Clinical Cancer Research, 2011. Doi: 10.1158/1078-0432. CCR-10-2887.
Rafal Zielinski, Ilya Lyakhov, Moinuddin Hassan, Monika Kuban, Kimberly Shafer-Weaver, Amir Gandjbakhche, and Jacek Capala.
“HER2-Affitoxin: A Potent Therapeutic Agent for the Treatment of HER2-Overexpressing Tumors”.
Scientists at the NCI have designed a novel protein, HER2-Affitoxin, aimed to treat HER2-positive breast cancer. In vitro experiments and mouse breast cancer models show that the agent is highly effective in eradication of HER2-over expressing cancer cell as well as tumors in mice. The results of the research are published in Clinical Cancer Research (doi: 10.1158/1078-0432.CCR-10-2887).
Jacek Capala, PhD, D.Sc, lead author of the study, and colleagues at the NCI designed and produced HER2-Affitoxin, which consists of an HER2-specific antibody linked to PE38, a modified bacterial toxin, that causes cell death by blocking protein translation. HER2-Affitoxin is an immunotoxin/affibody that is able to selectively bind to cancer cells overexpressing HER2.
The mechanism of targeted-cell killing is likely an internalization of a fraction of the HER2-Affitoxin into the cytosol of the cell whereupon the PE38 toxin portion of the molecule blocks enzymatic activity of protein crucial for protein synthesis and kills the cell.
The goal was to create a novel treatment for breast cancers that overexpress HER2 but that acquires resistance to standard treatments such as trastuzumab(Drug information on trastuzumab). Trastuzumab is an effective monoclonal antibody that binds and interferes with the HER2 receptor and is used to treat HER2-overexpressing breast cancer. Unfortunately, a subset of patients does not respond or acquires resistance to the treatment, creating an unmet need for this patient population.
HER2 is overexpressed in other cancers such as non–small lung carcinoma, ovarian carcinomas and B-cell acute lymphoblastic leukemia. Combined with breast cancer, HER2-amplified cancers account for 20% of all of these cancers combined. HER2 overexpression, particularly in breast cancer, is associated with a more aggressive form of cancer that has an unfavorable prognosis. While trastuzuman has changed the prognosis of many HER2-positive breast cancer patients, a subset of these patients represents an unmet need for treatment.
“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. When cells absorb the toxin, it interferes with protein production and, thereby, kills them,” said Capala.
The current study analyzed the in vivo characteristics of HER2-Affitoxin including pharmacokinetics and biodistribution analyses that showed fluorescently labeled HER2-Afflitoxin in the kidneys, liver, and a “significantly lower but still over-the-background signal” in mouse tumors. Efficacy experiments using mouse models with HER2-positive breast tumors showed tolerable treatment and an average of 60% reduction in tumor size 3 days after the first injectible dose. The tumors remained 5% of their size prior to treatment and did not regrow after 76 days post-first treatment. Notable, even relatively large and aggressive tumors stopped growing and most disappeared. This effect, according to Professor Capala, justifies moving the compound into first in-human clinical trials.