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| |  Chemically Altered Monoclonal Antibodies Kill Cancer Cells DALLAS -- July 10, 1997 -- Malignant human tumors in laboratory dishes and in transgenic mice have been successfully destroyed by chemically joining identical single-molecule monoclonal antibodies to form double molecules that signal cancer cells to die or stop dividing, according to scientists at UT Southwestern Medical Center at Dallas. This discovery raises the possibility of using the double molecules, called homodimers or dimers, to kill cancer in humans with little risk of toxicity, according to a report published in this week’s issue of the Proceedings of the National Academy of Sciences. The UT Southwestern scientists used monomer monoclonal antibodies, which had been ineffective in signaling apoptosis (programmed cell death) or growth arrest in tumors, to form dimers. These proteins attach themselves more tightly to cancer cells than do monomers of monoclonal antibodies. "In preparing antibodies for clinical use, senior research scientist Dr. Maria-Ana Ghetie noticed that in one, HD37, which signaled growth arrest, 15 percent to 20 percent of the molecules spontaneously formed dimers, so they were then double antibodies with four binding sites," said Dr. Ellen Vitetta, director of the Cancer Immunobiology Center. "When she separated those from the rest of the preparation, all of the signaling capacity could be attributed to those molecules. That led us to investigate whether other monoclonal antibodies might work the same way." Antibodies are Y-shaped proteins with binding sites at the ends of their two short arms, so each monomer has two areas where they can attach to a foreign body, in this case cancer cells. Two monoclonal antibodies crosslinked to form a dimer have four binding sites. This increases their avidity or effectiveness. The researchers converted several other monoclonal antibodies to homodimers, in these instances, IgG double molecules. IgG is the most common immunoglobulin; about 75 percent of the antibodies circulating in the blood are of this type. "We took antibodies that didn't signal at all or did so very weakly, and we made dimers. Sure enough, they signaled," said Vitetta, who holds the Scheryle Simmons Patigian Distinguished Chair in Cancer Immunobiology. "This could happen for a variety of reasons. More avid (effective) binding may be needed to initiate signaling, and four sites bind more strongly than two sites. Or it could be that by virtue of hyper-crosslinking more molecules on the cell, you send an overload signal to the cell. With many receptors, crosslinking is required to generate a normal positive or negative signal. Hyper-crosslinking may always give a negative one. "We don't know all the answers, but we do know that some of these molecules induce apoptosis, and some tell cells to stop dividing. Several pathways inside the cell convey these signals." Vitetta's research team tested four dimers in vitro on human lymphoma cells. The team also used a homodimer on human breast cancer cells. The dimers significantly and specifically halted the growth and/or induced death of the targeted cancer cells. In several controlled experiments, mice treated with one dose of dimer lived longer than rodents that either didn't receive any antibody or received the single-molecule antibodies. The researchers will now fine-tune dose regimens of these dimers to treat both lymphoma and breast cancer. Vitetta said results thus far are very encouraging. "These antibodies shouldn't be toxic; they're not carrying any warheads," she said. "And they should work on accessible primary tumors or metastatic disease. We certainly should be able to give larger doses with few side effects. This also raises the possibility of giving homodimers after conventional cancer therapy. "And we don't have to generate whole grocery stores full of new antibodies. They're already out there stored in lab freezers around the world. They just need to be re-evaluated as dimers. That is much easier than starting from square one and making panels of new antibodies. If dimers work, clinical grade reagents can be generated by genetic engineering. This will greatly reduce their cost and increase their availability."
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