PRO 140

PRO 140
Monoclonal antibody
Type ?
Source Humanized
Target CCR5
Clinical data
ATC code
  • none
Legal status
Legal status
  • investigational
Identifiers
ChemSpider
  • none
NIAID ChemDB
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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 and a phase 3 trial was begun in 2015.[3][4] In February 2018 Cytodyn Inc reported that the primary endpoint has been achieved in the PRO 140 pivotal combination therapy trial in HIV infection.[5]

Development

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 milligrams per kilogram and showed an average viral load decrease of -1.83 log10. On average, reductions of greater than -1 log10 per millilitre were maintained for between two and three weeks, from only a single dose of the drug.[6] The largest individual HIV RNA reductions ranged up to -2.5 log10 among patients receiving both the 2 and 5 mg/kg doses.[7]

In February 2018 Cytodyn Inc reported that the primary endpoint has been achieved in the PRO 140 pivotal combination therapy trial in HIV infection and will continue for an additional 24 weeks (end of August 2018) with PRO 140 weekly subcutaneous injections and optimized ART.[8] The report discloses that a single 350mg subcutaneous injection of PRO 140 resulted in a HIV-1 RNA viral load reduction greater than 0.5log or 68% within one week compared with those who received a placebo. The primary efficacy endpoint results will be presented at ASM Microbe 2018.[9][10]

Mechanism of action

PRO 140 is a lab-made antibody that functions as an entry inhibitor.[11][12] 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.[13] As such, it must be injected to be effective. However, once inside the body, PRO 140 binds to CCR5 for >60 days,[14] which may allow for dosing as infrequently as every other week.[15][16] 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.[13]

See also

References

  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. ↑ "Cytodyn Initiates First Clinical Site for Phase 3 Trial of PRO 140 :: CytoDyn Inc. (CYDY)". www.cytodyn.com. Retrieved 2015-08-22.
  5. ↑ "CytoDyn Reports Primary Endpoint Achieved in PRO 140 Pivotal Combination Therapy Trial in HIV Infection :: CytoDyn Inc. (CYDY)". www.cytodyn.com. Retrieved 2018-04-19.
  6. ↑ Derek Thaczuk. ICAAC: Phase 1 study provides 'proof of concept' for PRO 140, a monoclonal CCR5 antibody. AIDSmap.com. 21 Sept 2007.
  7. ↑ Liz Highleyman. Monoclonal Antibody CCR5 Inhibitor PRO 140 Produces Long-lasting HIV Suppression in Single-dose Study. 28 Sept 2007. HIVandHepatitis.com
  8. ↑ "CytoDyn Reports Primary Endpoint Achieved in PRO 140 Pivotal Combination Therapy Trial in HIV Infection :: CytoDyn Inc. (CYDY)". www.cytodyn.com. Retrieved 2018-04-19.
  9. ↑ "CytoDyn to Present Primary Efficacy Endpoint Results from its PRO 140 Pivotal Trial in Late-Breaking Session at ASM Microbe 2018 :: CytoDyn Inc. (CYDY)". www.cytodyn.com. Retrieved 2018-04-19.
  10. ↑ "SATURDAY - AAR LB15 / SATURDAY - AAR LB15 - Primary Efficacy Results of PRO 140 SC in a Pivotal Phase 2b/3 Study in Heavily Treatment-Experienced HIV-1 Patients :: CytoDyn Inc. (CYDY)". www.abstractsonline.com. Retrieved 2018-04-19.
  11. ↑ 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.
  12. ↑ 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.
  13. 1 2 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.
  14. ↑ "Progenics Pharmaceuticals' HIV Drug, PRO 140, Receives FDA Fast-Track Designation" Archived 2011-10-02 at the Wayback Machine.. Press release, 22 February 2006. Progenics Pharmaceuticals. progenics.com.
  15. ↑ "PRO 140". Progenics Pharmaceuticals. progenics.com.
  16. ↑ Tim Horn. "Single-Dose PRO 140 Has Lasting Effects". 21 Sept 2007. POZ.com.
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