Multivalent 4-1BB binding aptamers costimulate CD8+ T cells and inhibit tumor growth in mice.
4-1BB is a major costimulatory receptor that promotes the survival and expansion of activated T cells. Administration of agonistic anti-4-1BB Abs has been previously shown to enhance tumor immunity in mice. Abs are cell-based products posing significant cost, manufacturing, and regulatory challenges. Aptamers are oligonucleotide-based ligands that exhibit specificity and avidity comparable to, or exceeding, that of Abs. To date, various aptamers have been shown to inhibit the function of their cognate target. Here, we have described the development of an aptamer that binds 4-1BB expressed on the surface of activated mouse T cells and shown that multivalent configurations of the aptamer costimulated T cell activation in vitro and mediated tumor rejection in mice. Because aptamers can be chemically synthesized, manufacturing and the regulatory approval process should be substantially simpler and less costly than for Abs. Agonistic aptamers could therefore represent a superior alternative to Abs for the therapeutic manipulation of the immune system.
Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
James O
JO
McNamara
Despina
D
Kolonias
Fernando
F
Pastor
Robert S
RS
Mittler
Lieping
L
Chen
Paloma H
PH
Giangrande
Bruce
B
Sullenger
Eli
E
Gilboa
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D052157:Aptamers, Nucleotide / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D034801:Mastocytoma / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000819:agonists* / Q000276:immunology
D000906:Antibodies; D052157:Aptamers, Nucleotide; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9