ATA188

ATA188 is an allogeneic, or third-party derived, EBV-CTL product candidate that selectively targets the EBV antigens that we believe are important for the treatment of MS.

Multiple Sclerosis and EBV
There is a growing body of evidence documenting the close association of EBV with MS, and suggesting that B-cells and plasma cells that are EBV+ (i.e. express EBV antigens) have the potential to catalyze the autoimmune response and overall pathophysiology in MS.

  • Studies suggest that nearly all MS patients have been infected with EBV1,2,3
  • Having a clinical history of infectious mononucleosis (which is caused by EBV) more than doubles the risk of MS4
  • EBV+ B-cells and plasma cells have been detected in the brains of MS patients and EBV+ cells have been shown to be present in active MS lesions5,6
  • The immune responses in MS patients against EBV antigens correlate with the development of MS lesions on MRI of the brain, and with the progression of disability over 5-yr7

A person’s T-cells normally control the EBV infection and eliminate EBV+ B-cells and plasma cells. In people with MS, it has been shown their T-cells have a diminished response to EBV antigens (i.e. proteins). 8 As a result, the T-cells in patients with MS may be unable to control EBV+ B-cells and plasma cells, which could then accumulate in the brain. In the brain, they may generate antibodies and an overall immune reaction that attacks and destroys myelin, the protective layer that insulates nerves in the brain and spinal cord. This loss of myelin ultimately leads to MS symptoms. The concept of reducing B-cells to treat MS is reinforced by the recent approval of a medicine for MS that broadly targets B-cells.

Types of MS:
There are three types of MS: relapsing remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), and primary progressive multiple sclerosis (PPMS).

  • Individuals with RRMS experience times where they have flares of their disease symptoms, followed by periods of recovery. Following the flare, an individual may go back to their baseline function or have a less complete recovery, however during the recovery period, the disease does not progress.
  • Progressive MS is diagnosed when an individual has continuous progression of their disease and disability. There are two forms of progressive MS, PPMS and SPMS. An individual with PPMS has continuous progression of their disease from the time they first develop symptoms. An individual with SPMS is typically first diagnosed with RRMS. Over time, their RRMS worsens so that disease starts to continuously progress, even during recovery periods. When there is continuous progression, even in the recovery periods, the individual has developed SPMS.

Although currently approved therapies have shown good benefit in preventing relapses in MS, and newer medicines have been approved (or are soon to be approved) for progressive MS, there remain substantial unmet medical need for people suffering from the disease. Some of these include9

  • Further delaying progression and developing better treatments for progressive MS
  • Providing neuroprotection
  • Delaying or avoiding disability
  • Reducing active symptoms more effectively
  • Predicting who would benefit from specific treatments (ie, creating the means for individualizing treatment)

ATA188 Development Program
ATA188 is an allogeneic, or third-party derived, EBV-CTL product candidate that selectively targets specific EBV antigens so that it eliminates only those cells which are EBV positive, while sparing those that are not. We believe that eliminating only EBV positive B-cells, and plasma cells has the potential to meet an unmet need in MS and lead to both enhanced efficacy and a better side effect profile. We are also investigating autologous (MS patient-derived) ATA188 that is precision targeted using the same technology, and works in the same way as ATA188. Autologous ATA188 has been used on a compassionate basis to treat an individual with SPMS, whose condition was deteriorating, and autologous ATA188 is currently being evaluated in a Phase 1 clinical trial in progressive MS patients in Australia.

The ATA188 program is expected to enter into a Phase 1 clinical trial for MS in the second half of 2017. Autologous ATA188 is being evaluated in a Phase 1 clinical trial in Australia expected to complete in 2017. We look forward to additional development with both the autologous and allogeneic ATA188 to further evaluate the potential therapeutic utility of targeting EBV in the treatment of MS.

  1. Levin LI, Munger KL, O’Reilly EJ, Falk KI, Ascherio A. Primary Infection with the Epstein-Barr Virus and Risk of Multiple Sclerosis. Annals of neurology. 2010;67(6):824-830. doi:10.1002/ana.21978.
  2. Dobson R, Kuhle J, Middeldorp J, Giovannoni G. Epstein-Barr–negative MS: a true phenomenon? Neurology Neuroimmunology & Neuroinflammation. 2017;4(2):e318. doi:10.1212/NXI.0000000000000318.
  3. Endriz J, Ho PP, Steinman L. Time correlation between mononucleosis and initial symptoms of MS. Neurology® Neuroimmunology & Neuroinflammation. 2017;4(3):e308. doi:10.1212/NXI.0000000000000308.
  4. Handel AE, Williamson AJ, Disanto G, Handunnetthi L, Giovannoni G, Ramagopalan SV. An Updated Meta-Analysis of Risk of Multiple Sclerosis following Infectious Mononucleosis. Jacobson S, ed. PLoS ONE. 2010;5(9):e12496. doi:10.1371/journal.pone.0012496.
  5. Serafini B, Rosicarelli B, Franciotta D, et al. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. The Journal of Experimental Medicine. 2007;204(12):2899-2912. doi:10.1084/jem.20071030.
  6. Tzartos et.al., Association of innate immune activation with latent Epstein-Barr Virus in active MS lesions. Neurology. 2012 Jan 3;78(1):15-23. doi: 10.1212/WNL.0b013e31823ed057.
  7. Lünemann JD, Tintoré M, Messmer B, et al. Elevated EBNA1 Immune Responses Predict Conversion to Multiple Sclerosis. Annals of neurology. 2010;67(2):159-169. doi:10.1002/ana.21886.
  8. Pender MP, Csurhes PA, Burrows JM, Burrows SR. Defective T-cell control of Epstein–Barr virus infection in multiple sclerosis. Clinical & Translational Immunology. 2017;6(1):e126-. doi:10.1038/cti.2016.87.
  9. Mehr SR, Zimmerman MP. Reviewing the Unmet Needs of Patients with Multiple Sclerosis. American Health & Drug Benefits. 2015;8(8):426-431.