First, catch your tumor-targeting antibody. Then bait it with acancer-killing toxin and cast into the bloodstream. The seeing-eye monoclonal, pulling its toxin-baited hook, steers for theantigens on the tumor surface.

Antibody hits tumor-cell surface and unloads toxin; toxin killscell. Cancer cured.

That's the theory of conjugated antibody/toxin therapy. Neat,plausible, and, too often, wrong.

There are many good reasons why conjugates haven't lived upto their therapeutic promise, but probably only one real reason:The tumoricidal package doesn't penetrate the surface of themalignant cell, or if it does, it can't deliver the coup de grceinternally.

That explanation prompted a team of immunotherapists,chemists and biologists at the Pharmaceutical ResearchInstitute of Bristol-Myers Squibb (BMS) in Princeton, N.J., tocontrive a conjugate that dumps its death-dealing cargo onlyafter the package has penetrated to the interior of the tumorcell.

In today's Science, the researchers report using this inside-jobconcept to cure high percentages of mice with human tumorsimplanted under the skin. Their paper is titled "Cure ofXenografted Human Carcinomas by BR96-DoxorubicinImmunoconjugates."

The scientists subcutaneously inoculated nude mice (which,lacking immune defenses, could not reject the grafts) withhuman lung and colon cancer cells. Once these transplantedtumors were well established, 14 to 28 days later, the mice gotthree treatments four days apart with the BR96/doxorubicin(DOX) conjugate. It produced long-term cures in 72 to 100percent of 281 mice bearing lung tumors, and in 48 mice (also72 to 100 percent) with colon cancers. These animals"remained alive and tumor-free for more than one year withno indication of side effects."

Meanwhile, matched control mice, which received either notreatment, DOX alone or unconjugated BR96, showed little or noanti-cancer effects.

Attacking primary solid tumors in situ is one thing; zappingdistant metastases is quite another. To simulate such tumordissemination, Pamela Trail, lead author of the Science report,and her co-workers injected lung carcinoma cells, which cangrow as multicellular spheroids, into nude mice. Theydeveloped tumors at various sites -- lymph nodes, lung, spleen,liver, brain and under the skin. These metastasis-simulatinganimals, when treated with BR96/DOX conjugates, survived onaverage up to 200 days, and 70 percent proved free ofdetectable tumor. By contrast, half of the controls died duringthe first six days of the experiment, and none lasted beyondday 102.

In 16 athymic rats implanted with lung tumors, BRE96/DOXcured 100 percent, and 15 of the 16 remained alive and tumor-free 150 days after final treatment.

"We're planning on filing an IND (investigational new drugapplication) for human trials within the next six months, Trailtold BioWorld. Her laboratory at Princeton focuses ononcological drug discovery. "The preclinical success of ourparticular conjugate," she added, "is a combination of a verygood antibody that internalizes, and a chemistry that takesadvantage of this internalization."

Bruce Chabner, director of the cancer treatment division at theNational Cancer Institute, hailed that preclinical study as "veryimportant," he told BioWorld. "I didn't know if it would work,but it's one of the best immunological studies we've seen. Itcures animals permanently in two doses. I'm impressed."

But, Chabner added, "Other conjugate experiments haveresponded in animals, then failed in man. Everyone, includingourselves, is eager to do clinical trials on this BR96/DOXconjugate, to see if it works in humans too."

CONJUGATED ANTIBODY/TOXIN THERAPY: HOW IT WORKS

The aiming point of Bristol-Myers Squibb's (BMS) guidedmissile is a blood group-type antigen expressed on a majorityof breast, lung and colon carcinomas. To this target, the group'sSeattle-based immunology couple, Ingegerd and Karl ErikHellstr¿m, raised a monoclonal antibody in mice immunizedwith human breast cancer cells. They humanized this murinemolecule and named the resulting chimeric antibody BR96. It isproprietary to BMS. Both Hellstr¿ms are vice presidents of theBMS research institute.

Then the Princeton, N.J., group hitched the BR96 antibody to amolecule of doxorubicin, also called adriamycin. This potentanti-metabolite in the arsenal of cancer chemotherapists killstumor cells by intercalating into the DNA of their nuclei,preventing them from replicating.

To couple these two components -- the nose cone and thepayload -- the BMS chemists devised a two-part linker, basedon thioether for stability, and a hydrozone bond that comesapart in an acidic environment. This coupling system, theScience report's lead author, Pamela Trail, told BioWorld, ispatent pending.

When up to 200,000 antibodies home in on the tumor-associated antigens aboard a single cell, the complexespenetrate the cell membrane into the cytoplasm. There, theacidic lysosomes break the bond -- much like a steering-wheelcolumn designed to snap under impact -- and release thedoxorubicin to kill the cell. -- David N. Leff

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.