastric cancer is locally advanced or metastatic GEJ cancer.
  • the locally advanced or metastatic GEJ cancer is inoperable.
  • the GEJ cancer is an adenocarcinoma.
  • the subject being treated for the locally advanced or metastatic GEJ cancer has not had prior systemic therapy for the GEJ cancer.
  • the subject has not had prior systemic therapy, but has received neoadjuvant or adjuvant therapy.
  • the subject being treated for locally advanced or metastatic esophagogastric cancer e.g., GEJ cancer or gastric cancer
  • the CPS is a vCPS (visual CPS) and is less than 5.
  • gastric cancer or GC refers to cancer of the stomach.
  • a specific type of gastric cancer is “gastric adenocarcinoma.”
  • An adenocarcinoma is a type of cancerous tumor that is defined as neoplasia of epithelial tissue that has glandular origin, glandular characteristics, or both.
  • Gastric cancer is a leading cause of cancer-related death in the world, and it remains difficult to cure, primarily because most patients present with advanced disease.
  • the stomach begins at the gastroesophageal junction and ends at the duodenum. Histologically, the 90-95% of gastric malignancies are adenocarcinoma.
  • Curative therapy involves surgical resection, most commonly a total or subtotal gastrectomy, with an accompanying lymphadenectomy. The overall 5-year survival rate of patients with resectable gastric cancer ranges from 10% to 30%.
  • the gastric cancer is locally advanced or metastatic gastric cancer.
  • the locally advanced or metastatic gastric cancer is inoperable.
  • the gastric cancer is an adenocarcinoma.
  • the subject being treated for the locally advanced or metastatic gastric cancer has not had prior systemic therapy for the gastric cancer.
  • the subject has not had prior systemic therapy, but has received neoadjuvant or adjuvant therapy.
  • Neoadjuvant therapy encompasses all treatments that are administered before the primary cancer treatment, whereas adjuvant therapy describes regimens administered after the primary treatment.
  • adjuvant therapy typically includes a combination of chemotherapy and radiation therapy and is administered to patients who are surgical candidates for primary resection.
  • Neoadjuvant therapy is administered in advance of primary resection to reduce overall tumor burden and for ease of tumor removal.
  • Adjuvant therapy is then administered after primary resection to reduce risk of recurrence. Both neoadjuvant and adjuvant therapy can be utilized as adjuncts to primary surgical resection.
  • CPS Combined Positive Score
  • PD-L1 protein expression in viable cancer and immune cells determined by immunohistochemistry (IHC) is correlated with a therapeutic effect of immune checkpoint inhibitors, and is thus considered an important biomarker in deciding whether to treat a patient with anti-PD-l/ PD-L1 inhibitors.
  • CPS Combined Positive Score
  • PD-L1 expressing cells tumor cells, lymphocytes, macrophages
  • vCPS visually estimated Combined Positive Score
  • the subject being treated for locally advanced or metastatic esophagogastric cancer e.g., GEJ cancer or gastric cancer
  • the CPS is a vCPS (visual CPS) and is less than 5.
  • the subject’s tumor (subject suffering from esophagogastric cancer) has increased levels of DKK1 expression, as determined by one or more of the various standard mRNA or protein detection methods known in the art, e.g., in situ hybridization, immunohistochemistry, qPCR, RNA-Seq and NanoString.
  • H-score and % Positive Values also referred to herein as DKK1 Tumor Percentage Score (TPS)
  • the level of expression of a gene product of interest can be evaluated by methods of immunohistochemistry or in situ hybridization techniques.
  • Convenient semiquantitative measures of the level of expression are computing % positive value (% of tumor cells stained by DKK-1 RNA detecting reagent) or assigning an “H-score” (or “histo” score) to tumor samples.
  • H-score a staining intensity (0, 1+, 2+, or 3+) is determined for each cell in a fixed field.
  • the number of dots for each cell can be determined where 0 is no detected dots per cell, 1+ is 1-3 dots per cell, 2+ is 4-9 dots per cell and 3+ is 10+ dots per cell.
  • the H-score may then be based on a predominant staining intensity (or dot number per cell), or more complexly, can include the sum of individual percentages for each intensity (or dot number per cell) level seen.
  • a predominant staining intensity or dot number per cell
  • the percentage of cells at each staining intensity (or dot number per cell) level is calculated, and finally, an H-score is assigned using the following formula:
  • H-score [1 ⁇ (% cells 1+) + 2 x (% cells 2+) + 3 x (% cells 3+)]
  • the final H-score ranging from 0 to 300, gives more relative weight to higher- intensity or amount of staining (e.g., dots per cell) in any given tumor sample.
  • the sample can then be considered positive or negative on the basis of a specific discriminatory threshold. See, for example, Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al. Epidermal growth factor receptor in non-small-cell lung carcinomas: Correlation between gene copy number and protein expression and impact on prognosis.
  • an H-score (e.g., a predetermined value of the H-score) can be from 0 to 300, for example, 20 to 100, or 20 to 50.
  • Example of predetermined values of H-score are: 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100.
  • predetermined values of H-score are: 10 or greater, 20 or greater, 30 or greater, 40 or greater, 50 or greater, 60 or greater, 70 of greater, 80 or greater, or 90 or greater.
  • the predetermined value of H-score is: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
  • the measure of DKK1 expression can be a value of the fraction of tumor cells that stain positive for DKK1 (% positive).
  • a staining amount (0, 1+, 2+, or 3+), based on number of dots in the cell, is determined for each tumor cell in a fixed field.
  • the percentage of positive tumor cells is determined by adding up the total neoplastic cells with staining and dividing by the total number of neoplastic cells.
  • % Positive can range from 0 to 100. % Positive is also referred to herein as Tumor Percentage Score (TPS).
  • TPS Tumor Percentage Score
  • % Positive value (e.g., a predetermined value of % positive) can be from 15% to 50%, for example from 20% to 40%, or 20% to 25%.
  • Example predetermined values of % Positive or TPS are: 15% or greater, 20% or greater, 25% or greater, 30% or greater, 35% or greater, 40% or greater, 45% or greater, or 50% of greater.
  • the predertmined value of % positive or TPS is: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,
  • RNAscope® in situ hybridization technique developed by and commercially available from Advanced Cell Diagnostics, Inc., as described, for example, at the URL https://acdbio.com/ and from Flagship Biosciences, Broomfield, CO.
  • This technique relies on an optical signal from a hybridization probe cognate to the mRNA of interest. The signal can be detected either by a bright-field or epifluorescent microscopy. The technique permits detection of a single molecule.
  • RNAscope A Novel In Situ RNA Analysis Platform for Formalin-Fixed Paraffin-Embedded Tissues. Wang F., Flanagan J, Su N, Wang LC, Bui S, Nielson A, Wu X, Vo HT, Ma XJ, Luo Y (2012). J of Mol Diagnostics, 14(l):22-29.
  • Dickkopf-1 is a secreted modulator of Wnt signaling pathways, which influences a number of biological processes such as stem cell maintenance, cell fate decisions, cell proliferation, survival, migration and polarity determination during development and adult tissue homeostasis.
  • DKK1 has been most extensively characterized as an inhibitor of canonical Wnt/beta-catenin dependent signaling and this has been associated with contributing to an immune suppressive tumor microenvironment.
  • DKK1 has also been implicated in promoting tumor growth and metastasis through activation of noncanonical (beta-catenin independent Wnt signaling) and PI3K/AKT signaling pathways. DKK1 also regulates bone homeostasis during development and in adult organisms.
  • DKK1 inhibits osteoblastogenesis, or the differentiation of mesechymal stem cells to osteoblasts (OB), a process promoted by Wnt signaling.
  • OB bone formation
  • OC osteoclast
  • the esophagogastric cancer has increased levels of DKK1 expression, as determined by one or more of the various standard mRNA or protein detection methods known in the art, e.g., in situ hybridzidation or immunohistochemistry.
  • DKK1 antibodies have been described previously (see, e.g., U.S. Patent Nos. 8,148,498, incorporated by reference herein in its entirety).
  • the present DKK1 antibodies of the disclosure are therapeutically useful DKK1 antagonists possessing a number of desirable properties.
  • the DKK1 antibodies reduce DKK1 mediated inhibition of alkaline phosphatase, a marker or osteoblast activity, as well as treat various types of cancer (e.g., non-small cell lung cancer).
  • a full-length antibody as it exists naturally is an immunoglobulin molecule comprising 2 heavy (H) chains and 2 light (L) chains interconnected by disulfide bonds.
  • the amino terminal portion of each chain includes a variable region of about 100-110 amino acids primarily responsible for antigen recognition via the complementarity determining regions (CDRs) contained therein.
  • the carboxy-terminal portion of each chain defines a constant region primarily responsible for effector function.
  • Each light chain variable region (LCVR) and heavy chain variable region (HCVR) is composed of 3 CDRs and 4 FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the 3 CDRs of the light chain are referred to as "LCDR1, LCDR2, and LCDR3” and the 3 CDRs of the heavy chain are referred to as "HCDR1, HCDR2, and HCDR3.”
  • the CDRs contain most of the residues which form specific interactions with the antigen.
  • the numbering and positioning of CDR amino acid residues within the LCVR and HCVR regions is in accordance with the well-known Kabat numbering convention.
  • Light chains are classified as kappa or lambda, and are characterized by a particular constant region as known in the art.
  • Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, and define the isotype of an antibody as IgG, IgM, IgA, IgD, or IgE, respectively.
  • IgG antibodies can be further divided into subclasses, e.g., IgGl, IgG2, IgG3, IgG4.
  • Each heavy chain type is characterized by a particular constant region with a sequence well known in the art.
  • Mabs refers to an antibody that is derived from a single copy or clone including, for example, any eukaryotic, prokaryotic, or phage clone, and not the method by which it is produced.
  • Mabs of the present invention preferably exist in a homogeneous or substantially homogeneous population. Complete Mabs contain 2 heavy chains and 2 light chains.
  • DKK1 antibody encompasses both a full- length antibody as well as an antigen binding-fragment of the DKK1 antibody.
  • Antigen-binding fragments of such monoclonal antibodies include, for example, Fab fragments, Fab' fragments, F(ab')2 fragments, and single chain Fv fragments as well as bispecific and/or multivalent antibodies that may utilize the DKK1 antibody CDRs.
  • Monoclonal antibodies and antigen-binding fragments thereof can be produced, for example, by recombinant technologies, phage display technologies, synthetic technologies, e.g., CDR-grafting, or combinations of such technologies, or other technologies known in the art.
  • mice can be immunized with human DKK1 or fragments thereof, the resulting antibodies can be recovered and purified, and determination of whether they possess binding and functional properties similar to or the same as the antibody compounds disclosed herein can be assessed by the methods known in the art.
  • Antigen-binding fragments can also be prepared by conventional methods. Methods for producing and purifying antibodies and antigen-binding fragments are well known in the art and can be found, for example, in Harlow and Lane (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., chapters 5-8 and 15, ISBN 0- 87969-314-2.
  • Monoclonal DKK1 antibodies disclosed herein are engineered to comprise framework regions that are substantially human or fully human surrounding CDRs derived from a non-human antibody.
  • Antigen-binding fragments of such human engineered antibodies include, for example, Fab fragments, Fab' fragments, F(ab')2 fragments, and single chain Fv fragments.
  • Framework region or “framework sequence” refers to any one of framework regions 1 to 4.
  • Human engineered antibodies and antigen-binding fragments thereof encompassed by the antibodies disclosed herein include molecules wherein any one or more of framework regions 1 to 4 is substantially or fully human, i.e., wherein any of the possible combinations of individual substantially or fully human framework regions 1 to 4, is present.
  • this includes molecules in which framework region 1 and framework region 2, framework region 1 and framework region 3, framework region 1, 2, and 3, etc., are substantially or fully human.
  • Substantially human frameworks are those that have at least about 80% sequence identity to a known human germline framework sequence.
  • the substantially human frameworks have at least about 85%, about 90%, about 95%, or about 99% sequence identity to a known human germline framework sequence.
  • Human engineered antibodies in addition to those disclosed herein exhibiting similar functional properties can be generated using several different methods.
  • the specific antibody compounds disclosed herein can be used as templates or parent antibody compounds to prepare additional antibody compounds.
  • the parent antibody compound CDRs are grafted into a human framework that has a high sequence identity with the parent antibody compound framework.
  • the sequence identity of the new framework will generally be at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% identical to the sequence of the corresponding framework in the parent antibody compound. This grafting may result in a reduction in binding affinity compared to that of the parent antibody.
  • the framework can be back-mutated to the parent framework at certain positions based on specific criteria disclosed by Queen et al. (1991) Proc. Natl. Acad. Sci. USA 88:2869. Additional references describing methods useful in humanizing mouse antibodies include U.S. Pat. Nos.
  • the DKK1 antibody administered in the method of treatment described herein comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises complementarity determining regions (CDRs) LCDR1, LCDR2, and LCDR3 and the HCVR comprises CDRs HCDR1, HCDR2 and HCDR3.
  • LCVR light chain variable region
  • HCVR heavy chain variable region
  • the DKK1 antibody comprises a LCDR1 having the amino sequence of SEQ ID NO: 1, LCDR2 having the amino sequence of SEQ ID NO:2, LCDR3 having the amino sequence of SEQ ID NO:3, HCDR1 having the amino sequence of SEQ ID NO:4, HCDR2 having the amino sequence of SEQ ID NO:5, and HCDR3 having the amino sequence of SEQ ID NO:6.
  • the DKK1 antibody comprises a LCVR having the amino acid sequence of SEQ ID NO: 7 and a HCVR having the amino acid sequence of SEQ ID NO: 8.
  • the LCVR comprises the amino acid sequence of SEQ ID NO: 11 and the HCVR comprises the amino acid sequence of SEQ ID NO: 12.
  • the DKK1 antibody comprises a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 17 and a light chain (LC) having the amino acid sequence of SEQ ID NO: 18.
  • DKK1 antibody or antigen binding-fragment thereof comprising the HC and LC amino acid sequence of SEQ ID NO: 17 and SEQ ID NO: 18, respectively, is referred to herein as DKN-01.
  • DKN-01 has the molecular/empirical formula C 6394 H 9810 N 1698 O 2012 S 42 and a molecular weight of 144015 Daltons (intact).
  • the DKK1 antibody disclosed herein is an IgG 4 antibody with a neutralizing activity against human DKK1 comprising the sequence set forth in SEQ ID NO: 22, or a fragment thereof.
  • canonical Wnt signaling is important for osteoblast differentiation and activity.
  • Wnt-3a combined with BMP-4 induces multipotent mouse C2C12 cells to differentiate into osteoblasts with a measurable endpoint of alkaline phosphatase ("AP"), a marker of osteoblast activity.
  • AP alkaline phosphatase
  • DKK1 an inhibitor of canonical Wnt signaling, inhibits the differentiation and production of AP.
  • Neutralizing DKK1 antibodies prevent DKK1-mediated inhibition of AP.
  • Antibodies which block DKK1 inhibitory activity prevent the loss of AP activity (see U.S. Patent No. 8,148,498).
  • the DKK1 antibody possessing neutralizing activity is DKN- 01, which is an IgG4 antibody.
  • DKK1 antibodies disclosed herein possess high affinity (Kd) to DKK1 (e.g., human DKK1, SEQ ID NO: 22), as described in U.S. Patent No. 8,148,498.
  • DKK1 e.g., human DKK1, SEQ ID NO: 22
  • the present DKK1 antibodies possess a Kd of between 0.5xl0' 12 M and 3.0xl0 -11 M, at 37 °C.
  • Tislelizumab (also referred to as BGB-A317) is a humanized IgG4 anti-PD-1 monoclonal antibody (mAb) with high affinity and specificity for PD-1 that was engineered to minimize binding to Fc ⁇ R on macrophages to greatly reduce antibodydependent phagocytosis, a potential mechanism of T-cell clearance and resistance to anti-PD-1 therapy.
  • mAb monoclonal antibody
  • Tislelizumab was designed to bind to PD-1, a cell surface receptor that plays an important role in allowing tumor cells to evade the immune system. Many types of cancer cells have hijacked the PD-L1 expression system that normally exists in healthy cells. By expressing PD-L1, cancer cells can interact with PD-1 expressing cytotoxic T-lymphocytes, or CTLs and protect themselves from being killed by these CTLs. Tislelizumab can potentially restore the ability of CTLs to kill cancer cells by binding to PD-1, without activating the receptor, thereby preventing PD-L1 from engaging PD-1.
  • the tislelizumab administered in the method of treatment described herein comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises complementarity determining regions (CDRs) LCDR1, LCDR2, and LCDR3 and the HCVR comprises CDRs HCDR1, HCDR2 and HCDR3, [0090]
  • tislelizumab comprises a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 23 and a light chain (LC) having the amino acid sequence of SEQ ID NO: 24.
  • tislelizumab has the molecular/empirical formula C64io H9916 N1698-86 O2009 S40 and a molecular weight of 144024.0108 Daltons.
  • tislelizumab comprises a HCDR1 having the amino sequence of SEQ ID NO:25, HCDR2 having the amino sequence of SEQ ID NO:26, HCDR3 having the amino sequence of SEQ ID NO:27, LCDR1 having the amino sequence of SEQ ID NO:28, LCDR2 having the amino sequence of SEQ ID NO:29, and LCDR3 having the amino sequence of SEQ ID NO:30.
  • sequences of the tislelizumab that can be employed in the practice of the various example embodiments described herein.
  • sequences of the tislelizumab that can be employed in the practice of the various example embodiments described herein.
  • chemotherapeutic agents used to treat cancer - either alone or in combination with other drugs or treatments. These drugs are very different in their chemical composition (what they are made of), how they are prescribed and given, how useful they are in treating certain types of cancer, and the side effects they might have.
  • Not all medicines and drugs to treat cancer work the same way. Other drugs to treat cancer, such as targeted therapy, hormone therapy, and immunotherapy work differently than traditional or standard chemotherapeutic agents.
  • the chemotherapeutic agents used in the method of treatment described herein are traditional or standard chemotherapeutics agents and are not targeted therapy, hormone therapy or immunotherapy (e.g., biologies).
  • Chemotherapy drugs can target cells at different phases of the cell cycle. Chemotherapy drugs can be grouped by how they work, their chemical structure, and their relationships to other drugs. Some drugs work in more than one way, and may belong to more than one group.
  • Alkylating agents keep the cell from proliferating by damaging its DNA.
  • alkylating agents for use as the at least one chemotherapeutic agent of the method described herein include: Altretamine; Bendamustine; Busulfan; Carboplatin;
  • Carmustine Chlorambucil; Cisplatin; Cyclophosphamide; dacarbazine; Ifosfamide; Lomustine; Mechlorethamine; Melphalan; Oxaliplatin; Temozolomide;Thiotepa; and Trabectedin.
  • Examples of antimetabolites for use as the at least one chemotherapeutic agent of the method described herein include withouth limitation: Azacitidine; 5-fluorouracil (5-FU); 6-mercaptopurine (6-MP); Capecitabine; Cladribine; Clofarabine; Cytarabine (Ara-C); Decitabine; Floxuridine; Fludarabine; Gemcitabine, Hydroxyurea; Methotrexate; Nelarabine; Pemetrexed; Pentostatin; Pralatrexate;
  • Anthracyclines are anti-tumor antibiotics that interfere with enzymes involved in copying DNA during the cell cycle. They bind with DNA so it cannot make copies of itself, and a cell cannot divide.
  • Examples of anthracyclines for use as the at least one chemotherapeutic agent of the method described herein include without limitation: Daunorubicin; Doxorubicin, Doxorubicin liposomal; Epirubicin; Idarubicin; and Valrubicin.
  • Topoisomerase inhibitors are drugs that interfere with enzymes called topoisomerases.
  • Topoisomerase I inhibitors also called camptothecins
  • Irinotecan Irinotecan liposomal
  • Topotecan Irinotecan liposomal
  • Topoisomerase II inhibitors also called epipoclophyllotoxins
  • Etoposide VP-16
  • Mitoxantrone also acts as an anti-tumor antibiotic
  • Teniposide
  • Mitotic inhibitors include taxanes and vinca alkaloids.
  • Taxanes include without limitation: Cabazitaxel; Docetaxel; Nab-paclitaxel; and Paclitaxel.
  • Vinca alkaloids include without limitation: Vinblastine; Vincristine; Vincristine liposomal; and Vinorelbine.
  • Some chemotherapy drugs do not fit well into any of the listed categories. Examples include: All-trans-retinoic acid; Arsenic trioxide; Asparaginase; Eribulin; Hydroxyurea; Ixabepilone; Mitotane; Omacetaxine; Pegaspargase; Procarbazine; Romidepsin; and Vorinostat.
  • chemotherapeutic agents that can be used to treat esophagogastric cancer include: 5-FU (fluorouracil), often given along with leucovorin (folinic acid); Capecitabine; Carboplatin; Cisplatin; Docetaxel; Epirubicin; Irinotecan; Oxaliplatin; Paclitaxel; and Trifluridine and Tipiracil, a combination drug in pill form.
  • a combination of chemotherapeutic agents are administered in accordance with the method described herein.
  • Such combinations include: Oxaliplatin plus 5-FU/leucovorin (FOLFOX); oxaliplatin plus capecitabine (CAPOX, also referred to herein as XELOX); FLOT (5-FU/leucovorin, oxaliplatin, and docetaxel);
  • the one of more second therapeutics agents for use in the method of treating esophagogastric cancer is C APOX, FOLFOX, FLOT or FOLFIRI.
  • the one of more second therapeutic agents for use in the method of treating esophagogastric cancer is CAPOX.
  • the DKK1 antibody and tislelizumab and the one or more chemotherapeutic agents used in the combination described herein can be formulated separately or in combination, and can be co-administered either separately or toghether, for parenteral, oral, transdermal, sublingual, buccal, rectal, intranasal, intrabronchial or intrapulmonary administration.
  • one or more of the components of the combination therapy for use in the methods or compositions of the invention can be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and/or infusion (e.g., continuous infusion).
  • Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and/or dispersing agents can be used.
  • one or more of the components of the combination therapy can be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate).
  • binding agents e.g., polyvinylpyrrolidone or hydroxypropylmethylcellulose
  • fillers e.g., lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g., magnesium stearate, talc or silica
  • disintegrates e.g., sodium starch glycollate
  • wetting agents e.g., sodium lauryl sulphate
  • Liquid preparation for oral administration can be in the form of solutions, syrups or suspensions.
  • the liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agent e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
  • preservatives e.g., methyl or propyl p-hydroxy benzoates or sorb
  • one or more of the components of the combination therapy for use in the methods or compositions of the invention can be in the form of tablets or lozenges formulated in a conventional manner.
  • one or more of the components of the combination therapy for use in the methods or compositions of the invention can be in the form of suppositories.
  • the components of the combination therapy e.g., DKK1 antibody, tislelizumab and one or more chemotherapeutic agents
  • for use in the methods or compositions of the invention can be in the form of suppositories.
  • tablets can be formulated in conventional manner.
  • conventional formulations can be employed for intranasal, intrabronchial or intrapulmonary administration.
  • one or more of the components of the combination therapy for use in the methods or compositions of the invention can be formulated in a sustained release preparation.
  • the one or more of the components can be formulated with a suitable polymer or hydrophobic material which provides sustained and/or controlled release properties to the active agent compound.
  • one or more components of the combination therapy for use in the method of the invention can be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation.
  • Various methods of formulating controlled release drug preparations are known in the art.
  • Administration of one or more components of the combination therapy, or a pharmaceutically acceptable salt thereof, or a composition comprising one or more components of the combination therapy (or pharmaceutical salt thereof) of the invention useful to practice the methods described herein, can be continuous, hourly, four times daily, three time daily, twice daily, once daily, once every other day, twice weekly, once weekly, once every two weeks, once a month, or once every two months, or longer, or some other intermittent dosing regimen.
  • coadministration refers to administration of one treatment modality in addition to at least one other treatment modality.
  • in combination with refers to administration of one treatment modality before, during, or after administration of at least one other treatment modality to the individual.
  • coadministration includes receiving the DKN-01 antibody and the tislelizumab together in the same or different IV lines with their individual formulations.
  • the DKK1 antibody disclosed herein can be used for treating esophagogastric cancer in combination with tislelizumab and one or more chemotherapeutic agents.
  • Such combination administration can be by means of a single dosage form which includes a DKK1 antibody, tislelizumab and one or more chemotherapeutic agents, such single dosage form including a tablet, capsule, spray, inhalation powder, injectable liquid or the like.
  • combination administration can be by means of administration of different dosage forms, with one dosage form containing a DKK1 antibody, another dosage form including tislelizumab and yet another dosage form including the one more chemotherapeutic agents (if more than one chemotherapeutic agent is use it is understood that these agents can be administered using the same or different dosage forms).
  • the components of the combination therapy can be administered in any order.
  • tislelizumab can be administered before, simultaneously with, or after the administration of a DKK1 antibody and before, simultaneously with, or after the administration of the one or more chemotherapeutic agents.
  • the components of the combination therapy can be administered together in a single formulation or can be administered in separate formulations, e.g., either simultaneously or sequentially, or both.
  • the DKK1 antibody can be administered before or after tislelizumab.
  • the duration of time between the administration of the components of the combination therapy will be easily determined by the administering physician.
  • the components of the combination therapy may or may not be administered on similar dosing schedules.
  • the DKK1 antibody and tislelizumab may have different half-lives and/or act on different time-scales such that the DKK1 antibody is administered with greater frequency than tislelizumab or vice-versa.
  • the DKK1 antibody and tislelizumab can be administered together (e.g., in a single dosage or sequentially) on one day, followed by administration of only the one or more chemotherapeutic agents a set number of days later. The number of days in between administration of components of the combination therapy can be appropriately determined according to the safety and pharmacodynamics of each drug.
  • the treatment period for the combination treatment is a 21 -Day cycle which can be repeated until the patient is determined to not be gaining any clinical benefit from the combination therapy.
  • the patient can undergo from about one cycle to about 30 cycles of treatment (e.g., 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 7, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30).
  • an “effective amount” refers to an amount of the combination of therapeutic agents that is therapeutically or prophylactically sufficient to treat the target disorder.
  • An effective amount will depend on the age, gender, and weight of the patient, the current medical condition of the patient, and the nature of the esophagogastric cancer being treated. Those of skill in the art will be able to determine appropriate dosages depending on these and other factors.
  • Suitable doses per administration for a DKK1 antibody include doses of about or greater than about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about
  • each suitable dose can be administered over a period time deemed appropriate by a skilled practitioner.
  • each suitable dose can be administered over a period of about 30 minutes and up to about 1 hour, about 2 hours, about 3, hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, or about 8 hours.
  • a suitable does for the DKK1 antibody e.g., DKN-01
  • the selected dose can be administered intravenously over a period of about 30 minutes to about 2 hours.
  • a suitable dose for DKK1 antibody can be about 300 mg administered over a period of about 30 minutes and up to about 2 hours.
  • Another suitable dose for the DKK1 antibody can be about 600 mg administered over a period of about 30 minutes and up to about 2 hours.
  • Administration of these doses over the recited period of time can be accomplished using an intravenous route.
  • the DKK1 antibody e.g., DKN-01
  • Suitable doses per administration for tislelizumab can be determined based on the recommended dosing known for treatment.
  • a suitable dose per administration of tislelizumab is from about 20 mg to about 2000 mg intravenously. Such as from about 100 to 300 mg, for example about 200 mg.
  • the administration can be over the necessary period of time to deliver the desired dose in a safe and effective manner. In some instances, the time is at least a 30 minute period, a 60 minute period, a 2 hour period, a 3 hour period etc. This administration can be repeated every three weeks (21 days). In a particular embodiment, a suitable dose per administration is about 200 mg using an intravenous route. This dose can be repeated every three weeks.
  • An effective amount can be achieved in the methods of the invention by coadministering the combination of an intitial amount of DKK1 antibody (or a pharmaceutically acceptable salt, hydrate or solvate thereof), an initial amount of tislelizumab and an initial amount of one or more chemotherapeutic agents. It is understood that the administration of the amount of chemotherapeutic agents can vary if more than one chemotherapeutic agent is included. In one embodiment, the components of the combination (e.g., a DKK1 antibody, tislelizumab and one or more chemotherapeutic agents) are each administered in a respective effective amount (e.g., each in an amount which would be therapeutically effective if administered alone).
  • a respective effective amount e.g., each in an amount which would be therapeutically effective if administered alone.
  • the components of the combination are each administered in an amount which alone does not provide a therapeutic effect (a sub-therapeutic dose).
  • one or two components of the combination can be administered in an effective amount, while the remaining component is administered in a sub-therapeutic dose.
  • the DKK1 antibody can be administered in a sub-therapeutic dose
  • tislelizumab can be administered in an effective amount
  • the one or more therapeutic agents can be administered each at its effective amount.
  • the DKK1 antibody is DKN-01 and is administered at 300 mg, tislelizumab is administered at 200 mg, the one or more chemotherapeutic agents are oxaliplatin and capecitabine and are administered at 130 mg/m 2 and 1000 mg/m 2 .
  • the DKK1 antibody is DKN-01 and is administered at 600 mg and tislelizumab is administered at 200 mg.
  • DKN-01 is administered on Days 1 and 15 of a 21 -day cycle by IV infusion at about 300 mg
  • tislelizumab is administered on Day 1 of a 21-day cyles at about 200 mg by IV infusion
  • capecitabine is administered orally on Days 1-15 of a 21-day cycle
  • oxaliplatin is administered on Day 1 of a 21-day cycle by IV infusion at about 130 mg/m2.
  • DKN-01 is administered on Days 1 and 15 of a 21-day cycle by IV infusion at about 600 mg
  • tislelizumab is administered on Day 1 of a 21-day cyles at about 200 mg by IV infusion
  • capecitabine is administered orally on Days 1-15 of a 21-day cycle
  • oxaliplatin is administered on Day 1 of a 21-day cycle by IV infusion at about 130 mg/m2.
  • the term “subject” refers to a mammal, preferably a human, but can also mean an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • companion animals e.g., dogs, cats, and the like
  • farm animals e.g., cows, sheep, pigs, horses, and the like
  • laboratory animals e.g., rats, mice, guinea pigs, and the like.
  • treating includes achieving, partially or substantially, delaying, inhibiting or preventing the progression of clinical indications related to the esophagogastric cancer.
  • “treating” includes reduction in tumor growth, or prevention of further growth, as detected by standard imaging methods known in the art, including, for example, computed tomography (CT) scan, magnetic resonance imaging (MRI), chest x-ray, and CT/positron emission tomography (CT/PET) scans, and evaluated according to guidelines and methods known in the art.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • CT/PET CT/positron emission tomography
  • responses to treatment can be evaluted through the Response Evaluation Criteria in Solid Tumors (RECIST) (Revised RECIST Guideline version 1.1; see Eisenhauer et al., Eur.. J.
  • “treating” refers to a Complete Response (CR), which is defined according to the RECIST guideline as the disappearance of all target lesions, or a Partial Response (PR), which is defined as at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters.
  • CR Complete Response
  • PR Partial Response
  • Other means for evaluating tumor response to treatment include evaluation of tumor markers and evaluation of performance status (e.g., assessment of creatinine clearance; see Cockcroft and Gault, Nephron. 16:31-41, 1976).
  • An "objective response” refers to a measurable response, including complete response (CR) or partial response (PR).
  • objective response rate refers to the sum of complete response (CR) rate and partial response (PR) rate.
  • Complete response means the disappearance of all signs of cancer (e.g., disappearance of all target lesions) in response to treatment. This does not always mean the cancer has been cured.
  • partial response refers to a decrease in the size of one or more tumors or lesions, or in the extent of cancer in the body, in response to treatment.
  • PR refers to at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD.
  • progressive disease or “PD” refers to at least a 20% increase in the SLD of target lesions, taking as reference the smallest SLD recorded since the treatment started or the presence of one or more new lesions.
  • progression free survival refers to the length of time during and after treatment during which the disease being treated (e.g., cancer) does not get worse. Progression-free survival may include the amount of time patients have experienced a complete response or a partial response, as well as the amount of time patients have experienced stable disease.
  • ORR all response rate
  • all survival refers to the percentage of individuals in a group who are likely to be alive after a particular duration of time.
  • Sustained response refers to the sustained effect on reducing tumor growth after cessation of a treatment.
  • the tumor size may be the same size or smaller as compared to the size at the beginning of the medicament administration phase.
  • the sustained response has a duration of at least the same as the treatment duration, at least 1.5x, 2x, 2.5x, or 3x length of the treatment duration, or longer.
  • Duration of Response for purposes of the present invention means the time from documentation of tumor model growth inhibition due to drug treatment to the time of acquisition of a restored growth rate similar to pretreatment growth rate.
  • compositions suitable for administration can be incorporated into pharmaceutical compositions suitable for administration.
  • Such compositions typically comprise the DKK1 antibody, or tislelizumab and one or more chemotherapeutic agents, separate or together in any combination, and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated.
  • a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor EL(TM) (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the combination (e.g., a DKK1 antibody, tislelizumab and one or more chemotherapeutic agents) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid- derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
  • suppositories e.g., with conventional suppository bases such as cocoa butter and other glycerides
  • retention enemas for rectal delivery.
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
  • the DisTinGuish Study (NCT04363801) is a Phase 2a nonrandomized, open-label, multicenter study to be conducted concurrently in 2 Parts (Parts A and B). Approximately 72 patients aged 18 years or older with inoperable, histologically confirmed locally advanced or metastatic G/GEJ adenocarcinoma with measurable disease (RECIST vl.l) requiring therapy will be enrolled in the study. Both parts are designed to evaluate safety, tolerability, and efficacy of the combination therapy of intravenous (IV) DKN-01 and tislelizumab ⁇ CAPOX in G/GEJ adenocarcinoma patients. Treatment continues in repeating 21 -day cycles until patient meets criteria for discontinuation or is no longer deriving clinical benefit. Parts A and B will be enrolled concurrently. Two doses of DKN-01 will be evaluated in Part B (Part Bl and Part B2).
  • Part A First Line Treatment patients will receive IV DKN-01 (300 mg) on Days 1 and 15, IV tislelizumab (200 mg) on Day 1, IV oxaliplatin (130 mg/m2) on Day 1, and oral capecitabine (1000 mg/m2 twice daily [BID]) on Days 1-15 of each 21-day cycle. Part A is restricted to patients who have not had prior systemic therapy for locally advanced or metastatic disease. Patients may have received prior neoadjuvant or adjuvant therapy as long as it was completed without disease recurrence for at least 6 months.
  • Part Bl Stemline Treatment patients will receive IV DKN-01 (300 mg) on Days 1 and 15 and IV tislelizumab (200 mg) on Day 1 of each 21-day cycle. Patients enrolled in Part B are required to have DKK1-high (H-score ⁇ 35) G/GEJ adenocarcinoma (pre-screen biopsy) and may have had only 1 prior systemic therapy for locally advanced/metastatic disease (platinum + fluoropyrimidine-based therapy; ⁇ HER2 therapy if applicable). Patients may have received prior neoadjuvant or adjuvant therapy.
  • Part B2 (Second Line Treatment) patients will receive IV DKN-01 (600 mg) on Days 1 and 15 and IV tislelizumab (200 mg) on Day 1 of each 21-day cycle.
  • Part B Patients enrolled in Part B are required to have DKK1-high (H-score ⁇ 35) G/GEJ adenocarcinoma (pre-screen biopsy) and must have had only 1 prior systemic therapy for locally advanced/metastatic disease (platinum + fluoropyrimidine-based therapy; ⁇ HER2 therapy if applicable). Patients may have received prior neoadjuvant or adjuvant therapy.
  • PART A Details of Study and Results
  • DoR duration of response
  • DCR disease control rate
  • PFS progression- free survival
  • OS overall survival
  • the DKK1 expression level is correlated with cancer type in Table 8 below for Part A of the Study as of the first data cutoff.
  • the mITT (modified Intention-to-Treat) population included 22 patients; the response evaluable (RE) mITT population was 21 patients; ORR (Objective Response Rate assessed with RECIST vl.l) in mITT was 68% including one complete response (CR) and 14 partial responses (PR); DKK1-high mITT ORR was 90%; and DKK1-low mITT ORR was 56%.
  • FIG. 2 shows the results depicted as durable response by DKK1 expression based on data available as of the first data cutoff.
  • FIG. 3 shows the results of duration on trial by DKK1 expression based on data available as of the first data cutoff.
  • FIG. 4 is a graph showing that tumoral DKK1 expression predicts response to DKN-01 Therapy.
  • FIG. 9 is a graph showing best overall response by PD-L1 and DKK1 expression for study data as of the second data cutoff. Based on the data in FIG. 9, it can be seen that DKK1-high patients responded regardless of PD-L1 status (mITT): For PD-L1 -low expression (vCPS ⁇ 5) 79% ORR in PD-L1-low patients and 100% ORR in DKK1-high, PD- Ll-low patients. For PD-L1 high expression (vCPS ⁇ 5), 67% ORR in PD-L1 high patients and 75% ORR in DKK1-high, PD-L1 high patients.
  • mITT PD-L1 status
  • FIG. 17 is a graph showing best overall response by PD-L1 and DKK1 expression for study data as of the third data cutoff. Based on the data in FIG. 17, it can be seen that DKK1-high patients responded regardless of PD-L1 status (mITT): For PD-L1 - low expression (vCPS ⁇ 5) 79% (11/14) ORR in PD-L1-low patients and 100% (6/6) ORR in DKK1-high, PD-L1-low patients. For PD-L1 high expression (vCPS ⁇ 5), 67% (4/6) ORR in PD-L1 high patients and 75% (3/4) ORR in DKK1-high, PD-L1 high patients.
  • mITT PD-L1 status
  • FIG. 6 is a graph showing that durable response in the trial is independent of PD-L1 expression.
  • FIG. 7 is a plot showing that PD-L1 expression and DKK1 expression are not correlated.
  • First-line chemotherapy for advanced GC contains a platinum agent and a fluoropyrimidine.
  • the ORR typically observed can range from approximately 25% to 75% with median DoR up to 4.8 months; median OS of approximately 9-13 months is typical (See, Lancet 2010;376:687-97; Lancet 2014;383:31-9; Int J Hematol Oncol Stem Cell Res 2016;10:212-6; Cancer Chemother Pharmacol 2008;61 :623-9; and J Clin Oncol 2008;26: 1435-42).
  • response was independent of PD-L1 expression, and particularly strong in the less favorable to checkpoint inhibitor therapy, PD-L1 low (CPS ⁇ 5), population, for example based on the first cutoff data: a) Among those patients with PD-L1-low expression (vCPS ⁇ 5), the ORR was 79%, with 100% in DKK1-high patients and 57% in DKK1-low patients b) Among those patients with PD-L1-high expression (vCPS ⁇ 5), the ORR was 67%, with 75% ORR in DKK1-high patients and 50% in DKK1-low patients c) DKK1 levels could not be determined in one patient; however, the patient’s PD-L1 level was determined to be low (vCPS score less than 1) and the patient achieved a partial response
  • DKK1 high and DKK1 low patients had a similar median PFS of 11.3 and 12.0 months, respectively.
  • OS overall survival
  • the PFS for vCPS-low ( ⁇ 5) and vCPS-high ( ⁇ 5) is 10.7 and 11.6 months, respectively.
  • Data indicates that PD-L1 expression levels are not substantially affecting PFS.
  • Part C is a Phase 2 open-label multicenter study. Part C will enroll G/GEJ adenocarcinoma patients who have received no prior systemic treatment in the locally advanced/metastatic setting (first-line treatment). Part C is the open-label, randomized, controlled, 2-arm portion of the study to evaluate the efficacy and safety of tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) +/- DKN-01 in adult patients with inoperable, histologically confirmed locally advanced or metastatic G/GEJ adenocarcinoma with measurable disease (RECIST vl.l) requiring therapy.
  • CAPOX or mFOLFOX6 tislelizumab + chemotherapy regimen
  • RECIST vl.l histologically confirmed locally advanced or metastatic G/GEJ adenocarcinoma with measurable disease
  • Patients will be assigned to treatment using a central stratified block randomization scheme. Patients will be stratified at randomization by the following factors:
  • CAPOX chemotherapy regimen Patients in both groups receiving the CAPOX chemotherapy regimen will receive tislelizumab (200 mg, IV) on Day 1 of each 21 -day cycle.
  • the CAPOX regimen will include oxaliplatin 130 mg/m2 on Day 1 and capecitabine 1000mg/m2 BID on Days 1- 15 of each 21 -day cycle for a total of 28 doses.
  • Patients in the experimental group will receive DKN-01 (600 mg, IV) on Day 1 of each cycle. For Cycle 1 only, an additional loading dose of DKN-01 (600 mg, IV) will be administered on day 15.
  • Patients in the control group will not receive DKN-01 treatment. This dosing scheme is shown graphically below.
  • mFOLFOX6 chemotherapy regimen Patients in both groups receiving the mFOLFOX6 chemotherapy regimen will receive tislelizumab (400 mg, IV) every 6 weeks starting on CID 1 and continuing every third 14-day cycle (e.g., C4D1, C7D1 etc.).
  • the mFOLFOX6 regimen will be administered every 14 days and includes leucovorin calcium (folinic acid) 400 mg/m 2 IV on Day 1, fluorouracil 1200 mg/m 2 IV/day (Days 1 and 2), and oxaliplatin 85 mg/m 2 IV on Day 1.
  • Patients in the experimental group will receive DKN-01 (400 mg, IV) on Day 1 and an additional loading dose of DKN-01 (400 mg, IV) will be administered on Day 8.
  • Patients in the control group will not receive DKN-01 treatment. This dosing scheme is shown graphically below.
  • Inclusion criteria for Part C includes no previous systemic therapy for inoperable, locally advanced or metastatic G/GEJ adenocarcinoma. Patients may have received prior neoadjuvant or adjuvant therapy as long as it was completed without disease recurrence for at least 6 months since last treatment.
  • the primary study objective of Part C is to assess whether the addition of DKN- 01 to the combination of tislelizumab + chemotherapy regimen (CAPOX or mF0LF0X6 [leucovorin calcium, fluorouracil, and oxaliplatin]) improves PFS according to the RECIST vl .1 as assessed by the investigator in patients with advanced DKK1-high G/GEJ adenocarcinoma compared to tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) as a first-line therapy.
  • CAPOX or mF0LF0X6 leucovorin calcium, fluorouracil, and oxaliplatin
  • Secondary Study Objectives include: determining whether the addition of DKN- 01 to the combination of tislelizumab + chemotherapy regimen (CAPOX or mFOLFOX6) improves PFS according to RECIST vl. l as assessed by the investigator in all patients with advanced G/GEJ adenocarcinoma compared to tislelizumab + chemotherapy regimen (CAPOX or m FOLFOX6) as a first-line therapy; estimating the objective response rate (ORR) according to RECIST vl.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Peptides Or Proteins (AREA)
EP22786605.0A 2021-09-10 2022-09-12 Kombinationstherapie Pending EP4398889A1 (de)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US202163242896P 2021-09-10 2021-09-10
US202263300155P 2022-01-17 2022-01-17
US202263301364P 2022-01-20 2022-01-20
US202263403621P 2022-09-02 2022-09-02
PCT/US2022/043226 WO2023039249A1 (en) 2021-09-10 2022-09-12 Combination therapy

Publications (1)

Publication Number Publication Date
EP4398889A1 true EP4398889A1 (de) 2024-07-17

Family

ID=85507066

Family Applications (1)

Application Number Title Priority Date Filing Date
EP22786605.0A Pending EP4398889A1 (de) 2021-09-10 2022-09-12 Kombinationstherapie

Country Status (3)

Country Link
EP (1) EP4398889A1 (de)
JP (1) JP2024533439A (de)
WO (1) WO2023039249A1 (de)

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4522811A (en) 1982-07-08 1985-06-11 Syntex (U.S.A.) Inc. Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides
GB8308235D0 (en) 1983-03-25 1983-05-05 Celltech Ltd Polypeptides
US5225539A (en) 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
AR075989A1 (es) 2009-04-10 2011-05-11 Lilly Co Eli Anticuerpo dkk -1 (dickkopf-1) humano disenado por ingenieria
SI3702373T1 (sl) 2013-09-13 2022-11-30 Beigene Switzerland Gmbh Protitelesa proti PD-1 in njihova uporaba kot terapevtiki in diagnostiki
US20220381786A1 (en) * 2019-09-19 2022-12-01 Leap Therapeutics, Inc. Use of dkk-1 inhibitors for treating cancer

Also Published As

Publication number Publication date
JP2024533439A (ja) 2024-09-12
WO2023039249A1 (en) 2023-03-16

Similar Documents

Publication Publication Date Title
JP7507209B2 (ja) がんを治療するための、ｐｄ－１アンタゴニスト及びｖｅｇｆｒ／ｆｇｆｒ／ｒｅｔチロシンキナーゼ阻害剤の組合せ
US20190219585A1 (en) Immunohistochemical proximity assay for pd-1 positive cells and pd-ligand positive cells in tumor tissue
JP2020117524A (ja) 癌を処置するためのｐｄ−１アンタゴニストおよびａｌｋ阻害剤の併用
RU2737216C2 (ru) Комбинация антагониста pd-1 и эрибулина для лечения рака
TR201901507T4 (tr) Kanseri tedavi etmeye yönelik bir pd-1 antagonsitinin ve bir vegfr inhibitörünün kombinasyonu.
JP7482180B2 (ja) 癌のための併用療法
JP2024038251A (ja) 抗ｐｄ－１抗体によるがんの処置方法
KR20180071386A (ko) 항-pd-1 항체 및 항-ctla-4 항체의 조합물을 사용하는 폐암의 치료
JP2020517715A (ja) がん療法のためのバイオマーカー
EP2680839A1 (de) Gleichzeitige verabreichung von eribulin und farletuzumab zur behandlung von brustkrebs
AU2017347822A1 (en) Use of beta-catenin as a biomarker for treating cancers using anti-Dkk-1 antibody
KR20200071097A (ko) Parp 억제제 및 pd-1 축 결합 길항제의 조합
US20220154296A1 (en) Use of anti-pd-1 antibody in preparation of medicament for treating solid tumors
US20240141023A1 (en) Methods of treating cancer using dkk-1 inhibitors
US20220381786A1 (en) Use of dkk-1 inhibitors for treating cancer
CN113316589A (zh) 抗lag3抗体的给药方案以及与抗pd-1抗体组合用于治疗癌症的组合疗法
US20230082898A1 (en) Use of anti-pd-1 antibody in treatment of tumors
WO2023039249A1 (en) Combination therapy
WO2024015463A1 (en) Combination therapy
WO2023147673A1 (en) Combination therapy for use in treatment of non-small cell lung cancer
NZ722296B2 (en) Combination of a pd-1 antagonist and a vegfr inhibitor for treating cancer

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20240311

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR