Granted Patent
B2
US 12,629,418 · App. 17/823,383 · Granted May 19, 2026
Combination therapy using inhibitors of human growth and differentiation factor 15 (GDF-15) and immune checkpoint blockers
Inventors:
Jörg Wischhusen (Würzburg, DE); Markus Haake (Estenfeld, DE); Reinhard Dummer (Zürich, CH); Matthias Mehling (Basel, CH); Tina Schäfer (Würzburg, DE); Martina Selle (Würzburg, DE)
Assignee:
JULIUS-MAXIMILIANS-UNIVERSITÄT WÜRZBURG
A61K39/3955A61K31/7105A61K31/713A61K45/06A61P35/00C07K16/22C07K16/2818C07K16/2878G01N33/505G01N33/5064G01N33/574A61K2039/505A61K2039/507A61K2039/55C07K2317/34C07K2317/76G01N2500/10
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Abstract
The present invention relates to uses of inhibitors of human Growth and Differentiation Factor 15 (GDF-15), and to combined uses of such inhibitors with immune checkpoint blockers, in the treatment of solid cancers.
Claims (30)
1 . A method of increasing the percentage of CD8+ T-cells in a GDF-15-expressing solid cancer in a patient in need thereof, the method comprising administering to the patient a combination of an antibody that specifically binds to human GDF-15 (hGDF-15), or an antigen-binding portion thereof, and an immune checkpoint blocker selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA4 antibody, and combinations thereof.
2 . The method of claim 1 , wherein the level of hGDF-15 in a blood sample obtained from the patient before treatment is at least 1.2 ng/ml, 1.5 ng/ml, or 1.8 ng/ml.
3 . The method of claim 1 , wherein the cancer is selected from the group consisting of melanoma, colorectal cancer, prostate cancer, head and neck cancer, urothelial cancer, stomach cancer, oral squamous cell carcinoma, pancreatic cancer, liver cancer, testis cancer, ovarian cancer, endometrial cancer, cervical cancer, brain cancer, breast cancer, gastric cancer, renal cell carcinoma, Ewing's sarcoma, non-small cell lung cancer and small cell lung cancer.
4 . The method of claim 1 , wherein the cancer is stage III or stage IV melanoma, optionally wherein the cancer is unresectable stage III melanoma or stage IV melanoma not amenable to local therapy.
5 . The method of claim 1 ,
wherein the antibody that specifically binds to hGDF-15, or antigen-binding portion thereof;
(i) binds to a conformational or discontinuous epitope on hGDF-15, and wherein the conformational or discontinuous epitope is comprised by the amino acid sequences of SEQ ID NO: 25 and SEQ ID NO: 26, and/or
(ii) comprises a heavy chain variable domain which comprises a CDR1 region comprising the amino acid sequence of SEQ ID NO: 3, a CDR2 region comprising the amino acid sequence of SEQ ID NO: 4 and a CDR3 region comprising the amino acid sequence of SEQ ID NO: 5, and wherein the antibody or antigen-binding portion thereof comprises a light chain variable domain which comprises a CDR1 region comprising the amino acid sequence of SEQ ID NO: 6, a CDR2 region comprising the amino acid sequence ser-ala-ser and a CDR3 region comprising the amino acid sequence of SEQ ID NO: 7.
6 . The method of claim 1 , wherein:
(a) the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, and AMP-224;
(b) the anti-CTLA4 antibody is ipilimumab; and
(c) the anti-PD-L1 antibody is selected from the group consisting of BMS-936559, MPDL3280A, MEDI4736, and MSB0010718C.
7 . The method of claim 1 , further comprising administering to the patient polyinosinic: polycytidylic acid.
8 . The method of claim 1 , further comprising administering to the patient an anti-CD40 antibody.
9 . The method of claim 1 , wherein the antibody that specifically binds hGDF-15, or the antigen-binding portion thereof, increases the percentage of CD8+ T-cells in the cancer by increasing the adhesion of CD8+ T-cells to endothelial cells and thereby increasing entry of the CD8+ T-cells from the blood stream into the cancer.
10 . A method of treating a GDF-15-expressing solid cancer in a patient in need thereof, the method comprising administering to the patient a combination of an antibody that specifically binds to hGDF-15, or an antigen-binding portion thereof, and an immune checkpoint blocker selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA4 antibody, and combinations thereof.
11 . The method of claim 10 , wherein the level of hGDF-15 in a blood sample obtained from the patient before treatment is at least 1.2 ng/ml, 1.5 ng/ml, or 1.8 ng/ml.
12 . The method of claim 10 , wherein the cancer is selected from the group consisting of melanoma, colorectal cancer, prostate cancer, head and neck cancer, urothelial cancer, stomach cancer, oral squamous cell carcinoma, pancreatic cancer, liver cancer, testis cancer, ovarian cancer, endometrial cancer, cervical cancer, brain cancer, breast cancer, gastric cancer, renal cell carcinoma, Ewing's sarcoma, non-small cell lung cancer and small cell lung cancer.
13 . The method of claim 10 , wherein the cancer is stage III or stage IV melanoma, optionally wherein the cancer is unresectable stage III melanoma or stage IV melanoma not amenable to local therapy.
14 . The method of claim 10 ,
wherein the antibody that specifically binds to hGDF-15, or antigen-binding portion thereof;
(i) binds to a conformational or discontinuous epitope on hGDF-15, and wherein the conformational or discontinuous epitope is comprised by the amino acid sequences of SEQ ID NO: 25 and SEQ ID NO: 26, and/or
(ii) comprises a heavy chain variable domain which comprises a CDR1 region comprising the amino acid sequence of SEQ ID NO: 3, a CDR2 region comprising the amino acid sequence of SEQ ID NO: 4 and a CDR3 region comprising the amino acid sequence of SEQ ID NO: 5, and wherein the antibody or antigen-binding portion thereof comprises a light chain variable domain which comprises a CDR1 region comprising the amino acid sequence of SEQ ID NO: 6, a CDR2 region comprising the amino acid sequence ser-ala-ser and a CDR3 region comprising the amino acid sequence of SEQ ID NO: 7.
15 . The method of claim 10 , wherein:
(a) the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, and AMP-224;
(b) the anti-CTLA4 antibody is ipilimumab; and
(c) the anti-PD-L1 antibody is selected from the group consisting of BMS-936559, MPDL3280A, MEDI4736, and MSB0010718C.
16 . The method of claim 10 , further comprising administering to the patient polyinosinic: polycytidylic acid.
17 . The method of claim 10 , further comprising administering to the patient an anti-CD40 antibody.
18 . The method of claim 10 , wherein the antibody that specifically binds hGDF-15, or the antigen-binding portion thereof, increases the percentage of CD8+ T-cells in the cancer by increasing the adhesion of CD8+ T-cells to endothelial cells and thereby increasing entry of the CD8+ T-cells from the blood stream into the cancer.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jan 12, 2023
From: WISCHHUSEN, JÖRG; HAAKE, MARKUS; DUMMER, REINHARD; MEHLING, MATTHIAS; SCHAEFER, TINA; SELLE, MARTINA
To: JULIUS-MAXIMILIANS-UNIVERSITÄT WÜRZBURG
Reel/Frame 062361/0709 →
Priority Claims (2)
GB 1517531
· Oct 2, 2015
· national
GB 1607801
· Apr 29, 2016
· national
Continuity (2)
Division
15765176
References Cited (257)
US 8003099B2
· Auer et al.
· 2011
[cited by applicant]
US 9334331B2
· Igawa et al.
· 2016
[cited by applicant]
US 20010010908A1
· Billing-Medel et al.
· 2001
[cited by applicant]
US 20020052480A1
· Park et al.
· 2002
[cited by applicant]
US 20060148709A1
· Unsicker et al.
· 2006
[cited by applicant]
US 20070128636A1
· Baker et al.
· 2007
[cited by applicant]
US 20070180543A1
· Eling et al.
· 2007
[cited by applicant]
US 20090324604A1
· Liu et al.
· 2009
[cited by applicant]
US 20100278843A1
· Breit et al.
· 2010
[cited by applicant]
US 20150239968A1
· Wischhusen et al.
· 2015
[cited by applicant]
US 20170204174A1
· Wischhusen et al.
· 2017
[cited by applicant]
CN 102321173A
· 2012
[cited by applicant]
EP 2681308B1
· 2015
[cited by applicant]
EP 2899544A1
· 2015
[cited by applicant]
JP 2012515335A
· 2012
[cited by applicant]
WO WO2005099746A1
· 2005
[cited by applicant]
WO WO2009021293A1
· 2009
[cited by applicant]
WO 2009046495A1
· 2009
[cited by applicant]
WO 2009150256A1
· 2009
[cited by applicant]
WO 2011049645A1
· 2011
[cited by applicant]
WO 2011050407A1
· 2011
[cited by applicant]
WO WO2011127219A1
· 2011
[cited by applicant]
WO WO2012162561A2
· 2012
[cited by applicant]
WO WO2013012648A1
· 2013
[cited by applicant]
WO 2013023557A1
· 2013
[cited by applicant]
WO WO2014049087A1
· 2014
[cited by applicant]
WO WO2014100689A1
· 2014
[cited by applicant]
WO WO2015108907A2
· 2015
[cited by applicant]
WO 2015125159A1
· 2015
[cited by applicant]
WO WO2015144855A1
· 2015
[cited by applicant]
WO WO2016049470A1
· 2016
[cited by applicant]
Li et al. (2020) FEBS Openbio 10: 2750-2760.
[cited by examiner]
Tsui et al., “Growth differentiation factor-15: a p53- and demethylation-upregulating gene represses cell proliferation, invasion, and tumorigenesis in bladder carcinoma cells,” Sci Rep. Aug. 7, 2015;5:12870.
[cited by applicant]
Adkins et al., “A novel preclinical method to quantitatively evaluate early-stage metastatic events at the murine blood-brain barrier,” Cancer Prev Res (Phila). Jan. 2015;8(1):68-76.
[cited by applicant]
Abd El-Aziz et al., “Cleavage of growth differentiation factor 15 (GDF15) by membrane type 1-matrix metalloproteinase abrogates GDF15-mediated suppression of tumor cell growth,” Cancer Sci. Sep. 2007;98(9):1330-5.
[cited by applicant]
Altschul et al., “Basic local alignment search tool,” J Mol Biol. Oct. 5, 1990;215(3):403-10.
[cited by applicant]
Altschul et al., “Gapped BLAST and PSI-BLAST: a new generation of protein database search programs,” Nucleic Acids Res. Sep. 1, 1997;25(17):3389-402.
[cited by applicant]
Angell and Galon, “From the immune contexture to the Immunoscore: the role of prognostic and predictive immune markers in cancer,” Curr Opin Immunol. Apr. 2013;25(2):261-7.
[cited by applicant]
Arbabi Ghahroudi et al., “Selection and identification of single domain antibody fragments from camel heavy-chain antibodies,” FEBS Lett. Sep. 15, 1997;414(3):521-6.
[cited by applicant]
Artz et al., “GDF-15 inhibits integrin activation and mouse neutrophil recruitment through the ALK-5/TGF-(beta)RII heterodimer,” Blood. Jul. 28, 2016;128(4):529-41.
[cited by applicant]
Baek et al., “Nonsteroidal anti-inflammatory drug-activated gene-1 over expression in transgenic mice suppresses intestinal neoplasia,” Gastroenterology. Nov. 2006;131(5):1553-60.
[cited by applicant]
Baek et al., “Upregulation and secretion of macrophage inhibitory cytokine-1 (MIC-1) in gastric cancers,” Clin Chim Acta. Mar. 2009;401(1-2):128-33.
[cited by applicant]
Bauskin et al., “The propeptide mediates formation of stromal stores of PROMIC-1: role in determining prostate cancer outcome,” Cancer Res. Mar. 15, 2005;65(6):2330-6.
[cited by applicant]
Bauskin et al., “The TGF-beta superfamily cytokine MIC-1/GDF15: secretory mechanisms facilitate creation of latent stromal stores,” J Interferon Cytokine Res. Jun. 2010; 30(6):389-97.
[cited by applicant]
Blanco-Calvo et al., “Circulating levels of GDF15, MMP7 and miR-200c as a poor prognostic signature in gastric cancer,” Future Oncol. May 2014;10(7):1187-202.
[cited by applicant]
Boehm, “Nivolumab beim Nierenzellkarzinom in der Zweitlinie—verlängertes Überleben mit Immuntherapie,” Medscape. Sep. 28, 2015: https://deutsch.medscape.com/artikelansicht/4904107.
[cited by applicant]
Bootcov et al., “MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily,” Proc Natl Acad Sci U S A. Oct. 14, 1997;94(21):11514-9.
[cited by applicant]
Boyle et al., “Macrophage inhibitory cytokine-1 is overexpressed in malignant melanoma and is associated with tumorigenicity,” J Invest Dermatol. Feb. 2009;129(2):383-91.
[cited by applicant]
Brown et al., “Macrophage inhibitory cytokine 1: a new prognostic marker in prostate cancer,” Clin Cancer Res. Nov. 1, 2009;15(21):6658-64.
[cited by applicant]
Brown et al., “MIC-1 serum level and genotype: associations with progress and prognosis of colorectal carcinoma,” Clin Cancer Res. Jul. 2003;9(7):2642-50.
[cited by applicant]
Bruzzese et al., “Local and systemic protumorigenic effects of cancer-associated fibroblast-derived GDF15,” Cancer Res. Jul. 1, 2014;74(13):3408-17.
[cited by applicant]
Chen et al., “Prostate-derived factor as a paracrine and autocrine factor for the proliferation of androgen receptor-positive human prostate cancer cells,” Prostate. Apr. 1, 2007;67(5):557-71.
[cited by applicant]
Cheng et al., “Data mining The Cancer Genome Atlas in the era of precision cancer medicine,” Swiss Med Wkly. Sep. 16, 2015;145:w14183.
[cited by applicant]
Chothia and Lesk, “Canonical structures for the hypervariable regions of immunoglobulins,” J Mol Biol. Aug. 20, 1987;196(4):901-17.
[cited by applicant]
Chothia et al., “Conformations of immunoglobulin hypervariable regions,” Nature. Dec. 21-28, 1989;342(6252):877-83.
[cited by applicant]
Clackson et al., “Making antibody fragments using phage display libraries,” Nature. Aug. 15, 1991;352(6336):624-8.
[cited by applicant]
Cong et al., “Advertorial: Novel Bioassay to Assess PD-1/PD-L1 Therapeutic Antibodies in Development for Immunotherapy,” Genetic Engineering & Biotechnology News (GEN). May 15, 2015;35(10): https://www.genengnews.com/ma…
[cited by applicant]
Corre et al., “Bioactivity and prognostic significance of growth differentiation factor GDF15 secreted by bone marrow mesenchymal stem cells in multiple myeloma,” Cancer Res. Mar. 15, 2012;72(6):1395-406.
[cited by applicant]
Corre et al., “Concise review: growth differentiation factor 15 in pathology: a clinical role?” Stem Cells Transl Med. Dec. 2013;2(12):946-52.
[cited by applicant]
Cully, “Combinations with checkpoint inhibitors at wavefront of cancer immunotherapy,” Nat Rev Drug Discov. Jun. 2015; 14(6):374-5.
[cited by applicant]
Darvin et al., “Immune checkpoint inhibitors: recent progress and potential biomarkers,” Exp Mol Med. Dec. 13, 2018;50(12):1-11.
[cited by applicant]
Eisenhauer et al., “New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1),” Eur J Cancer. Jan. 2009; 45(2):228-47.
[cited by applicant]
Fisher et al., “MIC-1/GDF15 in Barrett's oesophagus and oesophageal adenocarcinoma,” Br J Cancer. Apr. 14, 2015;112(8):1384-91.
[cited by applicant]
Gajewski et al., “Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment,” Curr Opin Immunol. Apr. 2013;25(2):268-76.
[cited by applicant]
Galon et al., “Type, density, and location of immune cells within human colorectal tumors predict clinical outcome,” Science. Sep. 29, 2006;313(5795):1960-4.
[cited by applicant]
Garber, “Predictive biomarkers for checkpoints, first tests approved,” Nat Biotechnol. Dec. 9, 2015;33(12):1217-1218.
[cited by applicant]
Gentles et al., “The prognostic landscape of genes and infiltrating immune cells across human cancers,” Nat Med. Aug. 2015;21(8):938-945.
[cited by applicant]
Giudicelli et al., “IMGT/V-Quest, an integrated software program for immunoglobulin and T cell receptor V-J and V-D-J rearrangement analysis,” Nucleic Acids Res. Jul. 1, 2004;32(Web Server issue):W435-40.
[cited by applicant]
Gouttefangeas et al., “Flow Cytometry in Cancer Immunotherapy: Applications, Quality Assurance and Future,” Cancer Immunology: Translational Medicine from Bench to Bedside, Springer. 2015; chapter 25:471-86.
[cited by applicant]
Griner et al., “Growth differentiation factor 15 stimulates rapamycin-sensitive ovarian cancer cell growth and invasion,” Biochem Pharmacol. Jan. 1, 2013;85(1):46-58.
[cited by applicant]
Hadrup et al., “Effector CD4 and CD8 T cells and their role in the tumor microenvironment,” Cancer Microenviron. Aug. 2013;6(2):123-33.
[cited by applicant]
Herbertz et al., “Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway,” Drug Des Devel Ther. Aug. 10, 2015;9:4479-99.
[cited by applicant]
Herbst et al., “Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients,” Nature. Nov. 27, 2014;515(7528):563-7.
[cited by applicant]
Holliger et al., “‘Diabodies’: small bivalent and bispecific antibody fragments,” Proc Natl Acad Sci USA. Jul. 15, 1993;90(14):6444-8.
[cited by applicant]
Holt et al., “Domain antibodies: proteins for therapy,” Trends Biotechnol. Nov. 2003;21(11):484-90.
[cited by applicant]
Huang et al., “Molecular alterations in prostate carcinomas that associate with in vivo exposure to chemotherapy: identification of a cytoprotective mechanism involving growth differentiation factor 15,” Clin Cancer Res…
[cited by applicant]
Huh et al., “Macrophage inhibitory cytokine-1 regulates melanoma vascular development,” Am J Pathol. Jun. 2010; 176(6):2948-57.
[cited by applicant]
Husaini et al., “Macrophage inhibitory cytokine-1 (MIC-1/GDF15) slows cancer development but increases metastases in TRAMP prostate cancer prone mice,” PLoS One. 2012;7(8):e43833.
[cited by applicant]
Jackson and Linsley, “Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application,” Nat Rev Drug Discov. Jan. 2010;9(1):57-67.
[cited by applicant]
Jerby-Arnon et al., “A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade,” Cell. Nov. 1, 2018;175(4):984-997.e24.
[cited by applicant]
Ji et al., “An immune-active tumor microenvironment favors clinical response to ipilimumab,” Cancer Immunol Immunother. Jul. 2012;61(7):1019-31.
[cited by applicant]
Ji et al., “Twist promotes invasion and cisplatin resistance in pancreatic cancer cells through growth differentiation factor 15,” Mol Med Rep. Sep. 2015; 12(3):3841-3848.
[cited by applicant]
Johnen et al., “Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1,” Nat Med. Nov. 2007;13(11):1333-40.
[cited by applicant]
Jones et al., “Replacing the complementarity-determining regions in a human antibody with those from a mouse,” Nature. 1986;321(6069):522-5.
[cited by applicant]
Jones et al., “Supraphysiologic Administration of GDF11 Induces Cachexia in Part by Upregulating GDF15,” Cell Rep. Feb. 6, 2018;22(6):1522-1530.
[cited by applicant]
Joshi et al., “Growth differentiation factor 15 (GDF15)-mediated HER2 phosphorylation reduces trastuzumab sensitivity of HER2-overexpressing breast cancer cells,” Biochem Pharmacol. Nov. 1, 2011;82(9):1090-9.
[cited by applicant]
Junker, “Development and characterization of monoclonal antibodies to GDF-15 for potential use in cancer therapy,” Doctoral Thesis, Graduate School of Life Sciences, Julius-Maximilians-Universität Würzburg, Section: Inf…
[cited by applicant]
Kanasty et al., “Delivery materials for siRNA therapeutics,” Nat Mater. Nov. 2013; 12(11):967-77.
[cited by applicant]
Kang et al., “Tolfenamic acid induces apoptosis and growth inhibition in head and neck cancer: involvement of NAG-1 expression,” PLoS One. 2012;7(4):e34988.
[cited by applicant]
Kempf et al., “GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in miceGDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocard…
[cited by applicant]
Kim et al., “Implication of NAG-1 in synergistic induction of apoptosis by combined treatment of sodium salicylate and PI3K/MEK1/2 inhibitors in A549 human lung adenocarcinoma cells,” Biochem Pharmacol. May 1, 2008;75(9…
[cited by applicant]
Kim et al., “Macrophage inhibitory cytokine-1 activates AKT and ERK-1/2 via the transactivation of ErbB2 in human breast and gastric cancer cells,” Carcinogenesis. Apr. 2008;29(4):704-12.
[cited by applicant]
Kim et al., “NSAID-activated gene 1 mediates pro-inflammatory signaling activation and paclitaxel chemoresistance in type I human epithelial ovarian cancer stem-like cells,” Oncotarget. Nov. 1, 2016;7(44):72148-66.
[cited by applicant]
Knoepfel et al., “Selection of RNAi-based inhibitors for anti-HIV gene therapy,” World J Virol. Jun. 12, 2012;1(3):79-90.
[cited by applicant]
Köhler and Milstein, “Continuous cultures of fused cells secreting antibody of predefined specificity,” Nature. Aug. 7, 1975;256(5517):495-7.
[cited by applicant]
Lasithiotakis et al., “The incidence and mortality of cutaneous melanoma in Southern Germany: trends by anatomic site and pathologic characteristics, 1976 to 2003,” Cancer. Sep. 15, 2006;107(6):1331-9.
[cited by applicant]
Lavaud and Andre, “Strategies to overcome trastuzumab resistance in HER2-overexpressing breast cancers: focus on new data from clinical trials,” BMC Med. 2014; 12:132.
[cited by applicant]
Li et al., “GDF15 promotes EMT and metastasis in colorectal cancer,” Oncotarget. Jan. 5, 2016;7(1):860-72.
[cited by applicant]
Li et al., “Growth differentiation factor 15 is a promising diagnostic and prognostic biomarker in colorectal cancer,” J Cell Mol Med. Aug. 2016;20(8):1420-6.
[cited by applicant]
Li and Dewey, “RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome,” BMC Bioinformatics. Aug. 4, 2011;12:323.
[cited by applicant]
Liu et al., “Association of serum level of growth differentiation factor 15 with liver cirrhosis and hepatocellular carcinoma,” PLoS One. May 21, 2015;10(5):e0127518.
[cited by applicant]
Llopiz et al., “Combined immunization with adjuvant molecules poly(I:C) and anti-CD40 plus a tumor antigen has potent prophylactic and therapeutic antitumor effects,” Cancer Immunol Immunother. Jan. 2008;57(1):19-29.
[cited by applicant]
Long et al., “Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/Keynote-252): a phase 3, randomised, double-blind study,” Lancet Oncol. Aug. …
[cited by applicant]
Maasho et al., “NKG2D is a costimulatory receptor for human naive CD8+ T cells,” J Immunol. Apr. 15, 2005;174(8):4480-4.
[cited by applicant]
Meier et al., “Knockdown of platinum-induced growth differentiation factor 15 abrogates p27-mediated tumor growth delay in the chemoresistant ovarian cancer model A2780cis,” Cancer Med. Feb. 2015;4(2):253-67.
[cited by applicant]
Marks et al., “By-passing immunization. Human antibodies from V-gene libraries displayed on phage,” J Mol Biol. Dec. 5, 1991;222(3):581-97.
[cited by applicant]
Mehta et al., “A prospective study of macrophage inhibitory cytokine-1 (MIC-1/GDF15) and risk of colorectal cancer,” J Natl Cancer Inst. Apr. 2014; 106(4):dju016.
[cited by applicant]
Mehta et al., “Association Between Plasma Levels of Macrophage Inhibitory Cytokine-1 Before Diagnosis of Colorectal Cancer and Mortality,” Gastroenterology. Sep. 2015;149(3):614-22.
[cited by applicant]
Miller and Sadelain, “The journey from discoveries in fundamental immunology to cancer immunotherapy,” Cancer Cell. Apr. 13, 2015;27(4):439-49.
[cited by applicant]
Mimeault and Batra, “Divergent molecular mechanisms underlying the pleiotropic functions of macrophage inhibitory cytokine-1 in cancer,” J Cell Physiol. Sep. 2010;224(3):626-35.
[cited by applicant]
Mimeault et al., “Marked improvement of cytotoxic effects induced by docetaxel on highly metastatic and androgen-independent prostate cancer cells by downregulating macrophage inhibitory cytokine-1,” Br J Cancer. Mar. 1…
[cited by applicant]
Motz et al., “Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors,” Nat Med. Jun. 2014;20(6):607-15.
[cited by applicant]
Motzer et al., “Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma,” N Engl J Med. Nov. 5, 2015;373(19):1803-13.
[cited by applicant]
Neuzillet et al., “Targeting the TGF(beta) pathway for cancer therapy,” Pharmacol Ther. Mar. 2015; 147:22-31.
[cited by applicant]
Patel et al., “GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans,” Cell Metab. Mar. 5, 2019;29(3):707-718.e8.
[cited by applicant]
PCT International Search Report and Written Opinion from PCT/EP2016/073520, dated May 19, 2017.
[cited by applicant]
Peng et al., “Growth and differentiation factor 15 regulates PD-L1 expression in glioblastoma,” Cancer Manag Res. Apr. 2, 2019;11:2653-2661.
[cited by applicant]
Reardon et al., “An update on vaccine therapy and other immunotherapeutic approaches for glioblastoma,” Expert Rev Vaccines. Jun. 2013;12(6):597-615.
[cited by applicant]
Ribas et al., “Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (Keynote-002): a randomised, controlled, phase 2 trial,” Lancet Oncol. Aug. 2015; 16(8):908-18.
[cited by applicant]
Riechmann et al., “Reshaping human antibodies for therapy,” Nature. Mar. 24, 1988;332(6162):323-7.
[cited by applicant]
Rizvi et al., “Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer,” Science. Apr. 3, 2015;348(6230):124-8.
[cited by applicant]
Robert et al., “Pembrolizumab versus Ipilimumab in Advanced Melanoma,” N Engl J Med. Jun. 25, 2015;372(26):2521-32.
[cited by applicant]
Roth et al., “GDF-15 contributes to proliferation and immune escape of malignant gliomas,” Clin Cancer Res. Aug. 1, 2010;16(15):3851-9.
[cited by applicant]
Rothschild et al., “SAKK 16/14: Anti-PD-L1 antibody durvalumab (MED14736) in addition to neoadjuvant chemotherapy in patients with stage IIIA(N2) non-small cell lung cancer (NSCLC)—A multicenter single-arm phase II tria…
[cited by applicant]
Saerens et al., “Single-domain antibodies as building blocks for novel therapeutics,” Curr Opin Pharmacol. Oct. 2008; 8(5):600-8.
[cited by applicant]
Schiegnitz et al., “GDF 15 as an anti-apoptotic, diagnostic and prognostic marker in oral squamous cell carcinoma,” Oral Oncol. Jul. 2012;48(7):608-14.
[cited by applicant]
Schiegnitz et al., “Growth differentiation factor 15 as a radiation-induced marker in oral carcinoma increasing radiation resistance,” J Oral Pathol Med. Jan. 2016;45(1):63-9.
[cited by applicant]
Search Report Under Section 17(5) from GB1607801.6, dated Jan. 27, 2017.
[cited by applicant]
Sela-Culang et al., “The structural basis of antibody-antigen recognition,” Front Immunol. Oct. 8, 2013;4:302.
[cited by applicant]
Selander et al., “Serum macrophage inhibitory cytokine-1 concentrations correlate with the presence of prostate cancer bone metastases,” Cancer Epidemiol Biomarkers Prev. Mar. 2007;16(3):532-7.
[cited by applicant]
Senapati et al., “Overexpression of macrophage inhibitory cytokine-1 induces metastasis of human prostate cancer cells through the FAK-RhoA signaling pathway,” Oncogene. Mar. 4, 2010;29(9):1293-302.
[cited by applicant]
Senovilla et al., “Trial watch: Prognostic and predictive value of the immune infiltrate in cancer,” Oncoimmunology. Nov. 1, 2012;1(8):1323-1343.
[cited by applicant]
Shnaper et al., “Elevated levels of MIC-1/GDF15 in the cerebrospinal fluid of patients are associated with glioblastoma and worse outcome,” Int J Cancer. Dec. 1, 2009;125(11):2624-30.
[cited by applicant]
Siegel, “Recombinant monoclonal antibody technology,” Transfus Clin Biol. Jan. 2002;9(1):15-22.
[cited by applicant]
Spranger and Gajewski, “Tumor-intrinsic oncogene pathways mediating immune avoidance,” Oncoimmunology. Aug. 31, 2015;5(3):e1086862.
[cited by applicant]
Staff et al., “Elevated plasma growth differentiation factor-15 correlates with lymph node metastases and poor survival in endometrial cancer,” Clin Cancer Res. Jul. 15, 2011;17(14):4825-33.
[cited by applicant]
Staff et al., “Growth differentiation factor-15 as a prognostic biomarker in ovarian cancer,” Gynecol Oncol. Sep. 2010; 118(3):237-43.
[cited by applicant]
Stefanescu et al., “Mass spectrometric approaches for elucidation of antigenantibody recognition structures in molecular immunology,” Eur J Mass Spectrom (Chichester). 2007;13(1):69-75.
[cited by applicant]
Suchard et al., “A monovalent anti-human CD28 domain antibody antagonist: preclinical efficacy and safety,” J Immunol. Nov. 1, 2013;191(9):4599-610.
[cited by applicant]
Suckau et al., “Molecular epitope identification by limited proteolysis of an immobilized antigen-antibody complex and mass spectrometric peptide mapping,” Proc Natl Acad Sci U S A. Dec. 1990;87(24):9848-52.
[cited by applicant]
Tanno et al., “Growth differentiating factor 15 enhances the tumor-initiating and self-renewal potential of multiple myeloma cells,” Blood. Jan. 30, 2014;123(5):725-33.
[cited by applicant]
Tanno et al., “The TGF-(beta) Family Member Growth Differentiation Factor 15 (GDF15) Regulates the Self-Renewal of Multiple Myeloma Cancer Stem Cells,” Blood. Nov. 18, 2011;118(21):2954(abstract).
[cited by applicant]
Tanno et al., “Growth differentiation factor 15 in erythroid health and disease,” Curr Opin Hematol. May 2010;17(3):184-90.
[cited by applicant]
Taube et al., “Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy,” Clin Cancer Res. Oct. 1, 2014;20(19):5064-74.
[cited by applicant]
Thompson et al., “Human Anti-CD40 Antibody and Poly IC:LC Adjuvant Combination Induces Potent T Cell Responses in the Lung of Nonhuman Primates,” J Immunol. Aug. 1, 2015;195(3):1015-24.
[cited by applicant]
Topalian et al., “Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab,” J Clin Oncol. Apr. 1, 2014;32(10):1020-30.
[cited by applicant]
Topalian et al., “Immune checkpoint blockade: a common denominator approach to cancer therapy,” Cancer Cell. Apr. 13, 2015;27(4):450-61.
[cited by applicant]
Tsai et al., “Clinical characteristics predictive of response to pembrolizumab in advanced melanoma,” J Clin Oncol. 2015;33(15): 9031 (abstract).
[cited by applicant]
Tsui et al., “Growth differentiation factor-15 upregulates interleukin-6 to promote tumorigenesis of prostate carcinoma PC-3 cells,” J Mol Endocrinol. Sep. 5, 2012;49(2):153-63.
[cited by applicant]
Tumeh et al., “PD-1 blockade induces responses by inhibiting adaptive immune resistance,” Nature. Nov. 27, 2014;515(7528):568-71.
[cited by applicant]
Van der Burg et al., “Immunoguiding, the Final Frontier in the Immunotherapy of Cancer,” Cancer Immunotherapy Meets Oncology, Springer, Cham. 2014;37-51.
[cited by applicant]
Wallentin et al., “GDF-15 for prognostication of cardiovascular and cancer morbidity and mortality in men,” PLoS One. Dec. 2, 2013;8(12):e78797.
[cited by applicant]
Walsh et al., “NKG2D receptor signaling enhances cytolytic activity by virus-specific CD8+ T cells: evidence for a protective role in virus-induced encephalitis,” J Virol. Mar. 2008;82(6):3031-44.
[cited by applicant]
Wang et al., “The H6D genetic variation of GDF15 is associated with genesis, progress and prognosis in colorectal cancer,” Pathol Res Pract. Nov. 2015;211(11):845-50.
[cited by applicant]
Wang et al., “The prognostic value of PD-L1 expression for non-small cell lung cancer patients: a meta-analysis,” Eur J Surg Oncol. Apr. 2015;41(4):450-6.
[cited by applicant]
Westhrin et al., “Growth differentiation factor 15 (GDF15) promotes osteoclast differentiation and inhibits osteoblast differentiation and high serum GDF15 levels are associated with multiple myeloma bone disease,” Haem…
[cited by applicant]
Xu et al., “Growth differentiation factor 15 induces growth and metastasis of human liver cancer stem-like cells via AKT/GSK-3(beta)/(beta)-catenin signaling,” Oncotarget. Mar. 7, 2017;8(10):16972-16987.
[cited by applicant]
Yadav et al., “Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing,” Nature. Nov. 27, 2014;515(7528): 572-6.
[cited by applicant]
Yang et al., “Elevated level of serum growth differentiation factor 15 is associated with oral leukoplakia and oral squamous cell carcinoma,” J Oral Pathol Med. Jan. 2014;43(1):28-34.
[cited by applicant]
Yang et al., “GDF15 is a potential predictive biomarker for TPF induction chemotherapy and promotes tumorigenesis and progression in oral squamous cell carcinoma,” Ann Oncol. Jun. 2014;25(6):1215-22.
[cited by applicant]
Yoon et al., “Activin receptor-like kinase5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby derepressing eomesodermin in cytotoxic T lymphocytes,” EMBO Mol Med. Nov. 2013;5(11):1720-39.
[cited by applicant]
Yoshida et al., “Pharmacological profile and clinical efficacy of human anti-human PD-1 antibody nivolumab (OPDIVO®) as a new immune checkpoint inhibitor,” Nihon Yakurigaku Zasshi. Aug. 2015;146(2):106-14.
[cited by applicant]
Yu and Fu, “Tumor-infiltrating T lymphocytes: friends or foes?” Lab Invest. Mar. 2006;86(3):231-45.
[cited by applicant]
Zhang et al., “Prognostic value of pretreatment serum lactate dehydrogenase level in patients with solid tumors: a systematic review and meta-analysis,” Sci Rep. Apr. 22, 2015;5:9800.
[cited by applicant]
Zhao et al., “Identification of candidate biomarkers of therapeutic response to docetaxel by proteomic profiling,” Cancer Res. Oct. 1, 2009;69(19):7696-703.
[cited by applicant]
Zhou et al., “Growth differentiation factor-15 suppresses maturation and function of dendritic cells and inhibits tumor-specific immune response,” PLoS One. Nov. 13, 2013;8(11):e78618.
[cited by applicant]
Bridge, “Induction of an interferon response by RNAi vectors in mammalian cells” Nature Genetics, 2003.
[cited by applicant]
Melero Bermejo, “Initial results from the phase 2A trial of visugromab (CTL-002) + nivolumab in advanced/metastatic anti-PD1/-L1 relapsed/refractory solid tumors (The Gdfather-Trial)” American Society of Clinical Oncolo…
[cited by applicant]
Kanasty, “Action and Reaction: The Biological Response to siRNA and Its Delivery Vehicles” Molecular Therapy, 2012.
[cited by applicant]
Sindhu, “Illuminating the Gateway of Gene Silencing: Perspective of RNA Interference Technology in Clinical Therapeutics” Molecular Biotechnology, 2012.
[cited by applicant]
Yang, “GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand” Nature Medicine, 2017.
[cited by applicant]
Hsu, “Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15” Nature, 2017.
[cited by applicant]
Morral, “shRNA-Induced Interferon-Stimulated Gene Analysis” Cytokine Protocols, Methods in Molecular Biology, vol. 820, 2011.
[cited by applicant]
Min, “NAG-1/GDF15 Accumulates in the nucleus and modulates transcriptional regulation of the Smad pathway” Oncogene, 2015.
[cited by applicant]
Notice of Oppisition mailed from EPO on Sep. 6, 2023 in EP3355919.
[cited by applicant]
Response to Notice of Opposition in EP 3355919, filed with the EPO on Jan. 29, 2024.
[cited by applicant]
Ribas et al. “Masterkey-265: A phase 3, randomized, placebo-controlled study of talimogene laherparepvec plus pembrolizumab for unresectable stage IIIB-IVM1c melanoma” 2021.
[cited by applicant]
Noy et al., “Tumor-Associated Macrophages: From Mechanisms to Therapy” Immunity 41, Jul. 17, 2014.
[cited by applicant]
Paillon et al. “PD-1 inhibits T cell actin remodeling at the immunological synapse independently of its signaling motifs” Sci. Signal. 16, eadh2456 (2023) Nov. 28, 2023.
[cited by applicant]
Rosalia et al., “Use of enhanced interleukin-2 formulations for improved immunotherapy against cancer” Current Opinion in Chemical Biology 2014, 23:39-46.
[cited by applicant]
Zamarin et al. “Immune checkpoint modulation: Rational design of combination strategies” Pharmacology & Therapeutics 150 (2015) 23-32.
[cited by applicant]
Zamarin et al. “Potentiation of immunomodulatory antibody therapy with oncolytic viruses for treatment of cancer” pp. 1-10, Molecular Therapy—Oncolytics (2014) 1, 14004.
[cited by applicant]
Kaufman et al. “Oncolytic viruses: a new class of immunotherapy drugs” pp. 642-662, Nature Reviews, Sep. 2015, vol. 14.
[cited by applicant]
Crawford et al. A Phase Ib First-In-Patient Study Assessing the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Ponsegromab in Participants with Cancer and Cachexia. Clin Cancer Res. Feb. 1, 2024;30 (3):…
[cited by applicant]
Pebernard et al. “Determinants of interferon-stimulated gene induction by RNAi vectors” Di?erentiation (2004) 72:103-111.
[cited by applicant]
Kenworthy et al. “Short-hairpin RNAs delivered by lentiviral vector transduction trigger RIG-I-mediated IFN activation” Nucleic Acids Research, 2009, vol. 37, No. 19 6587-6599.
[cited by applicant]
Rudin et al. “Skyscrapper-02: Primary results of a phase III, randomized, double-blind, placebo-controlled study of atezolizumab (atezo) + carboplatin + etoposide (CE) with or without tiragolumab (tira) in patients (pts…
[cited by applicant]
Breen et al. “Investigating the effects of ponsegromab (anti-GDF-15 mAb) in combination with anti-cancer treatments in preclinical models” 7th Cancer Cachexia Conference, Sep. 29-30, 2023, Edinburgh, Scotland.
[cited by applicant]
Klar “Experimental Report: Correlation between serum GDF-15 and CD8 positive T cell density in the tumor of UC patients” Munich, Jan. 22, 2024.
[cited by applicant]
Second Experimental Report, Feb. 10, 2021.
[cited by applicant]
Experimental Report, May 26, 2021.
[cited by applicant]
Publication Information on Morral, “shRNA-Induced Interferon-Stimulated Gene Analysis” Cytokine Protocols, Methods in Molecular Biology, vol. 820, 2011.
[cited by applicant]
Abstract of Min, “NAG-1/GDF15 Accumulates in the nucleus and modulates transcriptional regulation of the Smad pathway” Oncogene, 2015.
[cited by applicant]
Al Qaraghuli et al. (2020), “Antibody-protein binding and conformational changes: identifying allosteric signalling pathways to engineer a better effector response,” Sci Rep. 10(1): 13696.
[cited by applicant]
Edwards et al. (20003), “The remarkable flexibility of the human antibody repertoire; isolation of over one thousand different antibodies to a single protein, BLyS,” J Mol Biol. 334(1): 103-118.
[cited by applicant]
Goel et al., (2004), “Plasticity within the antigen-combining site may manifest as molecular mimicry in the humoral immune response,” J Immunol. 173(12): 7358-7367.
[cited by applicant]
Khan et al. (2014), “Adjustable locks and flexible keys: plasticity of epitope-paratope interactions in germline antibodies,” J Immunol. 192(11): 5398-5405.
[cited by applicant]
Lloyd et al. (2009), “Modelling the human immune response: performance of a 1011 human antibody repertoire against a broad panel of therapeutically relevant antigens,” Protein Eng Des Sel. 22(3): 159-168.
[cited by applicant]
Poosarla et al. (2017), “Computational de novo design of antibodies binding to a peptide with high affinity,” Biotechnol Bioeng. 114(6): 1331-1342.
[cited by applicant]
Rabia et al. (2018), “Understanding and overcoming trade-offs between antibody affinity, specificity, stability and solubility,” Biochem Eng J. 137: 365-374.
[cited by applicant]
Ahmadzadeh et al., “Antibody humanization methods for development of therapeutic applications,” Monoclon Antib Immunodiagn Immunother. 2014 33(2):67-73.
[cited by applicant]
Mader et al., “Humanization strategies for an anti-idiotypic antibody mimicking HIV-1 gp41,” Protein Eng Des Sel. 2010 23(12):947-54.
[cited by applicant]
Breen et al., “GDF-15 Neutralization Alleviates Platinum-Based Chemotherapy-Induced Emesis, Anorexia, and Weight Loss in Mice and Nonhuman Primates,” Cell Metab. 2020 32(6): 938-950 e6. doi: 10.1016/j.cmet.2020.10.023. …
[cited by applicant]
Chen et al., “Selection and analysis of an optimized anti-VEGF antibody: crystal structure of an affinity-matured Fab in complex with antigen,” 1999 293(4): 865-81 doi: 10.1006/jmbi.1999.3192.
[cited by applicant]
De Pascalis et al., “Grafting of “abbreviated” complementarity-determining regions containing specificity-determining residues essential for ligand contact to engineer a less immunogenic humanized monoclonal antibody,” …
[cited by applicant]
Fairlie et al., “Epitope mapping of the transforming growth factor-beta superfamily protein, macrophage inhibitory cytokine-1 (MIC-1): identification of at least five distinct epitope specificities,” 2001 40(1):65-73. d…
[cited by applicant]
Fearon et al., “Definition and classification of cancer cachexia: an international consensus,” 2011 12(5):489-95. doi: 10.1016/S1470-2045(10)70218-7.
[cited by applicant]
Fearon et al., “Cancer cachexia: developing multimodal therapy for a multidimensional problem,” 2008 44(8): 1124-32. doi: 10.1016/j.ejca.2008.02.033. Epub Mar. 28, 2008.
[cited by applicant]
Qian et al., “Prostate cancer-associated gene expression alterations determined from needle biopsies,” Clin Cancer Res. 2009 15(9):3135-42. doi: 10.1158/1078-0432.CCR-Aug. 1982. Epub Apr. 14, 2009.
[cited by applicant]
Janeway et al., Immunobiology: The Immune System in Health and Disease. 5th Ed., New York, Garland Science 2001.
[cited by applicant]
Liu et al., “Association of serum level of growth differentiation factor 15 with liver cirrhosis and hepatocellular carcinoma,” 2015 PLoS One 10(5):e0127518. doi: 10.1371/journal.pone.0127518.
[cited by applicant]
Liu et al., “Macrophage inhibitory cytokine 1 reduces cell adhesion and induces apoptosis in prostate cancer cells,” Cancer Res. 2003 63(16):5034-40.
[cited by applicant]
MacCallum et al., “Antibody-antigen interactions: contact analysis and binding site topography,” 1996 J Mol Biol. 262(5):732-45. doi: 10.1006/jmbi.1996.0548.
[cited by applicant]
Murphy and Lynch, “Update on emerging drugs for cancer cachexia,” 2009 Expert Opin Emerg Drugs. 14(4):619-32. doi: 10.1517/14728210903369351.
[cited by applicant]
Park et al., “Expression of nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) inversely correlates with tumor progression in gastric adenomas and carcinomas,” 2008 J Cancer Res Clin Oncol. 134(9):1029-35. doi…
[cited by applicant]
Rudikoff et al., “Single amino acid substitution altering antigen-binding specificity,” 1982 Proc Natl Acad Sci U.S.A. 79(6):1979-83. doi: 10.1073/pnas.79.6.1979.
[cited by applicant]
Tisdale et al., “Mechanisms of cancer cachexia,” 2009 Physiol Rev. 89(2):381-410. doi: 10.1152/physrev.00016.2008.
[cited by applicant]
Vajdos et al., “Comprehensive functional maps of the antigen-binding site of an anti-ErbB2 antibody obtained with shotgun scanning mutagenesis,” 2002 J Mol Biol. 320(2):415-28. doi: 10.1016/S0022-2836(02)00264-4.
[cited by applicant]
Wang et al., “Macrophage inhibitory factor 1 acts as a potential biomarker in patients with esophageal squamous cell carcinoma and is a target for antibody-based therapy,” 2014 Cancer Sci. 105(2):176-85. doi: 10.1111/ca…
[cited by applicant]
Wang et al., “Universal PCR amplification of mouse immunoglobulin gene variable regions: the design of degenerate primers and an assessment of the effect of DNA polymerase 3′ to 5′ exonuclease activity,” 2000 J Immunol …
[cited by applicant]
Wu et al., “Humanization of a murine monoclonal antibody by simultaneous optimization of framework and CDR residues,” 1999 J Mol Biol. 294(1):151-62. doi: 10.1006/jmbi.1999.3141.
[cited by applicant]
Zhan et al., “The preparation and funtional characterization of an anti-GDF15 monoclonal antibody,” Chinese Masters These Full-Text Database, Medicine and Health Sciences (Abstract).
[cited by applicant]
Sebastian, “Review of catumaxomab in the treatment of malignant ascites,” Cancer Management and Research. 2010;2:283-286.
[cited by applicant]
Huehls et al. “Bispecific T cell engagers for cancer immunotherapy,” Immunology and cell biology. 2015;93(3):290-296.
[cited by applicant]
Wakefield and Hill, “Beyond TGFβ: roles of other TGFβ superfamily members in cancer,” Nat Rev Cancer. 2013;13 (5):328-41.
[cited by applicant]
Terabe et al., “Synergistic enhancement of CD8+ T cell-mediated tumor vaccine efficacy by an anti-transforming growth factor-β monoclonal antibody,” Clin Cancer Res. 2009; 15(21):6560-9.
[cited by applicant]
Messenheimer et al., “Timing of PD-1 Blockade is Critical to Effective Combination Immunotherapy with Anti-OX40,” Clin Cancer Res; 2017;23(20):6165-6177.
[cited by applicant]
Melero et al. “Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours” Nature. 2025;637:1218-1248.
[cited by applicant]
Melero et al. Supplementary Information “Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours” Nature. 2025.
[cited by applicant]
Clinical trial NCT02423343—A Study of Galunisertib (LY2157299) in Combination With Nivolumab in Advanced Refractory Solid Tumors and in Recurrent or Refractory NSCLC, or Hepatocellular Carcinoma.
[cited by applicant]
“Cancer Types,” <https://www.cancer.gov/types,> Feb. 2022.
[cited by applicant]
U.S. Appl. No. 15/765,176 2019-0160169, filed Mar. 30, 2019 May 30, 2019, Jörgb Wischhusen et al.
[cited by applicant]
Ammi et al., “Poly(I:C) as cancer vaccine adjuvant: Knocking on the door of medical breakthroughs”, Pharmacology & Therapeutics 146 (2015) pp. 120-131.
[cited by applicant]
Cohen et al., “Therapeutic Combinations of Immune-Modulating Antibodies in Melanoma and Beyond”, Seminars in Oncology, vol. 42, No. 3, Jun. 2015, pp. 488-494.
[cited by applicant]
Tosolini et al., “Large-scale microarray profiling reveals four stages of immune escape in non-Hodgkin lymphomas”Oncoimmunology 2016, vol. 5, No. 7, e1188246 (10 pages).
[cited by applicant]
Vonderheide and Glennie, “Agonistic CD40 Antibodies and Cancer Therapy”, Clin Cancer Res; 19(5) Mar. 1, 2013, pp. 1035-1043.
[cited by applicant]
Wischhusen and Haake, “Experimental Report: Combination treatment with anti-PD-1 + anti GDF-15 in a mouse model based on GD-15-transfected MC38 colon cancer cells,” 2020 (4 pages).
[cited by applicant]
Bluemel et al: “Epitope distance to the target cell membrane and antigen size determine the potency of T cell-mediated lysis by BiTE antibodies specific for a large melanoma surface antigen”, Cancer Immunology, Immunoth…
[cited by applicant]
Dickopf et al: “Format and geometries matter: Structure-based design defines the functionality of bispecific antibodies”, Computational and Structural Biotechnology Journal, vol. 18, May 14, 2020 (May 14, 2020), pp. 122…
[cited by applicant]
Dotan et al: “Impact of Rituximab (Rittman) on the Treatment of B-Cell Non-Hodgkin's Lymphoma”, Pharmacy and Therapeutics, vol. 35, No. 3, Mar. 1, 2010 (Mar. 1, 2010), pp. 1-10.
[cited by applicant]
Hoffman et al: “Blinatumomab, a Bi-Specific Anti-CD19/CD3 BiTEA® Antibody for the Treatment of Acute Lymphoblastic Leukemia: Perspectives and Current Pediatric Applications”, Frontiers in Oncology, vol. 4, Mar. 31, 2014…
[cited by applicant]
Li et al: “Adoptive Transfer of Tumor Reactive B Cells Confers Host T-Cell Immunity and Tumor Regression”, Clinical Cancer Research, vol. 17, No. 15, Jun. 20, 2011 (Jun. 20, 2011), pp. 4987-4995.
[cited by applicant]
Roda-Navarro et al: “Understanding the Spatial Topology of Artificial Immunological Synapses Assembled in T Cell-Redirecting Strategies: A Major Issue in Cancer Immunotherapy”, Frontiers in Cell and Developmental Biolog…
[cited by applicant]
International Search Report and Written Opinion for PCT/EP2016/073519 dated Jan. 5, 2017.
[cited by applicant]
Search Report for priority application GB1607800.8 dated Jan. 27, 2017.
[cited by applicant]
Lanitis et al., “Targeting the tunor vasculature to enhance T cell activity,” Current Opinion in Immunology. 1 2015;33:55-63.
[cited by applicant]
Vicent et al., “Bone Metastases in Lung Cancer Potential Novel Approaches to Therapy,” Am J Respir Crit Care Med. 2015;192(7):799-809.
[cited by applicant]
Herbertz et al., “Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway,” Drug Design, Development and Therapy. 2015;9:4479-4499.
[cited by applicant]