Multivalent 4-1BB binding aptamers costimulate CD8+ T cells and inhibit tumor growth in mice
James O. McNamara II, … , Bruce Sullenger, Eli Gilboa
James O. McNamara II, … , Bruce Sullenger, Eli Gilboa
Published December 3, 2007
Citation Information: J Clin Invest. 2008;118(1):376-386. https://doi.org/10.1172/JCI33365.
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Research Article Technical Advance Oncology Article has an altmetric score of 9

Multivalent 4-1BB binding aptamers costimulate CD8+ T cells and inhibit tumor growth in mice

Abstract

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.

Authors

James O. McNamara II, Despina Kolonias, Fernando Pastor, Robert S. Mittler, Lieping Chen, Paloma H. Giangrande, Bruce Sullenger, Eli Gilboa

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Figure 6

Regression of P815 mastocytoma tumors injected with bivalent 4-1BB aptamers.

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Regression of P815 mastocytoma tumors injected with bivalent 4-1BB aptam...
DBA-2 mice were implanted subcutaneously with 8 × 104 P815 tumor cells. When tumors became palpable, reaching an approximate diameter of 5 mm, tumors were injected with 30 μg Ab or aptamer dimer as indicated (n = 9 per group). Ab and aptamer dimer injections were repeated 2 days later. When tumor diameters reached or exceeded 12 mm, mice were sacrificed. (A) Individual tumor volumes measured 4, 6, and 8 days after injection of Ab or aptamer. Horizontal lines indicate mean tumor volumes. Differences between the control (PBS, isotype Ab, and mutM12-23 dimer) and experimental groups (4-1BB Ab and M12-23 dimer) at days 6 and 8 after injection were significant (P < 0.001, Student’s t test). The 4-1BB Ab– and M12-23 dimer–treated groups were not significantly different. (B) Tumor volume. Data are mean ± SEM. (C) Mice without tumors or with tumors that had not reached 12 mm diameter. Differences between the control and treatment groups were statistically significant (P < 0.01). (D) Mice that rejected the implanted tumors and age-matched control mice were rechallenged with P815 tumor cells 58 days after initial tumor implantation. Individual tumor volumes 13 days after rechallenge are shown. P < 0.01, naive versus 4-1BB Ab. P < 0.001, naive versus M12-23 dimer.