research update
“ The first person treated in the first clinical trial of Adcetris was one of my patients here at UAB. We went through all the steps of those studies, and it was approved by the FDA for Hodgkin’ s lymphoma a few years ago. It has dramatically improved treatment.”
Andres Forero, M. D.
Saleh:“ We were using recombinant DNA technology. We knew the gene for the Fc portion of the antibody [ which interacts with a patient’ s immune system ], so we took the gene for the human Fc portion, and the gene for the mouse Fab portion, which binds to the target. It was 80 percent human and 20 percent mouse: that’ s a chimeric antibody.
“ The kinetics for the chimeric antibody was multiple days. It wasn’ t 21 days, which is the half-life of human immunoglobulin, but it was much longer than mouse antibodies. About 5-7 days, as opposed to 5-6 hours.”
LoBuglio:“ We did the first trial in a human and it worked well. Our conclusion was that these genetically engineered antibodies were what had to be used for efficacy.”
Subsequent studies at UAB looked for therapeutic effects, but the response was poor.
LoBuglio:“ We pointed out that the antibodies probably needed to interact with a receptor or molecule that was vital to the survival of the tumor. It couldn’ t just attach— it had to be something that was critical. You had to find molecules on the surface of the tumor cells that could be inhibited to damage the tumor. It was clear that lots of monoclonal antibodies could localize to tumor sites, and if you radiolabeled them, which we did, you could tell it was getting there. It just wasn’ t getting to a deficit of the tumor. We had to find a vital molecule on the surface of the cell.
“ Rituxan was one of the drugs that had that benefit. It reacted with CD20 [ a cell membrane protein of the tetraspanin family ]. Just the attachment interfered with cancer cells and killed them in the test tubes.”
Rituxan was developed by a company called IDEC Pharmaceuticals, based in San Diego, California. LoBuglio had an advisory role with IDEC.
LoBuglio:“ We had quite a reputation by then. We ended up with faculty in pathology, radiation therapy, immunology, internal medicine. The kinds of work that are usually done in the mouse we were able to do in humans. The major reason for getting all these trials was the expertise that we had in monoclonals and design of experiments. Within three or four years, we could select whatever partners we wanted from the industrial side of the monoclonal antibody field. It’ s a $ 20- $ 30 million investment to make enough Mabs to give to humans, so companies are looking for people who can do this well.”
“ One company working with us made a genetically engineered antibody directed at an epidermal growth factor receptor. That trial showed that antibodies plus radiation could shrink tumors. We published that and then went in and did pivotal trials for FDA approval of the drug, which became Erbitux. That’ s still one of the primary treatments for head and neck cancer, and the pivotal trial was done here with our chair of radiation therapy as the principal investigator.
“ We also did a whole series of antibody trials with toxins attached to the antibody so that it delivered a drug or toxic molecule.”
Saleh:“ It’ s like a trojan horse. You have antibodies linked to chemotherapy, so the antibody attaches to the tumor and the chemotherapy sneaks in. You have to have a linker between the antibody and the chemotherapy payload, and the linkers had always been sort of shaky. Our first paper with that involved an immunoconjugate where the antibody was very potent but the linker was very shaky, and the chemotherapy would come off. There was quite a bit of toxicity. We were the first one to do an immunoconjugate therapy in humans here at UAB, but it was ineffective. We showed the immune response, but also that the linker was weak and the chemotherapy was coming off.”
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