Human Genome Sciences
MAPATUMUMAB
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Mapatumumab (HGS-ETR1) is a human monoclonal antibody that induces cancer-cell death in a highly targeted way by activating the protein known as TRAIL receptor 1. HGS is developing mapatumumab as a potential treatment for cancer.[1]

How Mapatumumab Works


Mapatumumab specifically binds to TRAIL receptor-1 and causes it to induce programmed cell death, or apoptosis, in cancer cells (see Figure 1). Mapatumumab does this by mimicking the activity of the natural protein TRAIL (tumor necrosis factor apoptosis-inducing ligand). Human Genome Sciences’ own studies, as well as those of others, show that TRAIL receptor 1 is expressed on a number of solid and hematologic cancers. It has been demonstrated that cell lines derived from a broad array of human cancer types are sensitive to killing by apoptosis induced by either native TRAIL or antibodies to TRAIL receptor.[2-23]

Figure 1. Mapatumumab selectively binds to TRAIL receptor 1, causing programmed cell death, or apoptosis, in cancer cells.


Potential Therapeutic Settings


Mapatumumab has potential either as a single agent or in combination with chemotherapy for the treatment of cancer. The results of preclinical and clinical studies to date demonstrate that mapatumumab directly triggers cancer cell death through apoptosis, inhibits tumor growth in a variety of cancer types, and reduces the size of tumors in certain cancers.[2-33] Mapatumumab is currently being studied in combination with Nexavar (sorafenib) for the treatment of advanced hepatocellular cancer.[24]

HGS1029

Ongoing Phase 1 trials are evaluating HGS1029 as monotherapy in patients with advanced solid and advanced lymphoid tumors. HGS1029 is an IAP inhibitor, a novel class of compounds that block the activity of IAP (inhibitor of apoptosis) proteins, allowing apoptosis to proceed and causing the cancer cells to die. When IAP proteins are over-expressed in cancer cells, they can help cancer cells resist apoptosis and resume growth and proliferation. HGS plans to continue the study of HGS1029 both alone and in combination with other anti-cancer agents, including mapatumumab.

How Mapatumumab Was Discovered


Using genomic techniques, HGS originally identified TRAIL receptor-1 as a member of the tumor necrosis factor receptor super-family of proteins. HGS studies, as well as those conducted by others, show that TRAIL receptor 1 plays a key role in triggering apoptosis, or programmed cell death, in tumors. HGS developed agonistic human monoclonal antibodies that bind TRAIL receptor 1 and stimulate it to trigger programmed cell death in cancer cells, in much the same way that native TRAIL does, but with the advantage of a longer serum half-life and an exclusive specificity for TRAIL receptor 1. The HGS-ETR1 antibody was generated by HGS through a collaboration with Cambridge Antibody Technology. [35]

For More Information about MAPATUMUMAB Clinical Trials


Health professionals and patients interested in clinical trials of HGS-ETR1, HGS-ETR2 or other HGS products may inquire by e-mailing This e-mail address is being protected from spam bots, you need JavaScript enabled to view it or by calling HGS at (877) 822-8472.

Footnotes

  1. (HGSI Press Release) 1. (HGSI Press Release) Human Genome Sciences Initiates Clinical Development of a Novel Anticancer Drug. April 30, 2002. 
  2. Humphreys RC, et al. TRAIL receptor antibodies synergize with chemotherapy to enhance anti-tumor activity in cholangiocarcinoma. AACR-NCI-EORTC 2007 International Conference on Molecular Targets and Cancer Therapeutics. Poster presentation. 
  3. Humphreys, RC. Development and evaluation of cancer therapeutic agents targeting TRAIL receptor 1 and 2. Cancer Drug Discovery and Development: The Oncogenomics Handbook (Ed.: La Rochelle WJ and Shimkets RA, Humana Press, 2005). 
  4. Younes A, et al. Activity of selective agonistic monoclonal antibodies to TRAIL death receptors R1 and R2 in primary and cultured tumor cells of lymphoid origin. 9th International Conference on Malignant Lymphoma, 2005. Oral presentation. 
  5. (HGSI Press Release) Human Genome Sciences Reports Results Of Preclinical Studies Of Trail-R1 And Trail-R2 Agonistic Human Monoclonal Antibodies At EORTC-NCI-AACR Symposium. October 1, 2004. 
  6. Humphreys RC, et al. HGS-TR2J, a human, agonistic, TRAIL Receptor-2 monoclonal antibody, induces apoptosis, tumor regression and growth inhibition as a single agent in diverse human solid tumor cell lines. 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, 2004: Abstract #204.
  7. W. Halpern, et al. Variable distribution of TRAIL receptor 1 in primary human tumor and normal tissues. 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, 2004: Abstract #225.
  8. Georgakis GV, et al. Selective agonistic monoclonal antibodies to the TRAIL receptors R1 and R2 induce cell death and potentiate the effect of chemotherapy and bortezomib in primary and cultured lymphoma cells. American Society of Clinical Oncology Annual Meeting, 2004. Abstract #6595. 
  9. Gillotte D, Zhang Y, Poortman C, et al. Human agonistic anti-TRAIL receptor antibodies, HGS-ETR1 and HGS-ETR2, induce apoptosis in ovarian tumor lines and their activity is enhanced by taxol and carboplatin. Proceedings from the AACR 2004; 73:3579. 
  10. Humphreys R, et al. Novel, agonistic, human anti-TRAIL receptor monoclonal antibodies, HGS-ETR1 and HGS-ETR2, are capable of potently inducing tumor regression and growth inhibition as single agents and in combination with chemotherapeutic agents in models of human NSCLC. AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. November 2003. Poster #B72.
  11. Humphreys R, et al. TRAIL-R1 mAb, a human agonistic monoclonal antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 1, induces apoptosis in human tumor cells in vitro and in vivo. American Association for Cancer Research 94th Annual Meeting, July 2003. Abstract #6429. 
  12. Younes A, Kadin ME. Emerging applications for the tumor necrosis factor family of ligands and receptors in cancer therapy. J Clin Oncol 2003;21:3526-3534. 
  13. Alderson, Basu, et al. TRAIL-R1 and TRAIL-R2 human agonistic monoclonal antibodies display in vitro and in vivo activity on human cancer cells. Society for Biological Therapy 2002. Oral presentation. 
  14. Pukac, Kanakaraj, Alderson, et al. TRM-1, a fully human TRAIL-R1 agonistic monoclonal antibody, displays in vitro and in vivo anti-tumor activity. American Association for Cancer Research 93rd Annual Meeting, April 2002. Abstract #4240. 
  15. Humphreys RC, et al. TRAIL-R1 and TRAIL-R2 human agonistic monoclonal antibodies display in vitro and in vivo activity on human cancer cells. Society for Biological Therapy 2002; oral presentation.
  16. Ashkenazi A. Targeting death and decoy receptors of the tumor necrosis factor superfamily. Nat Revs Cancer 2002; 2:420-430.
  17. Chuntharapai A, Dodge K, Grimmer K, et al. Isotype-dependent inhibition of tumor growth in vivo by monoclonal antibodies to death receptor 4. J Immunol 2001; 166:4891-4898. 
  18. Tanaka S, Sugimachi K, Shirabe K, et al. Expression and antitumor effects of TRAIL in human cholangiocarcinoma. Hepatology 2000; 32:523-527. 
  19. Buchsbaum DJ, Zhou T, Grizzle WE, et al. Apo-2L/TRAIL in cytokine reference. Academic Press 2000. 
  20. Ashkenazi A. Apo-2L/TRAIL in Cytokine Reference. Academic Press; 2000. 
  21. Pan G, et al. The receptor for the cytotoxic ligand TRAIL. Science 1997; 276: 111-113. 
  22. (HGSI Press Release) Human Genome Sciences Presents New Data Showing Anti-Tumor Activity and Safety of TRAIL Receptor Antibodies in Combination with Chemotherapy. October 24, 2007. 
  23. Mom CH, Sleijfer S, Gietema JA, Verweij J and de Vries EGE, et al. Mapatumumab, a fully human agonistic monoclonal antibody that targets TRAIL-R1, in combination with gemcitabine and cisplatin: a Phase 1b study in patients with advanced solid malignancies. 2006 AACR-NCI-EORTC International Conference on Molecular Therapeutics. November 8, 2006. Abstract #202. 
  24. (HGSI Press Release) Human Genome Sciences Reports Interim Results of Phase 1b Clinical Trial of HGS-ETR1 with Gemcitabine and Cisplatin in Patients with Advanced Solid Tumors. November 8, 2006.
  25. Younes A, Vose J, Zelenetz AD, Czuczman MS, et al. Results of a Phase 2 trial of HGS-ETR1 (agonistic human monoclonal antibody to TRAIL receptor 1) in subjects with relapsed/refractory non-Hodgkin's lymphoma (NHL) (ETR1-HM01). 47th Annual Meeting of the American Society of Hematology, 2005.
  26. (HGSI Press Release) Human Genome Sciences Reports Results of Phase 2 Clinical Trial of HGS-ETR1 in Patients with Advanced Non-Hodgkin's Lymphoma. December 12, 2005. 
  27. Hariharan S, Gore L, Eckhardt SG, Cohen RB, et al. A Phase 1 and pharmacological study of HGS-ETR1, an antibody targeting TRAIL-R1, in combination with paclitaxel and carboplatin in patients with advanced solid malignancies. 2005 AACR-NCI-EORTC International Conference on Molecular Therapeutics.
  28. Mom CH, Sleijfer S, Gietema JA, et al. A Phase 1 study of HGS-ETR1, a fully human monoclonal antibody to TRAIL-R1, in combination with gemcitabine and cisplatin in subjects with advanced solid malignancies. 2005 AACR-NCI-EORTC International Conference on Molecular Therapeutics. 
  29. (HGSI Press Release) Human Genome Sciences Reports Interim Results of Phase 1B Clinical Trials of HGS-ETR1 in Combination with Chemotherapy in Patients with Advanced Solid Tumors. November 17, 2005. 
  30. Kanzler S, Trarbach T, Heinemann V, Köhne CH, Seeber S, et al. Results of a Phase 2 trial of HGS-ETR1 (agonistic human monoclonal antibody to TRAIL receptor 1) in subjects with relapsed or refractory colorectal cancer (CRC). ECCO 13 - the European Cancer Conference, 2005: Abstract #630. 
  31. (HGSI Press Release) Human Genome Sciences Reports Results of Phase 2 Clinical Trial of HGS-ETR1 in Patients with Advanced Colorectal Cancer. November 1, 2005. 
  32. Bonomi P, Greco FA, et al. Results of a Phase 2 trial of HGS-ETR1 (agonistic human monoclonal antibody to TRAIL receptor 1) in subjects with relapsed/recurrent non-small cell lung cancer. 11th World Conference on Lung Cancer. July 4, 2005. Abstract #1851. 
  33. (HGSI Press Release) Human Genome Sciences Reports Results of Phase 2 Clinical Trial of HGS-ETR1 in Patients with Non-Small Cell Lung Cancer." July 5, 2005. 
  34. (HGSI Press Release) Human Genome Sciences Initiates Randomized Phase 2 Clinical Trial of HGS-ETR1 in Combination with Bortezomib. July 20, 2006. 
  35. (HGSI Press Release) Cambridge Antibody Technology and Human Genome Sciences Announce Second Drug Partnership. January 8, 2002.  

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To view announcements on Mapatumumab, click on the following:

Human Genome Sciences Announces Results of Randomized Phase 2 Trial of Mapatumumab in Multiple Myeloma - June 9, 2010 

Human Genome Sciences Announces Results of Randomized Phase 2 Trial of Mapatumumab in Non-Small Cell Lung Cancer - March 17, 2010

Human Genome Sciences Reports Initial Results Of Randomized Phase 2 Trial Of Hgs-Etr1 In Combination With Bortezomib In Advanced Multiple Myeloma - September 2, 2008  

Human Genome Sciences Completes Enrollment in Randomized Phase 2 Trial of HGS-ETR1 in Non-Small Cell Lung Cancer - August 22, 2008 

Human Genome Sciences Advances Oncology Portfolio - April 16, 2008 

Human Genome Sciences Initiates Second Randomized Phase 2 Trial of HGS-ETR1 in Combination with Chemotherapy - December 20, 2007 

Human Genome Sciences Presents New Data Showing Anti-Tumor Activity and Safety of Trail Receptor Antibodies in Combination with Chemotherapy - October 24, 2007

Human Genome Sciences Reports Growing Evidence that its Trail Receptor Antibodies have Significant Potential in the Treatment of a Broad Range of Cancers - April 27, 2007

Human Genome Sciences Reports Interim Results of Phase 1b Clinical Trial of HGS-ETR1 With Gemcitabine and Cisplatin in Patients with Advanced Solid Tumors - November 8, 2006

Human Genome Sciences Initiates Randomized Phase 2 Clinical Trial of HGS- ETR1 in Combination with Bortezomib - July 20, 2006

Human Genome Sciences Reports Results of Phase 2 Clinical Trial of HGS-ETR1 in Patients with Advanced Non-Hodgkin's Lymphoma - December 12, 2005

Human Genome Sciences Reports Interim Results of Phase 1b Clinical Trials of HGS-ETR1 in Combination with Chemotherapy in Patients with Advanced Solid Tumors - November 17, 2005

Human Genome Sciences Reports Results of Phase 1 Clinical Trials of HGS-ETR2 in Patients with Advanced Solid Tumors - November 17, 2005

Human Genome Sciences Reports Results of Phase 2 Clinical Trial of HGS-ETR1 in Patients with Advanced Colorectal Cancer - November 1, 2005

GlaxoSmithKline Exercises Option to Human Genome Sciences' TRAIL Receptor Antibody - August 18, 2005

Human Genome Sciences Reports Results of Phase 2 Clinical Trial of HGS-ETR1 in Patients with Non-Small Cell Lung Cancer - July 5, 2005

Human Genome Sciences Reports Interim Results of Phase 2 Clinical Trial of HGS-ETR1 in Patients with Advanced Non-Hodgkin's Lymphoma - June 13, 2005

Human Genome Sciences Reports Results of Phase 1 Clinical Trials of HGS-ETR2 and HGS-ETR1 in Patients with Advanced Solid Tumors - May 17, 2005

Human Genome Sciences Reports Results of Phase 1 Clinical Trial of HGS-ETR1 in Patients with Advanced Solid Tumors - April 18, 2005

Human Genome Sciences Completes Patient Enrollment in a Phase 2 Clinical Trial of HGS-ETR1 for the Treatment of Non-Hodgkin's Lymphoma - March 3, 2005

Human Genome Sciences Completes Patient Enrollment in a Phase 2 Clinical Trial of HGS-ETR1 for the Treatment of Colorectal Cancer - February 23, 2005

Human Genome Sciences Completes Patient Enrollment in a Phase 2 Clincial Trial of HGS-ETR1 for the Treatment of Non-Small Cell Lung Cancer - November 30, 2004

Human Genome Sciences Begins Dosing of Patients in a Phase 2 Clinical Trial of HGS-ETR1 in Non-Hodgkin's Lymphoma - October 13, 2004

Human Genome Sciences Initiation a Phase 2 Clinical Trial of HGS-ETR1 in Patients with Colorectal Cancer - October 13, 2004

Human Genome Sciences Reports Results of Preclinical Studies of TRAIL-R1 and TRAIL-R2 Agonistic Human Monoclonal Antibodies at EORTC-NCI-AACR Symposium - October 1, 2004

Human Genome Sciences Reports Results of Ongoing Phase 1 Clinical Trials of HGS-ETR1 in Patients With Advanced Cancers - September 29, 2004

Human Genome Sciences Reports Initial Results of Phase 1 Clinical Trials of HGS-ETR2 (TRAIL-R2 mAb) in Patients with Advanced Cancers - September 29, 2004

Human Genome Sciences Advances Anti-Cancer Drug to Phase 2 Clinical Development - September 8, 2004

Human Genome Sciences Reports Results of Phase 1 Clinical Trials of HGS-ETR1 (TRAIL-R1 mAb) in Patients with Advanced Cancers - June 7, 2004

Human Genome Sciences Initiates Clinical Development of TRAIL Receptor-2 Antibody for Treatment of Cancer - July 11, 2003

Human Genome Sciences Announces Joint Development Of Antibody For The Treatment Of Cancer With Kirin - December 3, 2002

Human Genome Sciences reports results of preclinical studies of AlbuleukinTM- and TRAIL-R1 and TRAIL-R2 agonistic human monoclonal antibodies at the Society for Biological Therapy - November 11, 2002

Takeda Exercises Option to Develop Novel Human Genome Sciences Antibody Drug in Japan - August 14, 2002

Human Genome Sciences And Cambridge Antibody Technology Commit to Exclusive Development of Antibody to TRAIL Receptor-2 - May 20, 2002

Human Genome Sciences Initiates Clinical Development of a Novel Anticancer Drug - April 30, 2002

Human Genome Sciences Presentations at the American Association for Cancer Research 93rd Annual Meeting - April 10, 2002

Cambridge Antibody Technology and Human Genome Sciences Announce Second Drug Partnership - January 8, 2002

 
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