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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