Fusion Product Delivers Potent Toxin to Malignant Cells

NEW ORLEANS--Diphtheria toxin-based "fusion toxins"can produce durable remissions in malignancies that express thetargeted receptor, and they are safe and well-tolerated, saidJohn R. Murphy, PhD, chief of biomolecular medicine, Boston UniversityMedical Center Hospital.

"For the first time we have been able to genetically redesigna potent biological poison and direct it toward a cell receptorof our choosing that is present on malignant cells. We are gratifiedthat it worked and that the adverse profile is mild," Dr.Murphy said at the American Cancer Society Science Writers Seminar.

By using recombinant technology to redesign native diphtheriatoxin, Dr. Murphy and his colleagues at Boston University, wherehe is professor of medicine, have been able to selectively intoxicatetarget malignant cells.

The researchers have genetically replaced the native diphtheriatoxin receptor binding domain with a variety of cytokines andgrowth factors, including interleukin 2 (IL-2), IL-4, IL-6, epidermalgrowth factor (EGF), CD4, and alpha-melanocyte stimulating hormone.

The resulting "fusion toxins" are specific and highlypotent in eliminating only those cells that carry the receptorrecognized by the cytokine/growth factor portion of the fusiontoxin. For example, the fusion toxin DAB-389 IL-2 binds, throughits IL-2 receptor binding domain, to cells having the IL-2 receptor,delivering a cytotoxic component into the cell.

High-Affinity IL-2 Receptors

Cutaneous T-cell lymphoma and non-Hodgkin's lymphoma have bothshown a response to this novel therapy. Theoretically, hairy cellleukemia and Hodgkin's disease, among other malignancies, couldalso be targeted. The target malignancies are those that expressthe high-affinity form of the IL-2 receptor, which seems especiallysusceptible to the drug, Dr. Murphy said.

The IL-2 receptor-targeted fusion toxin has been evaluated inseveral phase I and II trials conducted by Seragen Inc. of Hopkinton,Mass. In these preliminary studies, the DAB-389 IL-2 fusion toxinhas proven to be safe and well-tolerated, and to produce "durableremissions" in some patients, Dr. Murphy reported.

He described the response to the drug in 32 patients with stageI to IV cutaneous T-cell lymphoma refractory to treatment (seetable). Two 5-day courses of the drug produced complete remissionsin five patients and partial remissions in seven patients, fora response rate of 38%.

"Why did some patients respond and not others? We don't knowthe receptor status of all these patients, but we do know thatthe presence of high-affinity receptors is a prerequisite forresponse in vitro," he said. "We also know that onlypatients with high-affinity receptors have responded, and if theydid not, they usually did not have a complete high-affinity receptorcomplex on the cell surface."

Patients received IV fusion toxin at levels ranging from 9 to27 mcg/kg/day for 5 days every 3 to 4 weeks, as long as they showeda response. Adverse reactions have been mild and reversible. Somepatients experienced a dose-response acute fatigue syndrome, mildliver function abnormalities, asymptomatic hypertension, and hypoalbuminemia.

Two phase III randomized trials of DAB-389 IL-2 involving 20 centersare now in place, one placebo-controlled and the other open-labeled,Dr. Murphy said.

A separate Seragen study has begun to evaluate the EGF receptor-targetedfusion toxin, DAB-389 EGF, for the treatment of a number of solidtumors, including breast, colon, ovarian, bladder, and prostate.In this case, the EGF receptor may be overexpressed on the tumorcell surface.