BioWorld International Correspondent

SAN FRANCISCO - Parallel advances in the therapeutic uses of monoclonal antibodies and the discovery of a range of cancer antigens have inspired the development of antibody-radioisotope conjugates to deliver radiation directly to tumors.

But although two radiolabeled antibody products have been approved for the treatment of non-Hodgkin's lymphoma, dose-limiting toxicity means such products have yet to make a mark in the treatment of solid tumors.

"The major limitation of monoclonal antibody therapy is the slow penetration into the tumor, taking 24 to 48 hours," Gary Braslawsky, director, tumor biology at Biogen Idec Inc. in Cambridge, Mass., told delegates at the Biotechnology Industry Organization convention Wednesday in a session on radioimmunotherapeutics.

The slow clearance from circulation exposes bone marrow cells to toxic levels of radiation, and by the time the radioisotope reaches the tumor it has decayed.

"Yttrium has a three-day half-life, so it has lost effectiveness by the time it reaches the tumor," Braslawsky said.

It is still possible to deliver 2,000 RADs to the tumor, but in solid tumors 5,000 to 6,000 RAD is needed. "In other words, you need to deliver 2-3 times what you can achieve with an intact antibody," Braslawsky said.

That limitation switched attention to monoclonal antibody fragments, which have faster elimination from circulation, and so less dose limitation. "[They are] less toxic molecules, but there is poor localization to the tumor, and that's why they have failed to get clinical responses," Braslawsky said.

Now the focus is on engineering antibodies to develop versions that combine the targeting advantages of intact monoclonal antibodies with the fast blood clearance of antibody fragments.

Biogen Idec is developing a CH2 domain-deleted monoclonal antibody, linked to a yttrium-90 radioisotope. In preclinical development it showed improved tumor penetration, increased antitumor activity at tolerated doses, rapid clearance from circulation and an improved toxicity profile.

"You can dose much higher with domain-deleted antibodies and you end up delivering a lot more radioactivity," Braslawsky said.

Paul Chamberlain, director, biopharmaceuticals, drug development programs at MDS Pharma Services Inc. in Toronto, agreed it is possible to get improved localization of antibodies to tumors through antibody engineering. However, he also noted that a key influence that may be overlooked is the number of binding sites, that is, antigens, in the tumor.

"Binding-site number is more important than affinity when doses are high enough," Chamberlain said. "[Localization] really depends on antigen density, so rather than engineer for localization, be careful in your choice of antigens."

Haren Rupairi, chief medical officer at Corixa Corp. in Seattle, said he believes the efficacy of radioimmunotherapy in liquid tumors like non-Hodgkin's lymphoma, which are very sensitive to radiation, will be extrapolated to achieve efficacy in solid tumors, even though they are less sensitive to radiation.

He suggested a number of different strategies to improve outcomes in solid tumors, such as using radioimmunotherapeutics to treat minimal residual disease, increasing the dose intensity with stem cell support to mitigate bone marrow toxicity, localizing radioimmunotherapeutics to the tumor by direct injection and using them in combination therapy.

Rupairi said, "The question is - do we think we have gained enough experience from [radioimmunotherapy] in lymphoma to apply it to solid tumors? Yes, we do."

Corixa now is developing a radioimmunotherapeutic for non-small-cell lung cancer. The initial aim is treating patients with Stage III/IV disease. "I don't think [radioimmunotherapy] is used as much as it should be," Rupairi said. "I hope the trials coming out show it should be used more in the front line."

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