An Entry Inhibitor Candidate, Pro 140, Aims to Protect Healthy Immune Cells from HIV at the CCR5 Coreceptor
by Chael Needle
LifeGuide [Treatment Horizons]
Last month, Progenics Pharmaceuticals reported positive results from the first patient-enrolled trial of its drug candidate PRO 140, an entry inhibitor that targets CCR5 in order to block HIV. In the midnineties, Dr. Paul J. Maddon, who founded and heads up Progenics, helped discover the role of CCR5 in HIV infection. CCR5, a receptor for chemokines, is one of the entryways that HIV needs after first attaching to the primary receptor, CD4, in order to infect a cell. One other entryway, the CCX4 receptor, may be used as well, but most new HIV infections occur via CCR5.
The thirty-nine patients enrolled in the dose-escalation, placebo-controlled monotherapy study were either treatment-naive or had been on therapy but free of AIDS meds for three months; all had viral loads of 5,000 copies/mL and higher. Those who received the single 5.0 mg/kg dose, the highest dose studied, achieved an average maximum decrease of viral load of 98.5 percent, with individual reductions ranging up to 99.7 percent. In these patients, reductions in viral load of greater than ninety percent on average persisted for two to three weeks after dosing before returning to baseline at approximately thirty days. The response rate among the treatment groups increased as doses escalated, reaching a maximum of 100 percent of patients achieving at least a 1 log10 decrease in viral load in the highest dose cohort.
PRO 140 is a humanized IgG4 CCR5 monoclonal antibody. Discovered by Progenics researchers, PRO 140 is an artificial version of the protein molecules that our bodies produce in order to bind to foreign substances in the immune-response process. In this case, PRO 140 does not bind to a foreign substance but to CCR5. More specifically, it “binds only to the exact same amino acids on the CCR5 receptor that the virus binds to,” explains Richard W. Krawiec, PhD, vice president of corporate affairs at Progenics. With CCR5 “occupied,” HIV cannot complete replication, becomes inactive, and is then cleared from the body. As none of the existing classes of first-line HIV meds target CCR5, PRO 140—if approved—would most likely be indicated as a second-line therapy, or an optimized background therapy, for those patients whose viruses have developed drug resistance to first-line meds.
“When you use traditional AIDS medications, except Fuzeon and maraviroc, you’re slowing down the conveyor belt of new viruses coming out the other end, Krawiec says of this “very different” approach—protecting healthy cells rather than attacking HIV in its replication life cycle. In other words, the mechanism of action happens outside of the healthy immune-system cell and the conveyor belt of viral replication never gets a chance to start up.
PRO 140 has the potential for broad spectrum antiviral activity, in part because “[t]his monoclonal antibody is directed against a highly conserved site—my CCR5 receptor should be the same as your CCR5 receptor,” says Krawiec, adding that the high rate and frequency of HIV mutations increase drug-resistance potential while, on the other hand, the slower rate of CCR5 mutation makes development of resistance to PRO 140 theoretically less common. And unlike Fuzeon, which has a small window of opportunity for binding, he says, CCR5 is “always available to the monoclonal antibody. It’s not hidden—it’s on the human cell so you’re able to saturate all the CCR5 receptors. That’s the goal: to saturate them.”
The initial clinical studies were conducted using an IV drip, but Progenics has developed a subcutaneous formulation, which uses a small, painless needle and can be self-administered, Krawiec says. PRO 140 holds the potential to be dosed infrequently—two to three weeks at a time rather than the once or twice-a-day dosing of other small molecule drugs—because of where on the coreceptor it binds (a specific region on the N terminus, at the end of the protein, and the extracellular loop) and its ability to coat for a prolonged period of time.
As the drug candidate binds to a specific site and nowhere else, researchers believe PRO 140 will offer a favorable side effect profile; most side effects are produced by drugs “reacting off-target,” Krawiec reminds. And while most AIDS meds need to be processed by the liver, monoclonal antibodies are not; toxicity is lessened as a result. This site of action, and the levels of concentrations achieved, also mean that PRO 140 does not interfere with the normal function of CCR5, which is involved in the regulation of the body’s inflammatory response. This may likely be an important future concern as the effects of long-term CCR5 inhibition are still unknown.
In vitro, PRO 140 has also been shown to have potent antiviral activity against approximately 100 genetically diverse strains of HIV, as well as to be synergistic with and complementary to when combined with small-molecule CCR5 antagonists, such as vicriviroc and maraviroc, in development. Testing also showed that PRO 140 inhibited viruses that were resistant to small-molecule CCR5 antagonists.
With proof-of-concept clearly established in this Phase 1b trial, which also established that the candidate was generally well-tolerated, Progenics plans to continue research on PRO 140, which has been granted Fast Track status by the FDA.
Chael Needle wrote about hepatitis viruses A, B, and C in the May issue.
June2007
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