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TNX-355, anti-CD4 monoclonal antibody: Safety and preliminary Anti-HIV Activity
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Dan Kuritzkes, MD (Massachusetts General Hospital) reported in the opening session on New Drugs at the Retrovirus Conference 2003 on this new drug studied in an open-label, dose escalation study. TNX-355 is a humanized form of the murine antibody 5A8, a form of IgG4. It recognizes a unique epitope in domain 2 of CD4, and inhibits post-binding entry of HIV-1. It showed potent in vitro (test tube) inhibition of a broad spectrum of primary HIV-1 isolates, including all major clades, and inhibits R5 and X4 viruses. Kuritzkes reported that there was no development of viral resistance with in vitro passage in the presence of sub-inhibitory concentrations of TNX-355. In previous animal study, 3 mg/kg was administered by IV twice weekly to rhesus macaques and up to 1.7 log decrease in plasma SIV RNA levels were seen after 10 days. Viral load returned to baseline by day 20. There was no toxicity seen in the monkeys. There was no activation or depletion of CD4 seen in monkeys.
Kuritzkes reported on a Phase I, open-label, single-dose trial examining safety, and PK and PD (pharmacokinetica and pharmacodynamics). 30 HIV-infected patients enrolled in 5 dose groups; single doses of TNX-355: 0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, 10.0 mg/kg, 25.0 mg/kg by IV infusion.
Patients were stable on ART regimen (or no treatment) for 8 weeks prior to study entry. They had to have >100 CD4 count and >5,000 HIV-RNA. All 30 patients had HAART experience and 19/30 were failing at study entry. 27 men and 3 females had average CD4 of 341 and mean viral load of 4.78 log (60,000 copies/ml).
Antiviral Activity
Each dose, except the 0.3 mg/kg reduced viral load but interestingly viral load did not rebound back to baseline immediately after the single dose was administered. In the highest dose (25.0 mg/kg), mean change in viral load was -1 log by day 7 and remained at a -1 log reduction until day 21, and at day 28 viral load was about -0.75 log. Similarly, patients receiving 10.0 mg/kg achieved a nadir mean -1.5 log reduction by day 14 and the viral load started to rebound, and was -0.3 log by day 21.
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Kuritzkes reported the drug was well tolerated, there was no CD4 depletion during observation; there were no significant laboratory abnormalities; no unexpected adverse events, no serious adverse events; and no development of anti-TNX-355 antibody. The optimal doses are 10 and 25 mg/kg. The drug effect parallels the duration of complete CD4 cell coating. Kuritzkes suggested that a likely chronic dosing interval would be between 7-21 days. A multiple dose study is underway.
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