Targeting the PD-1/PD-L1 Immune Evasion Axis With DNA Aptamers as a Novel Therapeutic Strategy for the Treatment of Disseminated Cancers

被引:107
作者
Prodeus, Aaron [1 ,2 ]
Abdul-Wahid, Aws [2 ]
Fischer, Nicholas W. [1 ,2 ]
Huang, Eric H-B [2 ]
Cydzik, Marzena [2 ]
Gariepy, Jean [1 ,2 ,3 ]
机构
[1] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada
[2] Sunnybrook Res Inst, Phys Sci, Toronto, ON M5S 3M2, Canada
[3] Univ Toronto, Dept Pharmaceut Sci, Toronto, ON, Canada
来源
MOLECULAR THERAPY-NUCLEIC ACIDS | 2015年 / 4卷
基金
加拿大健康研究院;
关键词
cancer; DNA aptamer; immunotherapy; PD-1; RECEPTOR; PD-1; BIODISTRIBUTION; ANTI-PD-1; ANTIBODY; BLOCKS; LIGAND; SAFETY;
D O I
10.1038/mtna.2015.11
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Blocking the immunoinhibitory PD-1: PD-L1 pathway using monoclonal antibodies has led to dramatic clinical responses by reversing tumor immune evasion and provoking robust and durable antitumor responses. Anti-PD-1 antibodies have now been approved for the treatment of melanoma, and are being clinically tested in a number of other tumor types as both a monotherapy and as part of combination regimens. Here, we report the development of DNA aptamers as synthetic, nonimmunogenic antibody mimics, which bind specifically to the murine extracellular domain of PD-1 and block the PD-1: PD-L1 interaction. One such aptamer, MP7, functionally inhibits the PD-L1-mediated suppression of IL-2 secretion in primary T-cells. A PEGylated form of MP7 retains the ability to block the PD-1: PD-L1 interaction, and significantly suppresses the growth of PD-L1+ colon carcinoma cells in vivo with a potency equivalent to an antagonistic anti-PD-1 antibody. Importantly, the anti-PD-1 DNA aptamer treatment was not associated with off-target TLR-9-related immune responses. Due to the inherent advantages of aptamers including their lack of immunogenicity, low cost, long shelf life, and ease of synthesis, PD-1 antagonistic aptamers may represent an attractive alternative over antibody-based anti PD-1 therapeutics.
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页数:10
相关论文
共 43 条
  • [1] A focused immune response targeting the homotypic binding domain of the carcinoembryonic antigen blocks the establishment of tumor foci in vivo
    Abdul-Wahid, Aws
    Huang, Eric H. -B.
    Lu, Huixin
    Flanagan, Jean
    Mallick, Amirul Islam
    Gariepy, Jean
    [J]. INTERNATIONAL JOURNAL OF CANCER, 2012, 131 (12) : 2839 - 2851
  • [2] FASTAptamer: A Bioinformatic Toolkit for High-throughput Sequence Analysis of Combinatorial Selections
    Alam, Khalid K.
    Chang, Jonathan L.
    Burke, Donald H.
    [J]. MOLECULAR THERAPY-NUCLEIC ACIDS, 2015, 4 : e230
  • [3] B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells
    Azuma, Takeshi
    Yao, Sheng
    Zhu, Gefeng
    Flies, Andrew S.
    Flies, Sarah J.
    Chen, Lieping
    [J]. BLOOD, 2008, 111 (07) : 3635 - 3643
  • [4] At the Bedside: CTLA-4-and PD-1-blocking antibodies in cancer immunotherapy
    Callahan, Margaret K.
    Wolchok, Jedd D.
    [J]. JOURNAL OF LEUKOCYTE BIOLOGY, 2013, 94 (01) : 41 - 53
  • [5] B7 family checkpoint regulators in immune regulation and disease
    Ceeraz, Sabrina
    Nowak, Elizabeth C.
    Noelle, Randolph J.
    [J]. TRENDS IN IMMUNOLOGY, 2013, 34 (11) : 556 - 563
  • [6] Therapeutic antibodies: successes, limitations and hopes for the future
    Chames, Patrick
    Van Regenmortel, Marc
    Weiss, Etienne
    Baty, Daniel
    [J]. BRITISH JOURNAL OF PHARMACOLOGY, 2009, 157 (02) : 220 - 233
  • [7] Structure and Interactions of the Human Programmed Cell Death 1 Receptor
    Cheng, Xiaoxiao
    Veverka, Vaclav
    Radhakrishnan, Anand
    Waters, Lorna C.
    Muskett, Frederick W.
    Morgan, Sara H.
    Huo, Jiandong
    Yu, Chao
    Evans, Edward J.
    Leslie, Alasdair J.
    Griffiths, Meryn
    Stubberfield, Colin
    Griffin, Robert
    Henry, Alistair J.
    Jansson, Andreas
    Ladbury, John E.
    Ikemizu, Shinji
    Carr, Mark D.
    Davis, Simon J.
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2013, 288 (17) : 11771 - 11785
  • [8] PEGylation and Biodistribution of an anti-MUC1 Aptamer in MCF-7 Tumor-Bearing Mice
    Da Pieve, Chiara
    Blackshaw, Elaine
    Missailidis, Sotiris
    Perkins, Alan C.
    [J]. BIOCONJUGATE CHEMISTRY, 2012, 23 (07) : 1377 - 1381
  • [9] Dong H, 1999, NAT MED, V5, P1365
  • [10] Dong HD, 2002, NAT MED, V8, P793, DOI 10.1038/nm730