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Cancer Immunology, Immunotherapy

, Volume 65, Issue 5, pp 511–523 | Cite as

Systemic delivery of chTNT-3/CpG immunoconjugates for immunotherapy in murine solid tumor models

  • Julie K. Jang
  • Leslie A. Khawli
  • David C. Canter
  • Peisheng Hu
  • Tian H. Zhu
  • Brian W. Wu
  • Trevor E. Angell
  • Zhongjun Li
  • Alan L. EpsteinEmail author
Original Article

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.

Keywords

CpG oligodeoxynucleotides Toll-like receptor agonist Immunoconjugate Immunotherapy Solid tumors 

Abbreviations

ANOVA

Analysis of variance

cetuximab/CpG

CpG conjugated to cetuximab

chTNT-3

Chimeric tumor necrosis therapy-3 antibody

chTNT-3/CpG

CpG conjugated to chTNT-3

chTNT-3+CpG

Non-conjugated chTNT-3 and CpG

CpG

Cytosine guanine dinucleotide

CpG1585

CpG sequence 1585

CpG1826

CpG sequence 1826

DC

Dendritic cell

DNP

Dinitrophenyl haptens

EGFR

Epidermal growth factor receptor

GEE

Generalized estimating equations

125I-chTNT-3/CpG

125-Iodinated chTNT-3/CpG

IFN

Interferon

i.p.

Intraperitoneal

i.t.

Intratumoral

NK cells

Natural killer cells

PAMPs

Pathogen-associated molecular patterns

sc1585

Negative control sequence for CpG1585

sc1826

Negative control sequence for CpG1826

TCR

T cell receptors

TDLN

Tumor-draining lymph node

TH1

T-helper 1

TLR

Toll-like receptors

Treg

T regulatory cells

Notes

Acknowledgments

The authors would like to acknowledge Dr. Wendy Jean Mack (University of Southern California) for statistical assistance. The project described was supported in part by National Center for Advancing Translational Sciences (NCATS award UL1TR00013) and National Cancer Institute (NCI award P30CA014089). Julie K. Jang and Brian W. Wu are TL1 trainees under Southern California Clinical and Translational Science Institute (SC CTSI) (NCATS award TL1TR000132).

Compliance with ethical standards

Conflict of interest

Peisheng Hu and Alan L. Epstein are co-founders of Cancer Therapeutics Laboratories, Inc. This study was partially funded by Cancer Therapeutics Laboratories, Inc. All other authors declare no conflict of interest.

Supplementary material

262_2016_1813_MOESM1_ESM.pdf (8.7 mb)
Supplementary material 1 (PDF 8880 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Julie K. Jang
    • 1
  • Leslie A. Khawli
    • 1
  • David C. Canter
    • 1
  • Peisheng Hu
    • 1
  • Tian H. Zhu
    • 1
  • Brian W. Wu
    • 1
  • Trevor E. Angell
    • 2
  • Zhongjun Li
    • 3
  • Alan L. Epstein
    • 1
    Email author
  1. 1.Department of Pathology, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA
  2. 2.Department of Endocrinology, Metabolism, and Hypertension, Thyroid SectionBrigham and Women’s HospitalBostonUSA
  3. 3.Department of Blood Transfusion, Xinqiao HospitalThird Military Medical UniversityChongqingChina

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