Hybridon Inc. announced Friday that it has signed anagreement with The Wellcome Foundation Ltd. on its antisenseoligonucleotides to two cancer-associated genes, ras and c-erbB2.
Initially, Wellcome will test and evaluate several of Hybridon'santisense constructs, in particular for biological activity againstthe two oncogenes, both in vitro and in vivo. If any of thosecompounds looks promising, the two companies intend todiscuss further collaborations to develop and commercializethat compound as a cancer treatment.
The Wellcome Foundation, which is a wholly owned subsidiaryof Wellcome plc, will then receive an exclusive royalty-bearinglicense to the compound, including co-promotion rights in theU.S. with Hybridon.
This partnership with a multinational pharmaceutical companyis the second for privately held Hybridon of Worcester, Mass.The company entered into a multiyear R&D collaboration withHoffmann-La Roche and F. Hoffmann-La Roche AG in Februaryto develop antisense compounds for treating hepatitis B and Cviruses, and human papilloma virus.
The value of the two partnerships together exceeds $50 million,according to E. Andrews Grinstead, III, Hybridon's chiefexecutive officer.
The oncogene c-erb B2 has been implicated or found in breastcancer and cervical cancer, and ras is apparently associatedwith colon, lung and pancreatic cancers as well as leukemia. "Invivo tumor models have already shown that antisense works,"Grinstead told BioWorld. More than 60 scientific publicationssince 1989 have dealt with antisense inhibition of oncogenes,he said.
For instance, National Cancer Institute researcher LeonardNeckers and associates reported in 1991 in the journalAntisense Research and Development that an antisensenucleotide to the n-myc oncogene, when perfused into a regionof tumor growth in mice, was able to decrease that tumorgrowth by 50 percent.
And researchers from the University of Pennsylvania School ofMedicine and Lynx Therapeutics Inc. reported in theProceedings of the National Academy of Sciences last Decemberthat they had used antisense oligonucleotides to the c-mybprotooncogen to treat human leukemia in a SCID mouse model.The treated mice survived at least 3.5 times longer than thecontrols. In addition, animals receiving the c-myb antisenseconstruct had significantly less disease in the central nervoussystem or ovaries (the two sites most commonly infiltrated byleukemic cells).
In fact, Lynx, which was spun off from Applied Biosystems Inc.in October 1992, is sponsoring Phase I clinical trials at theUniversity of Nebraska Medical Center in Omaha on anantisense drug for treating acute myelogenous leukemia. Thefirst patient -- a 20-year old -- to ever receive an antisensedrug systemically was treated in June 1992. The antisensecompound was developed by Nebraska researcher Larry Smith.It blocks the activity of the p53 gene, which makes a DNA-regulating protein.
And Genta Inc. (NASDAQ:GNTA) of San Diego initiated clinicaltrials in June 1992 on its antisense compound G-1128 as an exvivo treatment for chronic myelogenous leukemia (CML), inwhich a patient's bone marrow is treated with the drug toblock translation of the protein that causes the cells toproliferate. The antisense drug did indeed seem to have apositive effect in cells from about 15 percent to 20 percent ofthe patients, but not in the others. "As it turns out, CML is amuch more complex disease than we thought," explained DonPicker, Genta's senior vice president of R&D. The initial event --a translocation between chromosomes 9 and 22 -- is whatmakes the abl gene unstable, but other translocationsapparently follow.
"It's not the only target we need to hit to get to the disease,"Picker told BioWorld. Genta scientists are now looking atseveral other commonly observed translocations to come upwith a combination of targets for their antisense constructs inthe future.
Also, the French antisense company Genset began clinical trialswith two antisense compounds for treating CML in February.This is another ex vivo approach, which involves treating bonemarrow cells with the oligonucleotide prior to bone marrowtransplant therapy.
Other companies involved in developing antisense drugs fortreating cancer include Isis Pharmaceuticals Inc.(NASDAQ:ISIP), Gilead Sciences Inc. (NASDAQ:GILD),PharmaGenics and Triplex Pharmaceutical Corp.
-- Jennifer Van Brunt Senior Editor
(c) 1997 American Health Consultants. All rights reserved.