Psoriasis, a devastating but non-lethal skin disease of unknown cause,wreaks misery of varying intensity on an estimated 2 percent of manypopulations in the world _ including some 4 million Americans.(See BioWorld Today, Sept. 29, 1994, p. 1.)
Research dermatologists wrestling with the etiology and therapy ofpsoriasis vulgaris (the commonest form), know that the culprits are acouple of cells found normally in all mammalian skin, but amok inpsoriatic skin.
One of these, the keratinocyte, is an epithelial cell that inhabits theouter epidermal skin layer, to which it contributes a steady supply ofkeratin. The other psoriatic suspect is the activated T lymphocyte,which infiltrates the skin to cope with its immune-defense needs.
To help determine which of these two cellular perpetrators is chickenand which is egg, scientists at Seragen Inc., of Hopkinton, Mass.,teamed up with the Laboratory for Investigative Dermatology at TheRockefeller University to test a genetically engineered fusion toxinthat targets T cells.
They report results of a preliminary Phase I/II clinical trial in theApril 28 Nature Medicine. Their paper bears the defining title:"Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenicbasis."
Its principal author, dermatologist (and "closet immunologist") JamesKrueger is acting administrative head of the Rockefeller lab. He toldBioWorld Today, "We launched into this Seragen project with twohopes: The first was that we would have in DAB389IL-2 a specificT-cell-targeting agent that would let us get to the bottom of whetherpsoriasis is primarily an immune-mediated disease, or one primarilymediated by epithelial cells."
Dose-Dependent Clinical Improvement
Krueger said that "in the course of trying to dissect this problem, wemight also be able to demonstrate clinical efficacy of a new type ofsystemic therapeutic agent." He made the point that "this study, in 10moderate-to-severe patients, was not designed to get at thattherapeutic question, but to test dosage levels of DAB389IL-2."
As reported in their paper, "Four patients showed striking clinicalimprovement and four moderate improvement, after two cycles oflow-dose IL-2 toxin."
To which Krueger added, "We have had one patient who cleared upcompletely on this regimen, and has stayed so now for more than ayear. Given that the doses were very low _ practically microscopic_ this is reasonably encouraging that the approach couldtheoretically give long-lasting benefit."
By early March 1995, 23 psoriasis sufferers had taken his lab'sintravenous fusion toxin cure, with similar encouraging results, asKrueger reported to a conference on "Cytokine therapy: advances inclinical application and commercialization" in Washington.
"As we continued to use this agent," he said, "and increased the dose,we have begun to see more consistent responses than at the lowdoses." Top score went to four patients who, treated with threecourses of the third and highest dose, saw the severity of their diseasedecrease an average 53 percent.
Meanwhile, Seragen, which developed, and manufactures,DAB389IL-2 under license from Harvard University, is preparing fora larger, placebo-controlled, Phase II trial.
The company's senior vice president, microbiologist/immunologistJean Nichols, told BioWorld Today, "We are just submitting theprotocol for that trial to the FDA, with a view to initiating it aroundmid-year. It will be a 60-patient study at somewhere between fourand six clinical sites in the U.S."
She made the point that this dose-ranging trial of DAB389IL-2 "willexamine even higher doses" than the just-reported study at TheRockefeller. She expects it to run "approximately six months,dependent on patient accrual."
Diphtheria Toxin Executes Murderous T Cells
At the same time, Seragen will be "conducting some separate, moreresearch-oriented, studies" with Krueger.
"DAB," Nichols explained, "stands for diphtheria toxin fragment A-fragment B, genetically fused to human interleukin-2 through aminoacid 389 on the toxin chain."
This construct, she continued, "targets high-affinity IL-2 receptors onactivated T lymphocytes. Once bound, it enters the cell, wherefragment A of the toxin acts to inhibit protein synthesis, thus killingthe cell."
In such disease-affected skin, Nichols said, "keratinocytes andactivated T lymphocytes are proliferating, and feeding on each other.Our approach of targeting the T cells blocks this whole feedbackprocess. Seragen's longer-term strategy," she added, "involvespossibly targeting the keratinocytes too, and perhaps blocking thepsoriatic process from either direction."
In the decade since Krueger's co-author, Alice Gottlieb, observedthat psoriatic lesions might be an immunity-mediated process, hesaid, "a number of much less specific immunosuppressive drugs thanSeragen's IL-2 toxin have been used to treat psoriasis, with thesuggestion that much of its pathology might be related to T cells."
Thus, such clinically effective maintenance therapies as cyclosporineand PUVA (psoralen-ultraviolet-A radiation), Krueger said, are non-specific, and probably target both kinds of cells."
The Rockefeller dermatologist views psoriasis "as a sort of wound-healing reaction of the skin to an immune-insult that over-reacts. Theessential thing to realize," he emphasized, "is that skin undergoes aphysiologically programmed response, which can be turned off whenyou get rid of T cells. Nature," he concluded, "has designed the skinto sustain major insult and _ unlike end organs in other autoimmunediseases _ to repair itself, and restore everything to normal." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.