Antibody to CCR5 receptor safe, effective, suitable for weekly dosing, preliminary study shows

This article is more than 14 years old. Click here for more recent articles on this topic

A monoclonal antibody to the CCR5 receptor appears safe, effective in reducing HIV viral load and durable, with a single infusion of the antibody providing persistent high-level blockade of the CCR5 receptor for up to 28 days at higher doses, Jay Lalezari, developer of T-20, reported on Friday at the Forty-Sixth Interscience Conference on Antimicrobial Agents and Chemotherapy in San Francisco.

CCR5 is a human cellular protein found on CD4 cells, to which HIV binds during the process of cellular infection. (It is one of the so-called ‘co-receptors’ to which HIV binds in addition to the CD4 protein.) HIV has distinct genetic forms (tropisms), which preferentially infect cells with either CCR5 or CXCR4 co-receptors. The tropism tends to shift over the course of HIV infection, with CCR5 tropic virus predominant earlier, and the more virulent CXCR4 tropic form becoming more dominant later in infection.

An artificial antibody based on the CCR5 protein has shown promise as a therapeutic treatment for HIV in laboratory studies. This Phase I clinical trial examined the safety profile and preliminary efficacy of this antibody, CCR5mAb004, developed by Human Genome Sciences, in humans.

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.

tropic

When HIV selectively attaches to a particular coreceptor on the surface of a host CD4 cell. HIV can attach to either the CCR5 coreceptor (R5-tropic) or the CXCR4 coreceptor (X4-tropic) or both (dual-tropic).

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. 

tropism

When HIV selectively attaches to a particular coreceptor on the surface of a host CD4 cell. HIV can attach to either the CCR5 coreceptor (R5-tropic) or the CXCR4 coreceptor (X4-tropic) or both (dual-tropic).

protein

A substance which forms the structure of most cells and enzymes.

The study group was composed of 63 HIV-positive participants with viral loads above 5000 copies/mL and CD4 counts above 250 cells/mm3. All participants were confirmed to have CCR5-tropic virus, and were either treatment-naïve or had been on a treatment interruption for at least eight weeks by the time they entered the study.

At baseline the mean age in each dosing group was around 40 years, more than 80% were male and all groups apart from the 20mg/kg group were fairly evenly split between treatment-naïve and treatment-experienced patients. The mean CD4 count lay between 300 and 500 cells/mm3 in all groups apart from the placebo group, in which the mean was around 640 cells/ mm3. The 40mg/kg group showed a trend towards the lowest CD4 counts within this range.

Participants were given a single treatment dose by IV infusion, at one of six dosages: 0.4, 2, 8, 20 or 40 mg/kg of body weight, or a placebo dose containing no active antibody. This was a dose escalation study in which investigators proceeded to the next dose only if the current dose had proved to be safe. Ten participants were randomized to each dosing group.

Observations included: side effects, blood chemistry and drug blood levels, CD4 counts, viral load, and specific measurements of the activity of the antibody. These observations were made immediately before and after infusion, and then at days 1, 2, 4, 7, 14, 21, 28, 42, and 56 afterwards.

The CCR5mAb004 antibody appeared to be safe and well tolerated: no serious toxicities were seen even at the highest doses. Two participants (at the 2 mg/kg dose) had infusion-related allergic reactions (urticarial rash); oral antihistamines were sufficient to control these, and subsequent dosing groups were pretreated with diphenhydramine.

At the three highest doses, viral load was reduced at least tenfold (1 log) in about half of the participants two weeks after treatment. At the very highest treatment dose, 40% sustained tenfold or greater viral load reduction for at least 28 days after dosing. There was no evidence that HIV shifted to a CXCR4 tropic type in the treated individuals.

At doses of 8mg/kg or above, 80% of CCR% receptors sampled were found to be occupied by the antibody 28 days after dosing, and at least 40% of receptors remained occupied above this dosing threshold at day 56, suggesting the potential for weekly, fortnightly or even monthly dosing. The antibody has an elimination half-life of five to eight days, but concentrations remain above the IC90 out to day 28 at the highest dose.

Tropism shift to a mixed-tropic CCR5/CXCR4 virus population was detected in five patients, predominantly in the 20 and 40mg/kg groups. In two cases the shift occurred by day 28, while in a further two, it did not become apparent until day 56. The final patient was found to have mixed-tropic virus at baseline. All participants who experienced the shift to mixed-tropic virus had viral load above 10,000 copies/ml at baseline, and presenting the data, Jay Lalezari noted that three of the five tropism shifts occurred in the 40mg/kg group, which showed a trend towards a lower mean CD4 count at baseline, suggesting a higher likelihood that CXCR4-tropic virus was already present at levels below the detection limit of the assay in these patients.

Researchers concluded that the IV-infused monoclonal antibody CCR5mAb004 is ‘safe, well tolerated and demonstrates meaningful antiviral activity in CCR5-tropic HIV-1 infected patients.’ A follow-up antibody, HGS101, is estimated to be five times as potent as HGS104, the antibody presented at this meeting.

References

Lalezari J et al. A phase 1, dose-escalation, placebo-controlled study of a fully human monoclonal antibody (CCR5mAb004) against CCR5 in patients with CCR5-tropic HIV-1 infection. Forty-Sixth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract H-1668, 2006.