New way of attacking HIV looks promising in early trial

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A new monoclonal antibody treatment that blocks HIV’s ability to infect human cells is safe and effective, according to a preliminary trial in patients the results of which are published in the March 1st edition of the Journal of Infectious Diseases

HGS004 is a human monoclonal antibody that binds to and inhibits the activity of the CCR5 receptor on the cell surface. HIV uses both the CCR5 and the CD4 receptors to gain entry to the cell but CCR5 is the primary receptor enabling HIV transmission and replication from the early stages of infection through to progression to AIDS.

Small-molecule CCR5 inhibitors like maraviroc and vicriviroc have already been shown to be effective HIV treatments, leading to maraviroc gaining a license last year.

Glossary

CCR5

A protein on the surface of certain immune system cells, including CD4 cells. CCR5 can act as a co-receptor (a second receptor binding site) for HIV when the virus enters a host cell. A CCR5 inhibitor is an antiretroviral medication that blocks the CCR5 co-receptor and prevents HIV from entering the cell.

receptor

In cell biology, a structure on the surface of a cell (or inside a cell) that selectively receives and binds to a specific substance. There are many receptors. CD4 T cells are called that way because they have a protein called CD4 on their surface. Before entering (infecting) a CD4 T cell (that will become a “host” cell), HIV binds to the CD4 receptor and its coreceptor. 

monoclonal antibody

Monoclonal antibodies are antibodies that are made by identical immune cells, which are all clones of a unique parent cell. Some of them have an effect on the immune system. 

strain

A variant characterised by a specific genotype.

 

intravenous

Injected into a vein.

But monoclonal antibody drugs have advantages compared to traditional small-molecule drugs. They can be dosed less frequently - biweekly or even monthly- and usually do not interfere with other drugs allowing a greater freedom of combination. They also should theoretically work against resistant strains. However, they have to be injected, rather than taken orally.

Preclinical research with HGS004 has shown that it binds tightly to human CCR5, prevents HIV entry and viral transmission.

But this new study has looked at its effects in 63 patients infected with CCR5-tropic HIV as a “proof of concept” study - a trial to demonstrate clinical efficacy with a small number of strictly selected patients.

All patients were randomised to receive a single intravenous dose of HGS004 at one of five doses – 0.4, 2, 8, 20 or 40 mg per kg body weight- or placebo. After 14 days 54% of patients in the 8, 20 and 40mg/kg group had a greater than log10 drop in HIV RNA levels. In the 40mg/kg cohort four out of 10 patients had a greater than log10 reduction in HIV at day 28.

The antibody was well tolerated at all doses, with no increase in toxicities seen at higher doses.

The US authors say this study suggests HGS004 is safe and shows meaningful anti-HIV activity. But they suggest further studies should be carried out with HGS101 – a derivative of HGS004 which is five to ten times more potent but retains other characteristics of the original.

References

Lalezari J et al. Safety, pharmacokinetics, and antiviral activity of HGS004, a novel fully human IgG4 monoclonal antibody against CCR5, in HIV-1 infected patients. J of Infect Dis 197: 721-727, 2008.