Abstract
4269
The cellular and molecular mechanisms of action of β-glucans with anti-tumor activity have remained elusive. β-glucans belong to the family of biological response modifiers and have existed for centuries in Asian folk medicine and have been used clinically for decades, particularly in Japan, for cancer treatment. Previous studies from this lab indicated that β-glucans derived from yeast, mushroom, and barley prime neutrophils (PMNs) for cytotoxicity against iC3b-opsonized tumors as a result of complement activation by anti-tumor monoclonal antibodies (mAb). Specifically, whole β(1,3; 1,6) glucan particles (WGP) derived from saccharomyces cerevisiae (s. cerevisiae) that were fed to mice were shuttled by gastrointestinal macrophages (Mφ) to the bone marrow and spleen where they were degraded into smaller soluble fragments that primed PMN complement receptor 3 (CR3, CD11b/CD18, αmβ2 integrin, Mac-1) for cytotoxicity against iC3b-opsonized tumors. The present study demonstrates the in vivo efficacy, in combination with anti-tumor mAb, and describes the mechanism of action of PGG-Betafectin, a soluble β(1,3; 1,6) glucan polymer also purified from s. cerevisiae. Intravenous (i.v.) administration of PGG-Betafectin demonstrated anti-tumor activity in combination with anti-tumor mAb in implantable syngeneic and xenograft tumor models. Murine lymphoma RMAS cells engineered with human MUC1 were implanted in wildtype C57Bl/6 mice. Tumor bearing mice treated with PGG-Betafectin and anti-MUC1 mAb BCP8 achieved significant therapeutic efficacy compared to mice treated with PGG-Betafectin or mAb alone. Similar anti-tumor activity was observed in SCID mice challenged with Her2/neu positive human SKOV-3 ovarian carcinoma treated with PGG-Betafectin in conjunction with Herceptin. In addition, PGG-Betafectin, molecular weight of 150 kD, was added to a murine Mφ (J774.1 cells) culture, and by 7 days was processed by Mφ to a 25 kD fragment as determined by size-exclusion HPLC with a Sephacryl S-200 HR column. Subsequent experiments showed that the 25 kD fraction, but not the 150 kD parent, exhibited biological activities including direct binding to human PMNs as well as induction of the activation epitope of human CR3 (CD11b) lectin-like domain (LLD) as detected by the CBRM1/5 mAb. Lastly, the 25 kD fraction, but not the 150 kD parent, primed PMNs for anti-tumor activity in in vitro cytotoxicity assays. Thus, i.v. administered yeast-derived pharmaceutical-grade PGG-Betafectin is processed by Mφ, in an analogous manner to WGP, yielding a smaller active moiety of β-glucan that is able to prime PMN CR3 for cytotoxicity against iC3b- and mAb-opsonized tumors (Support: RO1 CA 86412, DAMD17-02-01-0445, Kentucky Lung Cancer Research Program, and Research Gift Funds from Biopolymer Engineering, Inc.)
- American Association for Cancer Research