Early development of the Toll-like receptor 9 agonist, PF-3512676, for the treatment of patients with advanced cancers.

Abstract

BACKGROUND:

Unmethylated oligodeoxynucleotides (ODNs) with cytosine-phosphate-guanine (CpG) motifs can potently activate the immune system through Toll-like receptor (TLR) 9. PF-3512676 is a synthetic CpG ODN that induces strong Th1-type immune responses through TLR9 and is now in clinical development.

OBJECTIVE:

To review discovery and development of synthetic CpG ODNs and their effects on immune cells and to relate preclinical and early clinical development of PF-3512676.

METHODS:

A literature search was performed on databases available through the National Library of Medicine (PubMed), the European Society of Medical Oncology and the American Society of Clinical Oncology.

RESULTS/CONCLUSIONS:

Unmethylated CpG motifs were identified as the element of bacillus Calmette-Guérin responsible for immunostimulatory activity. Preclinical studies identified the mechanism of action (i.e., TLR9) and an optimal human sequence for antitumor activity. On the basis of preclinical studies, PF-3512676, a B-class CpG ODN, was selected for further clinical development. Phase I/II clinical trials have shown PF-3512676 to be well tolerated and to have antitumor activity as a single agent in patients with several types of advanced cancer, and to show promise as a vaccine adjuvant.

• Authors: Ahmad A Tarhini, John M Kirkwood, Arthur M Krieg
• Journal: Expert opinion on drug discovery (Expert Opin Drug Discov) Vol. 4 Issue 5 Pg. 587-603 (May 2009) ISSN: 1746-0441 [Print] England
• PMID: 23485088 (Publication Type: Journal Article)