Use of oligonucleotide aptamer ligands to modulate the function of immune receptors

Eli Gilboa, James McNamara, Fernando Pastor

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

The paucity of costimulation at the tumor site compromises the ability of tumor-specific T cells to eliminate the tumor. The recent U.S. Food and Drug Administration approval of ipilumimab, an antibody that blocks the inhibitory action of CTLA-4, and clinical trials targeting 4-1BB and PD-1 or PD-L1, have underscored the therapeutic potential of using immunomodulatory antibodies to stimulate protective immunity in human patients. Nonetheless, systemic administration of immunomodulatory antibodies has been associated with dose-limiting autoimmune pathologies, conceivably reflecting also the activation of resident autoreactive T cells. Arguably, targeting immunomodulatory ligands to the disseminated tumor lesions of the patient would reduce such drug-associated toxicities. We have recently developed a new class of inhibitory (CTLA-4) and agonistic (4-1BB and OX-40) ligands composed of short oligonucleotide (ODN) aptamers that exhibited bioactivities comparable or superior to that of antibodies. To reduce toxicity, the immunomodulatory aptamers were targeted to the tumor by conjugation to a second aptamer that bound to a product expressed on the surface of the tumor cell, the targeting aptamer, generating a bispecific aptamer conjugate analogous to bispecific antibodies. In a proof-of-concept study in mice, we have shown that an agonistic 4-1BB-binding aptamer conjugated to a prostate-specific membrane antigen (PSMA)-binding aptamer led to the inhibition of PSMA-expressing tumors, was more effective than, and synergized with, vaccination, and exhibited a superior therapeutic index compared with nontargeted costimulation with 4-1BB antibodies or 4-1BB aptamers. The cell-free chemically synthesized ODN aptamers offer significant advantages over antibodies in terms of synthesis, cost, as well as conjugation chemistry needed to generate bispecific ligand fusions.

Original languageEnglish
Pages (from-to)1054-1062
Number of pages9
JournalClinical Cancer Research
Volume19
Issue number5
DOIs
StatePublished - Mar 1 2013

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Oligonucleotides
Ligands
Antibodies
Neoplasms
Bispecific Antibodies
T-Lymphocytes
Drug Approval
Drug-Related Side Effects and Adverse Reactions
Immunity
Vaccination
Clinical Trials
Pathology
Costs and Cost Analysis
Food
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Use of oligonucleotide aptamer ligands to modulate the function of immune receptors. / Gilboa, Eli; McNamara, James; Pastor, Fernando.

In: Clinical Cancer Research, Vol. 19, No. 5, 01.03.2013, p. 1054-1062.

Research output: Contribution to journalArticle

Gilboa, Eli ; McNamara, James ; Pastor, Fernando. / Use of oligonucleotide aptamer ligands to modulate the function of immune receptors. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 5. pp. 1054-1062.
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