Using the human antibody, L19, which they developed themselves and specifically recognizes the blood vessels in tumor tissue, researchers at ETH Zurich have succeeded in eliminating lymphatic tumors in both mice and humans. For their study, they combined L19 with known anticancer substances.
The fastest growing sector in pharmaceutical biotechnology is monoclonal antibodies. Their products are used especially in cancer therapy. There is a good reason for this: Monoclonal antibodies specifically recognize molecular targets, including those typical for cancer.
Most antibody-based cancer medications on the market, such as herceptin, avastin or erbitux for instance, cannot cure the disease. The monoclonal “rituximab”, however, which generated over four billion dollars in 2008 for Roche/Genentech, produces impressive therapeutic results. Combined with CHOP – a form of chemotherapy – it increased the 5-year life expectancy of patients suffering from a certain type of non-Hodgkin lymphoma by 15%.
Finding the tumor blood vessels with L19
One avenue towards the development of more selective anti-cancer drugs consists in the targeted delivery of bioactive molecules (e.g., drugs, cytokines,radionuclides) to the tumor environment by means of monoclonal antibodies specific to tumor-associated markers. In this context, the targeted delivery of therapeutic agents to newly-formed blood vessels (“vascular targeting”) is particularly attractive, because of the dependence of tumors on new blood vessels to sustain growth and invasion, and because of the accessibility of neo-vascular structures for therapeutic agents injected intravenously.
The team headed by ETH Zurich professor Dario Neri from the Institute of Pharmaceutical Science has developed a number of these antibodies over the last decade. In the last issue of the journal Blood, the ETH Zurich researchers describe how they managed to completely eliminate certain lymphatic tumors in both mice and humans.
The Neri team used their own antibody, L19, for their research. Three cancer drugs based on the L19 antibody are currently in phases 1 and 2 of various clinical trials in association with the companies Bayer Schering Pharma and Philogen, which Dario Neri co-founded. L19-based therapeutic approaches have already produced some exceptional results: When patients with Hodgkin’s lymphoma were treated with radioimmunotherapy (i.e., by administration of the monoclonal antibody L19 coupled to the radionuclide 131I), there was a noticeable decrease in cancer lesions (see photo).
New improved rituximab
Not only did the ETH Zurich researchers succeed in finding therapies for humans in their studies; in a second article they also showed how the substance L19-IL2 dramatically improves the effect of the aforementioned cancer substance rituximab in mice, leading to the complete elimination of non-Hodgkin lymphoma. Up to now, rituximab is typically used in combination with chemotherapy (e.g., with the CHOP regimen).
The success of the Neri team’s new therapeutic approach relies on the ability of the immunocytokine L19-IL2 to attract and activate certain white blood cells, including the so-called natural killer cells, towards the tumor, thus potentiating the therapeutic activity of rituximab. The fact that the treated mice did not lose weight suggests that the new combination treatment modality may be well tolerated, thus providing a rationale for the clinical testing of L19-IL2 in combination with rituxan or other antibodies.
- Sauer et al. Expression of the oncofetal ED-B–containing fibronectin isoform in hematologic tumors enables ED-B–targeted 131I-L19SIP radioimmunotherapy in Hodgkin lymphoma patients. Blood, DOI: 10.1182/blood-2008-06-160416
- Schliemann et al. Complete eradication of human B-cell lymphoma xenografts using rituximab in combination with the immunocytokine L19-IL2. Blood, 2009; 113 (10): 2275 DOI: 10.1182/blood-2008-05-160747
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