PRO 140

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PRO 140 ?
Monoclonal antibody
Source Humanized
Target CCR5
Clinical data
Legal status investigational
Identifiers
CAS number  YesY
ATC code None
NIAID ChemDB 088103
Chemical data
Formula ?
 YesY (what is this?)  (verify)

PRO 140 is a humanized monoclonal antibody targeted against the CCR5 receptor found on T lymphocytes of the human immune system. It is being investigated as a potential therapy in the treatment of HIV infection.[1] The United States Food and Drug Administration has designated PRO 140 for fast-track approval.[2] In February 2008, the drug entered Phase 2 clinical trials.[3]

Development[edit]

PRO 140 is being developed by Cytodyn Inc. In May 2007, results from the phase I clinical trial of the drug demonstrated "potent, rapid, prolonged, dose-dependent, highly significant antiviral activity" for PRO 140. Participants in the highest-dosing group received 5 mg per kilogram (2.3 mg/lb) and showed an average viral load decrease of -1.83 log10. On average, reductions of greater than -1 log10 copies/ml were maintained for between two and three weeks, from only a single dose of the drug.[4] The largest individual HIV RNA reductions ranged up to -2.5 log10 among patients receiving both the 2 and 5 mg/kg doses.[5]

Mechanism of action[edit]

PRO 140 is a lab-made antibody that functions as an entry inhibitor.[6][7] PRO 140 binds to the CCR5 receptor on the CD4 cells, and interferes with HIV's ability to enter the cell. PRO 140, a humanized form of a PA14 antibody, is a chemokine-receptor CCR5 monoclonal antibody and can inhibit CCR5 tropic HIV-1 at concentrations that do not antagonize the natural activity of CCR5 in vitro. HIV-1 entry is mediated by the HIV-1 envelope glycoproteins gp120 and gp41. The gp120 will bind CD4 and the CCR5co receptor molecule, and this triggers gp41-mediated fusion of the viral and cellular membranes. CCR5 is hence needed for the entry of the virus and this infection of healthy cells. PRO 140, the anti-CCR5 monoclonal antibody, can stop HIV from entering the cell and stop viral replication. It prevents the virus-cell binding at a distinct site in the CCR5 co-receptor without interfering with its natural activity. Unlike other entry inhibitors, PRO 140 is a monoclonal antibody. The mechanism of inhibition is competitive rather than allosteric.[8] As such, it must be injected to be effective. However, once inside the body, PRO 140 binds to CCR5 for >60 days,[9] which may allow for dosing as infrequently as every other week.[10][11] Compared to highly-active antiretroviral therapy which has been shown to have treatment-related toxicities for HIV-infected patients, PRO140 has no multi-drug resistance or toxicities.[8]

See also[edit]

External links[edit]

References[edit]

  1. ^ "CytoDyn Announces Acquisition of PRO 140". CytoDyn Inc. October 17, 2012. 
  2. ^ Brian Lawler. Progenics' Intriguing Study Results. The Motley Fool. 2 May 2007.
  3. ^ "Phase 2 clinical trials started on PRO 140". AIDS Patient Care and STDs 22 (2): 159–60. February 2008. doi:10.1089/apc.2008.9960. PMID 18273941. 
  4. ^ Derek Thaczuk. ICAAC: Phase 1 study provides 'proof of concept' for PRO 140, a monoclonal CCR5 antibody. AIDSmap.com. 21 Sept 2007.
  5. ^ Liz Highleyman. Monoclonal Antibody CCR5 Inhibitor PRO 140 Produces Long-lasting HIV Suppression in Single-dose Study. 28 Sept 2007. HIVandHepatitis.com
  6. ^ Biswas P, Tambussi G, Lazzarin A (2007). "Access denied? The status of co-receptor inhibition to counter HIV entry". Expert Opin Pharmacother 8 (7): 923–33. doi:10.1517/14656566.8.7.923. PMID 17472538. 
  7. ^ Pugach P, Ketas TJ, Michael E, Moore JP (August 2008). "Neutralizing antibody and anti-retroviral drug sensitivities of HIV-1 isolates resistant to small molecule CCR5 inhibitors". Virology 377 (2): 401–7. doi:10.1016/j.virol.2008.04.032. PMC 2528836. PMID 18519143. 
  8. ^ a b L, Li, Sun T, Yang K, Zhang P, and Jia WQ. "Monoclonal CCR5 Antibody for Treatment of People with HIV Infection (Review)." Cochrane Database of Systematic Reviews 2 (2011): n. pag. Print.
  9. ^ "Progenics Pharmaceuticals' HIV Drug, PRO 140, Receives FDA Fast-Track Designation". Press release, 22 February 2006. Progenics Pharmaceuticals. progenics.com.
  10. ^ "PRO 140". Progenics Pharmaceuticals. progenics.com.
  11. ^ Tim Horn. "Single-Dose PRO 140 Has Lasting Effects". 21 Sept 2007. POZ.com.