Repligen Corp. began enrolling patients today in a Phase Iclinical study with its HIV therapeutic vaccine candidateRP400c.

The safety trial, which will include about 20 "relativelyhealthy" -- a T4 count of 500 or greater and no evidence ofopportunistic infections -- HIV seropositive people, will beconducted at the University of Colorado Health Sciences Centerin Denver. The trial will also attempt to evaluate the putativevaccine's ability to enhance both humoral and cellular immuneresponses to HIV.

Repligen's vaccine candidate is a subunit immunogen that isspecifically directed at generating neutralizing antibodies to theV3 loop of HIV. Repligen scientists had determined about sixyears ago that this V3 loop, a segment of the virus' envelopeprotein gp120, is the primary target for antibodies thatneutralize the virus.

The RP400c immunogen is a synthetic peptide that "sits downon the V3 domain" of HIV strain MN, which is the mostcommon strain in North America and Europe, explainedSandford Smith, president and chief executive officer of theCambridge, Mass., company. "We believe we will see significantneutralizing antibody titer (in the clinic)," he added.

The V3 approach may hold the potential to elicit a broadimmune response to a variety of HIV strains. A sequenceanalysis of 350 separate viral isolates demonstrated that theconsensus sequence is similar to that of the MN strain of thevirus, Smith told BioWorld.

Repligen's vaccine strategy, he continued, is to "start with amonovalent vaccine, then add another peptide that wouldcover the same region of other virus prototypes. ... We couldcover about 80 percent of the range of variants by the additionof three or four more peptides."

At the same time, Repligen and its collaborators are refiningmethods to determine exactly how neutralizing antibodies bindto the V3 loop. In fact, the results of one long-term analysis ofthe three-dimensional structure of the "tip of the loop" is beingpresented today at the International AIDS Conference in Berlinby collaborator Ian Wilson of The Scripps Research Institute.

Using X-ray crystallography, Wilson imaged the structures oftwo Repligen monoclonal antibodies in combination with boundV3 peptides. These results provide information on the waythese broadly neutralizing antibodies recognize the V3 loop,and on the precise shape of the loop itself. Analyses such asthese "will enable us to design future vaccines that would beeven more effective," Repligen's Smith told BioWorld.

The discovery of the V3 loop was part of a collaborativeresearch agreement between Repligen (NASDAQ:REGN) andMerck & Co. Inc. on a prophylactic vaccine. "It doesn't cover theuse of products we would develop for therapeutic purposes,"Smith told BioWorld.

The companies have now modified their agreement to allowRepligen to independently pursue research and clinical testingof the RP400c immunogen as a potential therapeutic HIVvaccine. But after the completion of either Phase I or Phase IItrials, Merck has the option to compensate Repligen for itsdevelopment costs and participate as a co-developer and co-promoter of a product candidate.

If Merck decides not to pursue joint development, Repligen willbe granted exclusive worldwide marketing and promotionrights to RP400c after completion of Phase II trials.

-- Jennifer Van Brunt Senior Editor

(c) 1997 American Health Consultants. All rights reserved.

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