Affitoxin Destroys HER2-Positive Tumors in Mouse Trial

A paper disclosed that “Affitoxin,” a novel protein that combines HER2-specific “Affibody” molecules and a modified bacterial toxin, PE38 (a truncated version of Pseudomonas aeruginosa exotoxin A), was an effective anticancer agent in a mouse xenograft model and a potential candidate for clinical studies.

Affibody molecules are small proteins being developed by the Swedish biotechnology company, Affibody AB (Stockholm, Sweden). They are engineered to bind to a large number of target proteins or peptides with high affinity, imitating monoclonal antibodies, and are therefore a member of the family of antibody mimetics. Affibody molecules are used in biochemical research and are being developed as potential new biopharmaceutical drugs.

In the current study investigators at the [US] National Cancer Institute (Bethesda, MD, USA) attached an Affibody molecule specific for the breast cancer marker HER2 (Human Epidermal growth factor Receptor 2) to the bacterial toxin PE38. They used this “Affitoxin” to treat athymic nude mice bearing BT-474 breast cancer, SK-OV-3 ovarian cancer, or NCI-N87 gastric carcinoma xenografts. The mice were injected with the drug every third day. Affitoxin immunogenicity in female BALB/c mice was investigated using standard antibody production and splenocyte proliferation assays.

Results published in the July 26, 2011, online edition of the journal Clinical Cancer Research revealed after binding to HER2, P38 was internalized and delivered to the cytosol of the tumor cells, where it blocked protein synthesis and ultimately killed the cells. HER2-Affitoxin was effective in eliminating HER2-overexpressing cells at low picomolar concentrations. Therapeutic efficacy studies showed complete eradication of relatively large BT-474 tumors and significant effects on SK-OV-3 and NCI-N87 tumors. HER2-Affitoxin cleared quickly from circulation and it was well tolerated by mice at doses of 0.5 mg/kg and below. Immunogenicity studies indicated that HER2-Affitoxin induced antibody development after the third injected dose.

“Unlike the current HER2-targeted therapeutics, such as Herceptin, this protein does not interfere with the HER2 signaling pathway but, instead, uses HER2 as a target to deliver a modified form of bacterial toxin specifically to the HER2-positive cancer cells,” said senior author Dr. Jacek Capala, an investigator at the National Cancer Institute. “When cells absorb the toxin, it interferes with protein production and, thereby, kills them. Herceptin has revolutionized the treatment of patients with HER2-positive breast cancer, but a significant number of tumors acquire resistance to the drug. Affitoxin could offer another therapeutic option for those patients whose tumors no longer respond to Herceptin.”

Related Links:
Affibody AB
National Cancer Institute