Stanford clinician David Maloney will report at the 35th AnnualAmerican Society of Hematology (ASH) meeting in St. Louis thisafternoon how a naked monoclonal antibody shrank tumors insix out of nine relapsed B-cell lymphoma patients. The chimericmonoclonal, genetically engineered by Idec PharmaceuticalsCorp., targets an antigenic marker, CD20, that appears on thesurface of all B cells, malignant and healthy alike.
"New developments with monoclonal antibodies may soon takeimmunotherapy in more productive directions," Maloney is totell the audience. His presentation, in the session onlymphomas, myelomas and chronic lymphocytic leukemia, istitled "Phase I Clinical Trial Using Escalating Single-DoseInfusion of Chimeric Anti-CD20 Monoclonal Antibody (IDEC-C2B8) in Patients with Recurrent B-cell Lymphoma."
Fifteen adults with low-grade lymphoma took part in thisstudy at Stanford University School of Medicine. In intravenousinfusions lasting several hours, they received one of five dosesranging from 10 to 500 milligrams per square meter of bodysurface. Within two to three days after the treatment, all 15patients showed a reduction in peripheral-blood B cells (thewhite blood cells that manufacture immunoglobulin PPantibodies for the immune system).
Tumors actually shrank in size in the six of nine participantswho got the highest doses, and this effect persisted for at leasttwo months. Two of the six, moreover, achieved a partialresponse to their disease and have been in remission withoutadditional therapy for five to seven months since the trial.
Also, at the higher doses, the anti-CD20 monoclonal had anaverage half-life of 4.4 days PP four times the usual murineantibody behavior PP with useful levels present for more than14 days in the six most responsive patients.
Current treatment for B cell lymphoma relies mainly on cancerchemotherapy and radiation. Other biotechnology companiesare experimenting with monoclonal antibodies hooked ontocell-killing isotopes or toxins.
Lymphomas are among the fastest-growing types of cancer inthe U.S., increasing at 7 percent annually. This year anestimated 43,000 new cases will be diagnosed; 167,000Americans are currently receiving treatment for their disease.
"Over 90 percent of lymphoma tumors in the U.S. carry theCD20 antigen on their B cells," observed Richard Krawiec, Idec'sdirector of investor relations and corporate communications. Asa result, Idec's monoclonal is designed to wipe out all B cells --tumorous or normal -- and leave it to the body's bone marrowto spontaneously replenish the full complement of healthycells. Meanwhile, the intact cellular immune defenses guardagainst opportunistic infections. "That's why we call ourantibody 'pan-B,' " Krawiec explained. "It takes the patient backto a neonatal state when he had no B cells at all and lived onmom's antibodies while his own B cells grew and matured."
The malignancy comes in three grades, low, intermediate andhigh, with life expectancy averaging 6.6, 2.2 and 1.1 years,respectively, after initial diagnosis. Presidential candidate PaulTsongas has low-grade lymphoma, in which repeated relapsesand ever-shorter remissions follow repeated bouts ofchemotherapy or radiation. Stanford enrolled its trial cohortfrom people with low-grade B cell lymphoma.
Idec (NASDAQ:IDPH) of San Diego also is sponsoring a follow-on,open-label Phase I/II trial building on the first Phase I lessonthat success tends to be dose-related. Again at Stanford and ata number of centers in the San Diego area, several small groupsof patients each received four doses of the chimeric monoclonalat seven-day intervals, increasing by group.
Last month, after this Phase I aspect of the new trial, thedosage levels showing the best clinical responses began, withother trial volunteers being treated to evaluate efficacy. Idecexpects the Phase II study to possibly be completed nextspring. Discussions with the FDA would then ensue.
A subsequent pivotal clinical trial would presumably follow,Krawiec said, with material manufactured in Idec's pilot plantin San Diego for the first time. Previous supplies have comefrom small batches fermented at the company's site inMountain View, Calif.
"Using our high-yield, 2,700-liter fermenters and mammalian-cell expression systems, we will be able to cost-effectivelyproduce commercial quantities of IDEC-C2B8 in our newbiologicals manufacturing facility," said William Rastetter,Idec's president and chief executive officer.
Cost is a major argument in Idec's list of advantages for itsanti-B cell monoclonal. "We can produce antibodies in the$100-per-gram range through genetically engineering ourchimeric mouse/human monoclonal into a Chinese hamsterovary cell line," Krawiec said. "This is an order of magnitudelower than the typical $1,000-per-gram price tag. We have ahigh-expression vector that typically yields greater than agram of antibody per liter, again 10 times the 100 mg/L oftypical good hybridomas."
Idec's antibody, which targets all B cells flying the CD20 flag,combines the entire human constant region with the mousebinding region. The human component provides the antibody'sactivity; the murine region recognizes the CD20 marker on theB cell. By sticking to the B cell's surface rather than penetratingits cytoplasm, as antibody-conjugates under development do,the naked antibody calls in cell-lysing complement moleculesand engulfing phagocytes to kill off the B cells.
Conventional wisdom eschews putting mixed mouse/humanmonoclonals into patients for fear of the human anti-mouseantibody (HAMA) immune rejection effect. "Lymphomapatients are immunocompromised," said Krawiec. "What theyhave is a cancer of the immune system, further impaired bychemotherapy, so we did not see a HAMA response in thisPhase I study."
Administering the antibody is an outpatient procedure, withside effects (mainly chills, fever, nausea, and rash) limited tothe several hours it takes to infuse the dose. In future clinicalpractice, patients would receive antihistamines and analgesicsto quench this transient discomfort, but such drugs wereomitted during the trials to avoid adding a wild card to theregimen.
With patents pending, "Idec is certainly willing to discuss thelicensing of this product," Krawiec said. Company policy, heobserved, has been to retain U.S. and North American rightswhile licensing other worldwide rights to other pharmaceuticalcompanies.
Idec's stock was up $1 on Monday, closing at $7.88 a share.
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.