PRO 542 is a protein that has been designed to inhibit HIV entry by binding onto the gp120 region of HIV (one of the proteins sticking out from the surface of the virus used to engage with CD4 receptors on the surface of lymphocytes). It is manufactured from the virus binding domains of the CD4 molecule, fused to human immunoglobulin G. It is also known as recombinant CD4-IgG2. PRO 542 is the latest in the line of soluble CD4 receptors, a group of agents which showed little efficacy when tested in the years before the emergence of HAART. See Drugs used by people with HIV: Entry and fusion inhibitors for more information on these approaches.

It is manufactured by Progenics and is currently undergoing phase II trials in the United States.

A single dose phase I study found that the compound was well tolerated and resulted in viral load reductions of up to 2 log₁₀. Viral load reduction was dose dependent. It was also noted that infectious virus could not be recovered for more than 72 hours after a single infusion, leading investigators to suggest that PRO 542 may have particular value as a prophylaxis against HIV infection, either in perinatal treatment or after occupational or sexual exposure.

As a compound that must be infused, PRO542 may have value in children who are reluctant or unable to take tablets. A phase II study in six children found that the compound was associated with viral load reductions of greater than 0.7 log.

PRO 542 is also synergistic with T-20 in vitro; doses of each drug could be reduced by tenfold if used together, but viral replication was suppressed just as well as if either drug had been used alone. Investigators note that this synergy may allow the dosing regimen of each drug to be simplified, which is of particular concern with products that have to be administered by injection or infusion.

Delivery and tolerability

One grade 3 neutropenia was reported in one patient four weeks after a single infusion of PRO 542, and the only adverse event reported in paediatric studies was a fever in one child with a previous history of such reactions to immunoglobulin infusions.

PRO 542 must be injected because it is a protein that would be broken down in the stomach. A dose escalation study used intravenous infusion to define the highest tolerated dose, and pediatric studies have used intravenous infusions four times a week to deliver the drug. The half-life of the drug after a single infusion is 3.3 to 4.2 days, suggesting that it may not be necessary to infuse this compound every day; once or twice weekly dosing (as with some of the interferon alfa products) may be possible at doses above 10mg/kg. In the phase I/II dose ranging studies in children, PRO 542 was given once weekly, and levels above the in vitro IC ₅₀ were maintained for approximately five days.

PRO 542 does not appear to be immunologically reactive; no antibodies to the protein were detected.

References

Jacobson JM et al. Single dose safety, pharmacology and antiviral activity of the human immunodeficiency virus (HIV) type 1 entry inhibitor PRO 542 in HIV-infected adults. Journal of Infectious Diseases 182: 326-329, 1999.

Nagashima KA et al. Human immunodeficiency virus type 1 entry inhibitors PRO 542 and T-20 are potently synergistic in blocking virus-cell and cell-cell fusion. Journal of Infectious Diseases 183: 1121-1125, 2001.

Shearer WT et al. Recombinant CD4-IgG2 in human immunodeficiency virus type 1-infected children: phase 1/2 studies. Journal of Infectious Diseases 182: 1774-1749, 2000.