Use of Oligonucleotide Aptamer Ligands to Modulate the Function of Immune Receptors

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.

Agonists of Co-stimulation in Cancer Immunotherapy Directed Against CD137, OX40, GITR, CD27, CD28, and ICOS

“…Two 2F'-pyrimidine RNA agonistic aptamers against murine CD28 receptor selected by SELEX have been described recently (173).…”

Clinical Development of Immunostimulatory Monoclonal Antibodies and Opportunities for Combination

“…Further development of the protocols will generate higher affinity aptamers with enhanced bioactivity and better therapeutic potential. Several features commented on by Gilboa and colleagues in this issue (101) indicate that these biomolecules are an alternative platform to mAbs with some unique features.…”

Agonistic CD200R1 DNA Aptamers Are Potent Immunosuppressants That Prolong Allogeneic Skin Graft Survival

“…As in the case of antibodies, aptamers can be derived to either block protein–protein interactions or act as agonists to cell surface receptors, suggesting the use of such functional aptamers as therapeutic agents. 26,27,28 In contrast to antibodies and other protein-based agents, aptamers have a number of advantages including a long shelf life, low immunogenicity, and cost-effective scalable chemical synthesis. 26,27,28 However, aptamers as therapeutic entities do display poor pharmacokinetic profiles as unprotected RNA or DNA aptamers are rapidly removed from circulation due to renal filtration and nuclease degradation.…”

“…26,27,28 In contrast to antibodies and other protein-based agents, aptamers have a number of advantages including a long shelf life, low immunogenicity, and cost-effective scalable chemical synthesis. 26,27,28 However, aptamers as therapeutic entities do display poor pharmacokinetic profiles as unprotected RNA or DNA aptamers are rapidly removed from circulation due to renal filtration and nuclease degradation. 27 Their pharmacokinetic properties can be improved upon site-specific conjugation of polyethylene glycol (PEG) polymers to aptamer termini to reduce renal filtration as well as the incorporation of nuclease resistant 2'-F or 2'-O-Me nucleotides in the case of RNA aptamers to impart nuclease resistance.…”