Drug Conjugates Advance In Clinical Trials

Many new therapies combining a highly potent drug compound and delivery molecule are targeting cancer. As was evident at the recent American Society of Clinical Oncology meeting in Chicago, several such conjugates are showing promise as they advance in development.

Wyeth—which sells the only marketed drug conjugate, Mylotarg, for treating myeloid leukemia—now has a second conjugate called CMC-554 in Phase II and Phase III clinical studies. It too uses the cytotoxic agent calicheamicin, which causes breaks in cancer cell DNA, but couples it to an antibody with affinity for the CD22 antigen on lymphoma cells.

Genentech, having licensed technology from ImmunoGen, is developing trastuzumab-DM1, which uses the antibody in its breast cancer drug Herceptin. The conjugate adds the cytotoxic power of ImmunoGen's DM1, a maytansinoid compound that's 1,000 times more potent then traditional anticancer agents. It's the first clinical candidate in Genentech's antibody-drug conjugate program, and the company is expected to make a decision this year about whether it will pursue Phase III studies.

Sanofi-Aventis has licensed two conjugates from ImmunoGen that are both in Phase I studies. Like Mylotarg, AVE9633 targets myeloid leukemia with a CD33 antibody. But it is bound to another maytansinoid, DM4. Meanwhile, the conjugate designated SAR3419 is a potential treatment in Phase I studies for non-Hodgkin's lymphoma and other B-cell hematological malignancies using a CD19-targeting monoclonal antibody and DM4.

ImmunoGen has its own conjugates under development. IMGN901 uses DM1 and targets the CD56 antigen in multiple myeloma (in Phase I trials) and small-cell lung cancer (in Phase II) and has shown preclinical potential against ovarian cancer. And IMGN242, which has shown evidence of activity in Phase II testing, uses DM4 and targets an antigen found on gastrointestinal tumors.

Other ultrapotent agents being investigated as conjugates include analogs of the bacterial natural product CC-1065, which selectively binds and alkylates double-stranded DNA. And Seattle Genetics is developing auristatins that inhibit microtubule assembly. Its SGN-35, now in Phase I trials, uses an auristatin and an antibody against the cell-surface protein CD30 to target Hodgkin's lymphoma and other hematologic malignancies. In preclinical work, SGN-75 has been found to deliver an auristatin payload into CD70-expressing solid tumors.

Likewise, CuraGen has moved its CR011-vcMMAE into Phase II trials for treating advanced melanoma. The agent is an antibody against glycoprotein NMB, which plays a role in how cancer cells invade and metastasize, attached to an auristatin using Seattle Genetics' technology.

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