Display options
Cite
Schoeberl B, Kudla A, Masson K, et al. Systems biology driving drug development: from design to the clinical testing of the anti-ErbB3 antibody seribantumab (MM-121). NPJ Syst Biol Appl. 2017;3:16034doi: 10.1038/npjsba.2016.34.
Schoeberl, B., Kudla, A., Masson, K., Kalra, A., Curley, M., Finn, G., Pace, E., Harms, B., Kim, J., Kearns, J., Fulgham, A., Burenkova, O., Grantcharova, V., Yarar, D., Paragas, V., Fitzgerald, J., Wainszelbaum, M., West, K., Mathews, S., Nering, R., Adiwijaya, B., Garcia, G., Kubasek, B., Moyo, V., Czibere, A., Nielsen, U. B., & MacBeath, G. (2017). Systems biology driving drug development: from design to the clinical testing of the anti-ErbB3 antibody seribantumab (MM-121). NPJ systems biology and applications, 316034. https://doi.org/10.1038/npjsba.2016.34
Schoeberl, Birgit, et al. "Systems biology driving drug development: from design to the clinical testing of the anti-ErbB3 antibody seribantumab (MM-121)." NPJ systems biology and applications vol. 3 (2017): 16034. doi: https://doi.org/10.1038/npjsba.2016.34
Schoeberl B, Kudla A, Masson K, Kalra A, Curley M, Finn G, Pace E, Harms B, Kim J, Kearns J, Fulgham A, Burenkova O, Grantcharova V, Yarar D, Paragas V, Fitzgerald J, Wainszelbaum M, West K, Mathews S, Nering R, Adiwijaya B, Garcia G, Kubasek B, Moyo V, Czibere A, Nielsen UB, MacBeath G. Systems biology driving drug development: from design to the clinical testing of the anti-ErbB3 antibody seribantumab (MM-121). NPJ Syst Biol Appl. 2017 Jan 05;3:16034. doi: 10.1038/npjsba.2016.34. eCollection 2017. PMID: 28725482; PMCID: PMC5516865.
Copy Download .nbib Format: NLM
Share it on

NPJ Syst Biol Appl. 2017 Jan 05;3:16034. doi: 10.1038/npjsba.2016.34. eCollection 2017.

Systems biology driving drug development: from design to the clinical testing of the anti-ErbB3 antibody seribantumab (MM-121).

NPJ systems biology and applications

Birgit Schoeberl, Art Kudla, Kristina Masson, Ashish Kalra, Michael Curley, Gregory Finn, Emily Pace, Brian Harms, Jaeyeon Kim, Jeff Kearns, Aaron Fulgham, Olga Burenkova, Viara Grantcharova, Defne Yarar, Violette Paragas, Jonathan Fitzgerald, Marisa Wainszelbaum, Kip West, Sara Mathews, Rachel Nering, Bambang Adiwijaya, Gabriela Garcia, Bill Kubasek, Victor Moyo, Akos Czibere, Ulrik B Nielsen, Gavin MacBeath

Affiliations

  1. Merrimack Pharmaceuticals, Cambridge, MA, USA.
  2. Celgene, San Francisco, CA, USA.
  3. PatientsLikeMe, Cambridge, MA, USA.
  4. Synlogic, Cambridge, MA, USA.
  5. L.E.A.F. Pharmaceuticals, Radnor, PA, USA.
  6. Torque, Cambridge, MA, USA.

PMID: 28725482 PMCID: PMC5516865 DOI: 10.1038/npjsba.2016.34

Abstract

The ErbB family of receptor tyrosine kinases comprises four members: epidermal growth factor receptor (EGFR/ErbB1), human EGFR 2 (HER2/ErbB2), ErbB3/HER3, and ErbB4/HER4. The first two members of this family, EGFR and HER2, have been implicated in tumorigenesis and cancer progression for several decades, and numerous drugs have now been approved that target these two proteins. Less attention, however, has been paid to the role of this family in mediating cancer cell survival and drug tolerance. To better understand the complex signal transduction network triggered by the ErbB receptor family, we built a computational model that quantitatively captures the dynamics of ErbB signaling. Sensitivity analysis identified ErbB3 as the most critical activator of phosphoinositide 3-kinase (PI3K) and Akt signaling, a key pro-survival pathway in cancer cells. Based on this insight, we designed a fully human monoclonal antibody, seribantumab (MM-121), that binds to ErbB3 and blocks signaling induced by the extracellular growth factors heregulin (HRG) and betacellulin (BTC). In this article, we present some of the key preclinical simulations and experimental data that formed the scientific foundation for three Phase 2 clinical trials in metastatic cancer. These trials were designed to determine if patients with advanced malignancies would derive benefit from the addition of seribantumab to standard-of-care drugs in platinum-resistant/refractory ovarian cancer, hormone receptor-positive HER2-negative breast cancer, and EGFR wild-type non-small cell lung cancer (NSCLC). From preclinical studies we learned that basal levels of ErbB3 phosphorylation correlate with response to seribantumab monotherapy in mouse xenograft models. As ErbB3 is rapidly dephosphorylated and hence difficult to measure clinically, we used the computational model to identify a set of five surrogate biomarkers that most directly affect the levels of p-ErbB3: HRG, BTC, EGFR, HER2, and ErbB3. Preclinically, the combined information from these five markers was sufficient to accurately predict which xenograft models would respond to seribantumab, and the single-most accurate predictor was HRG. When tested clinically in ovarian, breast and lung cancer, HRG mRNA expression was found to be both potentially prognostic of insensitivity to standard therapy and potentially predictive of benefit from the addition of seribantumab to standard of care therapy in all three indications. In addition, it was found that seribantumab was most active in cancers with low levels of HER2, consistent with preclinical predictions. Overall, our clinical studies and studies of others suggest that HRG expression defines a drug-tolerant cancer cell phenotype that persists in most solid tumor indications and may contribute to rapid clinical progression. To our knowledge, this is the first example of a drug designed and clinically tested using the principles of Systems Biology.

Conflict of interest statement

The authors declare no conflict of interest.

References

  1. Cell. 2012 May 11;149(4):780-94 - PubMed
  2. Mol Cancer Ther. 2015 Sep;14(9):2072-80 - PubMed
  3. Cancer Epidemiol Biomarkers Prev. 2010 Apr;19(4):982-91 - PubMed
  4. Sci Signal. 2009 Jun 30;2(77):ra31 - PubMed
  5. J Clin Invest. 2013 Oct;123(10 ):4329-43 - PubMed
  6. Br J Pharmacol. 2011 Mar;162(6):1239-49 - PubMed
  7. Cancer Res. 1987 Jan 15;47(2):414-8 - PubMed
  8. Breast Cancer Res. 2011 Mar 11;13(2):R29 - PubMed
  9. Nat Biotechnol. 2005 Feb;23(2):191-4 - PubMed
  10. Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10773-8 - PubMed
  11. J Clin Oncol. 2015 Dec 1;33(34):4032-8 - PubMed
  12. Am J Transl Res. 2015 Apr 15;7(4):733-50 - PubMed
  13. Clin Cancer Res. 2015 Mar 1;21(5):1106-14 - PubMed
  14. Sci Signal. 2013 Sep 24;6(294):ra84 - PubMed
  15. Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):3320-5 - PubMed
  16. Nat Rev Cancer. 2005 Jan;5(1):65-72 - PubMed
  17. PLoS One. 2013;8(2):e56765 - PubMed
  18. Biometrics. 1982 Dec;38(4):963-74 - PubMed
  19. Mol Cancer Ther. 2015 Nov;14 (11):2642-52 - PubMed
  20. J Natl Cancer Inst. 2016 Jan 11;108(5):null - PubMed
  21. J Biol Chem. 1998 Oct 23;273(43):28238-46 - PubMed
  22. Sci Transl Med. 2012 Oct 31;4(158):158rv11 - PubMed
  23. Breast. 2003 Dec;12(6):362-7 - PubMed
  24. Mol Cancer Ther. 2002 Jul;1(9):707-17 - PubMed
  25. Nat Rev Drug Discov. 2002 Jul;1(7):493-502 - PubMed
  26. N Engl J Med. 2007 Jul 5;357(1):39-51 - PubMed
  27. Cancer Cell. 2010 Mar 16;17(3):298-310 - PubMed
  28. Nat Rev Drug Discov. 2010 Jul;9(7):523-35 - PubMed
  29. Cancer. 2015 Oct 15;121(20):3600-11 - PubMed
  30. Nucleic Acids Res. 2015 Jan;43(Database issue):D542-8 - PubMed
  31. Mol Cancer Ther. 2012 Mar;11(3):582-93 - PubMed
  32. Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37 - PubMed
  33. Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):5021-6 - PubMed
  34. EBioMedicine. 2015 Feb 12;2(3):264-71 - PubMed
  35. Science. 2007 May 18;316(5827):1039-43 - PubMed
  36. Cancer Res. 2010 Mar 15;70(6):2485-94 - PubMed
  37. J Biol Chem. 2001 Mar 30;276(13):9817-24 - PubMed
  38. Nature. 2007 Jan 25;445(7126):437-41 - PubMed
  39. Methods Enzymol. 2012;502:67-87 - PubMed
  40. J Clin Oncol. 2016 Dec 20;34(36):4345-4353 - PubMed
  41. Mol Syst Biol. 2009;5:239 - PubMed
  42. J Natl Cancer Inst. 2005 Dec 21;97(24):1808-15 - PubMed
  43. Nature. 2011 Feb 10;470(7333):198-203 - PubMed
  44. BMC Biol. 2014 Mar 21;12:20 - PubMed
  45. Cell Syst. 2015 Jul 29;1(1):25-36 - PubMed
  46. Carcinogenesis. 2010 Jan;31(1):2-8 - PubMed
  47. Nature. 2012 Jan 26;483(7387):100-3 - PubMed
  48. Nat Chem Biol. 2006 Sep;2(9):458-66 - PubMed
  49. Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21608-13 - PubMed

Publication Types