Immunotoxins still had exciting potential as anticancer agents, suggested Dr
Randall Johnson (Smithkline Beecham, US), describing the current progress of
such agents. There had been many attempts at this technology, but few had been
successful so far, he said.
Immunotoxins were conjugates of a monoclonal antibody (MAb) with a “warhead”
that were targeted to cells bearing specific antigens. Warheads included drugs,
toxins or radionucleotides.
There was a “litany of limitations” [of immunotoxin therapy], commented
Dr Johnson. These limitations included instability of the MAb-toxin linker,
inadequate potency of the warhead, antigenicity of the MAb, recognition of a
non-target antigen and variable expression of the designated antigen on the
target tumour cells. To get successful immunotoxin therapy it was a matter of
combining effective components, he suggested.
Phase I clinical trials were now underway with an immunotoxin therapy (huC242-DM1)
using a humanised MAb raised against a carbohydrate epitope of the MUC1 mucin,
said Dr Johnson. This epitope was expressed by colon, gastric, lung and pancreatic
cancer cells — cancers poorly served by existing therapies. A novel, stable
disulphide linkage system was used to attach four molecules of a highly potent
toxin (DM1) to each antibody. DM1 was derived from the natural product maytansine
and, when unconjugated, it had severe dose limiting toxicities. However, in
in vitro studies, huC242-DM1 was even effective where a low proportion of tumour
cells (20 to 30 per cent) expressed the antigen, he said. This was found to
be a “bystander” effect mediated by the drug efflux pump, p-glycoprotein.
Thus, following promising studies with the agent in chemorefractory animal models,
two phase I trials had begun in humans (dosing weekly and three times weekly),
said Dr Johnson. So far, there was no evidence of dose limiting toxicity even
though the “dose equivalents” given exceeded those tolerable with
the free drug. Dosing three times weekly was approaching the maximum tolerated
dose, with apparent elevation of liver enzymes.