title: Monoclonal antibody against cell surface GRP78 as a novel agent in suppressing PI3K/AKT signaling, tumor growth, and metastasis.
abstract: OBJECTIVE
  The ER chaperone GRP78 translocates to the surface of tumor cells and promotes survival, metastasis, and resistance to therapy. An oncogenic function of cell surface GRP78 has been attributed to the activation of the phosphoinositide 3-kinase (PI3K) pathway. We intend to use a novel anti-GRP78 monoclonal antibody (MAb159) to attenuate PI3K signaling and inhibit tumor growth and metastasis.
  
  
  METHODS
  MAb159 was characterized biochemically. Antitumor activity was tested in cancer cell culture, tumor xenograft models, tumor metastasis models, and spontaneous tumor models. Cancer cells and tumor tissues were analyzed for PI3K activity. MAb159 was humanized and validated for diagnostic and therapeutic application.
  
  
  RESULTS
  MAb159 specifically recognized surface GRP78, triggered GRP78 endocytosis, and localized to tumors but not to normal organs in vivo. MAb159 inhibited tumor cell proliferation and enhanced tumor cell death both in vitro and in vivo. In MAb159-treated tumors, PI3K signaling was inhibited without compensatory MAPK pathway activation. Furthermore, MAb159 halted or reversed tumor progression in the spontaneous PTEN-loss-driven prostate and leukemia tumor models, and inhibited tumor growth and metastasis in xenograft models. Humanized MAb159, which retains high affinity, tumor specific localization, and the antitumor activity, was nontoxic in mice, and had desirable pharmacokinetics.
  
  
  CONCLUSIONS
  GRP78-specific antibody MAb159 modulates the PI3K pathway and inhibits tumor growth and metastasis. Humanized MAb159 will enter human trials shortly.
authors.affiliation: Authors' Affiliations: Departments of Pathology, Biochemistry and Molecular Biology, and Radiology; School of Pharmacy, University of Southern California Keck School of Medicine, USC Norris Comprehensive Cancer Center; and VasGene Therapeutics Inc., Los Angeles, California.
authors.forename: Ren
authors.initials: R
authors.lastname: Liu
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Li
authors.forename: Wenming
authors.initials: W
authors.lastname: Gao
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhou
authors.forename: Shiuan
authors.initials: S
authors.lastname: Wey
authors.forename: Satyajit K
authors.initials: SK
authors.lastname: Mitra
authors.forename: Valery
authors.initials: V
authors.lastname: Krasnoperov
authors.forename: Dezheng
authors.initials: D
authors.lastname: Dong
authors.forename: Shuanglong
authors.initials: S
authors.lastname: Liu
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.forename: Genyuan
authors.initials: G
authors.lastname: Zhu
authors.forename: Stan
authors.initials: S
authors.lastname: Louie
authors.forename: Peter S
authors.initials: PS
authors.lastname: Conti
authors.forename: Zibo
authors.initials: Z
authors.lastname: Li
authors.forename: Amy S
authors.initials: AS
authors.lastname: Lee
authors.forename: Parkash S
authors.initials: PS
authors.lastname: Gill
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D053492:Elafin / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D019073:HT29 Cells; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000276:immunology; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053492:Elafin; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; C506806:PI3 protein, human; D051057:Proto-Oncogene Proteins c-akt
references.citation: Antioxid Redox Signal. 2009 Sep;11(9):2299-306
references.pmid: 19331544
references.citation: Mol Ther. 2010 Mar;18(3):561-9
references.pmid: 20010917
references.citation: Biochem J. 2011 Mar 1;434(2):181-8
references.pmid: 21309747
references.citation: Clin Cancer Res. 2005 Jan 1;11(1):397-405
references.pmid: 15671571
references.citation: Oncogene. 2013 Feb 14;32(7):805-18
references.pmid: 22508478
references.citation: Curr Mol Med. 2006 Feb;6(1):45-54
references.pmid: 16472112
references.citation: Cancer Res. 2011 Apr 15;71(8):2848-57
references.pmid: 21467168
references.citation: Nature. 2006 May 25;441(7092):475-82
references.pmid: 16598206
references.citation: Cancer Res. 1992 Mar 15;52(6):1399-405
references.pmid: 1540948
references.citation: Am J Pathol. 2011 Feb;178(2):838-52
references.pmid: 21281816
references.citation: PLoS One. 2012;7(10):e45690
references.pmid: 23049684
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19444-9
references.pmid: 19033462
references.citation: Mol Pharm. 2007 May-Jun;4(3):435-47
references.pmid: 17373820
references.citation: Mol Cell Biol. 2008 Jan;28(2):666-77
references.pmid: 17991893
references.citation: Carcinogenesis. 2013 Sep;34(9):2080-9
references.pmid: 23689352
references.citation: Cancer Res. 2007 Apr 15;67(8):3496-9
references.pmid: 17440054
references.citation: Clin Cancer Res. 2013 Apr 15;19(8):2107-16
references.pmid: 23470966
references.citation: Am J Pathol. 2010 Apr;176(4):2029-38
references.pmid: 20133814
references.citation: PLoS One. 2012;7(12):e51735
references.pmid: 23272152
references.citation: Melanoma Res. 2012 Jun;22(3):225-35
references.pmid: 22495669
references.citation: Cancer Res. 2007 Aug 1;67(15):7525-33
references.pmid: 17671224
references.citation: Histol Histopathol. 2011 Jun;26(6):663-71
references.pmid: 21472681
references.citation: Mol Cancer Res. 2008 Aug;6(8):1268-75
references.pmid: 18708359
references.citation: Nat Rev Cancer. 2004 Dec;4(12):966-77
references.pmid: 15573118
references.citation: Cancer Res. 2008 Jan 15;68(2):498-505
references.pmid: 18199545
references.citation: Blood. 2012 Jan 19;119(3):817-25
references.pmid: 21937694
references.citation: J Biol Chem. 2002 Nov 1;277(44):42082-7
references.pmid: 12194978
references.citation: Horm Cancer. 2010 Feb;1(1):44-54
references.pmid: 20631921
references.citation: Biochim Biophys Acta. 2012 Aug;1826(1):13-22
references.pmid: 22426159
references.citation: Cancer Cell. 2004 Sep;6(3):275-84
references.pmid: 15380518
references.citation: Lab Invest. 2008 Apr;88(4):375-86
references.pmid: 18268478
references.citation: J Biol Chem. 2010 May 14;285(20):15065-15075
references.pmid: 20208072
references.citation: Adv Genet. 2010;69:97-114
references.pmid: 20807604
references.citation: Cancer Res. 2007 Oct 15;67(20):9809-16
references.pmid: 17942911