Monoclonal Antibodies Deliver Chemotherapy Drugs Directly to Cell Surface MUC1
By BiotechDaily International staff writers
Posted on 14 Jun 2012
Monoclonal antibodies directed at the SEA domain of the mucin 1 cell surface associated protein (MUC1) have been used to kill cancer cells by carrying drugs directly to MUC1 proteins expressed on their cell surface.
Mucin 1 is a glycoprotein with extensive O-linked glycosylation of its extracellular domain that is encoded by the MUC1 gene. Mucins line the apical surface of epithelial cells in the lungs, stomach, intestines, eyes and several other organs. Mucins protect the body from infection, as pathogens bind to oligosaccharides in the extracellular domain, preventing them from reaching the cell surface. Overexpression of MUC1 is often associated with colon, breast, ovarian, lung, and pancreatic cancers.
MUC1 is a particularly appealing target for antibody targeting, being selectively overexpressed in many types of cancers and a high proportion of cancer stem-like cells. However, the occurrence of MUC1 cleavage, which leads to the release of the extracellular alpha-subunit into the circulation where it can sequester many anti-MUC1 antibodies, renders the target to some degree problematic.
To attack this problem, investigators at Tel Aviv University (Israel) generated a set of unique MUC1 monoclonal antibodies that targeted a region termed the SEA domain that remains tethered to the cell surface after MUC1 cleavage. They reported in the April 16, 2012, online edition of the journal Cancer Research that in breast cancer cell populations, these antibodies bound the cancer cells with high affinity. Starting with a partially humanized antibody, DMB5F3, they created a recombinant chimeric antibody that bound a panel of MUC1+ cancer cells with higher affinities relative to cetuximab (anti-EGFR1) or tratuzumab (anti-erbB2) control antibodies.
DMB5F3 internalization from the cell surface occurred in an efficient temperature-dependent manner. DMB5F3 antibodies linked to an anticancer drug were cytotoxic against MUC1+ cancer cells at low concentrations.
In general, investigators have developed antibodies that targeted the "tandem repeat" zone of the MUC1 protein, a section that repeats itself many times. However, targeting this section has a crucial flaw. “The tandem repeat is in the alpha section of the protein," said senior author Dr. Daniel Wreschner, professor of cell research and immunology at Tel Aviv University. “This alpha section can detach from the cell and be ejected into the bloodstream. At that point, the antibodies will bind to the alpha section in the blood, diminishing their ability to bind to the cancer cell. People who are not eligible to be treated by antibodies already on the market could, following more research and development, likely be eligible for this one.”
Tel Aviv University