Even though it is only in the research stage, SangStat MedicalCorp.'s strategy to prevent graft tissue rejection kindledinterest at the recent Transplantation Society Conference inParis.
Carol Clayberger, a professor in the cardiothoracic surgerydepartment at Stanford University, which collaborates withSangStat, hinted at the peptide's potential. "Our resultsdemonstrate that short synthetic peptides derived from HLAmolecules are immunosuppressive in vitro, and may beexploited therapeutically to treat human diseases."
"Interest was great because it's the first time an HLA (humanimmune system) molecule derivative is being used with someeffect on the graft-specific immune response," said PhilippePouletty, SangStat's president and chief executive officer.
Some members of the Paris audience asked whether the sameimmune-modulating peptide might also be useful in treatingautoimmune diseases. "At this stage we have no data, noresults," Pouletty said. "It's only in the research stage, so Idon't want to make any claim about our peptide's possible usein treating autoimmune diseases."
"Since Paris, we have begun looking at two or three potentialcollaborations," Pouletty said. "One relates to xenografting --where the organ donor is an animal of a different species fromhuman. Two others concern autoimmune diseases, specifically,rheumatoid arthritis and type I diabetes," he said.
Pouletty said he expects the 10-residuepeptide, trademarkedAllotrap, to enter a Phase I clinical trial early in 1993 at theOrgan Transplantation Center in Nantes, France, with whichSangStat of Menlo Park, Calif., has a joint venture. The trialwill look at safety, drug pharmacokinetics and the biologicaleffect on T cells before and after the peptide is administered.
Rats injected with the peptide before being grafted withhuman heart and skin cells showed pronounced inhibition of invivo immune responses, including dodging graft rejection.
"Allotrap," Pouletty explained, is a coined word that describesthe synthetic peptide as a trap for distinguishing "non-self"antigens on allografts [non-identical human organ donors]from"self" antigens. A fetus, he said, is essentially a graft, butimmunologically tolerated by its mother as "self" without theneed for immunosuppressive drugs.
"Allotrap aims to imitate this mechanism, and have a graftorgan transplant seen a little the way a fetus is seen by itsmother. If our peptide succeeds, this will be a majorimprovement in transplantation."
An early major transplantation improvement was introducedsix years ago by the Ortho Pharmaceutical Co. of Raritan, N.J.This was Orthoclone OKT3, based on monoclonal antibodiesthat block the immune system's T lymphocytes. These are thebad-guy cells that orchestrate organ graft rejection. OKT3 iscurrently one of the transplant surgeon's anti-rejectiontherapies of choice.
Allotrap purportedly works upstream at the level of T cellprogenitors. "So it's a very different mechanism, as opposed todrugs like OKT3," Pouletty stated. "It inhibits mostly those Tcells programmed to attack "non-self" antigens, and so triggergraft rejection. OKT3 recognizes cell-membrane markers on allof the billions of T cells in a patient's body." This, he pointedout, "results in profound immunosuppression with major sideeffects -- fever, infection, lymphomas."
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.