title: Systemic delivery of chTNT-3/CpG immunoconjugates for immunotherapy in murine solid tumor models.
abstract: CpG oligodeoxynucleotides (CpG) potently activate the immune system by mimicking microbial DNA. Conjugation of CpG to chTNT-3, an antibody targeting the necrotic centers of tumors, enabled CpG to accumulate in tumors after systemic delivery, where it can activate the immune system in the presence of tumor antigens. CpG chemically conjugated to chTNT-3 (chTNT-3/CpG) were compared to free CpG in their ability to stimulate the immune system in vitro and reduce tumor burden in vivo. In subcutaneous Colon 26 adenocarcinoma and B16-F10 melanoma models in BALB/c and C57BL/6 mice, respectively, chTNT-3/CpG, free CpG, or several different control constructs were administered systemically. Intraperitoneal injections of chTNT-3/CpG delayed tumor growth and improved survival and were comparable to intratumorally administered CpG. Compared to saline-treated mice, chTNT-3/CpG-treated mice had smaller average tumor volumes by as much as 72% in Colon 26-bearing mice and 79% in B16-bearing mice. Systemically delivered free CpG and CpG conjugated to an isotype control antibody did not reduce tumor burden or improve survival. In this study, chTNT-3/CpG retained immunostimulatory activity of the CpG moiety and enabled delivery to tumors. Because systemically administered CpG rapidly clear the body and do not accumulate into tumors, chTNT-3/CpG provide a solution to the limitations observed in preclinical and clinical trials.
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, HMR 205, Los Angeles, CA, 90033, USA.
authors.forename: Julie K
authors.initials: JK
authors.lastname: Jang
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, HMR 205, Los Angeles, CA, 90033, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Khawli
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, HMR 205, Los Angeles, CA, 90033, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Canter
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, HMR 205, Los Angeles, CA, 90033, USA.
authors.forename: Peisheng
authors.initials: P
authors.lastname: Hu
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, HMR 205, Los Angeles, CA, 90033, USA.
authors.forename: Tian H
authors.initials: TH
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, HMR 205, Los Angeles, CA, 90033, USA.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Wu
authors.affiliation: Department of Endocrinology, Metabolism, and Hypertension, Thyroid Section, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Trevor E
authors.initials: TE
authors.lastname: Angell
authors.affiliation: Department of Blood Transfusion, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Zhongjun
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, HMR 205, Los Angeles, CA, 90033, USA. aepstein@usc.edu.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Epstein
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000276:immunology* / Q000493:pharmacokinetics; D007167:Immunotherapy / Q000379:methods*; D015552:Injections, Intralesional; D007274:Injections, Intraperitoneal; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology; D016019:Survival Analysis; D014018:Tissue Distribution; D047368:Tumor Burden / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; C408982:CPG-oligonucleotide; D016207:Cytokines; D018796:Immunoconjugates; D009838:Oligodeoxyribonucleotides; D011993:Recombinant Fusion Proteins
keywords: CpG oligodeoxynucleotides; Immunoconjugate; Immunotherapy; Solid tumors; Toll-like receptor agonist