FDA Fast Tracks Autologous Treg Therapy ABA-101 for Progressive Multiple Sclerosis

Samantha Singer, MS, MBA

According to a recent announcement, the FDA has granted fast track designation to Abata Therapeutics’ autologous regulatory T cell (Treg) therapy ABA-101 for the treatment of patients with progressive multiple sclerosis (MS).¹

In animal models, the agent has shown a tolerable safety profile with antigen-dependent Treg functionality, anti-inflammatory cytokine production, suppression of the production of inflammatory cytokines, and therapeutic effect. ABA-101 was specifically designed for patients with progressive MS who have imaging evidence of ongoing inflammatory tissue injury and are HLA-DRB1*15:01 positive-an estimated patient group of about 45,000 in the US today.

"There are no effective treatments for progressive MS, and rapidly advancing new therapies is critical for patients and their families. We are very pleased that the FDA granted us Fast Track designation as it will enable us to expedite our efforts to bring ABA-101 to patients," Samantha Singer, MS, MBA, president and chief executive officer at Abata, said in a statement.¹ "We are focused on initiating our Phase 1 study this year in patients and evaluating the potential impact of this important new therapy."

To date, the only disease-modifying treatment available for patients with primary progressive MS is ocrelizumab (Ocrevus; Genentech). Siponimod (Mayzent; Novartis) is the only approved treatment for secondary progressive MS. Since Tregs suppress autoreactive T cells, they pose as a novel cell therapy for MS. Furthermore, they show interesting reparative properties such as remyelination, mediated by growth-regulatory protein cellular communication network factor 3, and neural stem cell proliferation.

READ MORE: IMU-838 Shows Reduction of Brain Lesions in Phase 2 EMPhASIS Trial for Relapsing-Remitting Multiple Sclerosis

In 1995, researchers published the first convincing demonstration of immune suppressive capacity encased in a CD4+ T cell population identified by constitutive expression of CD25. In the study, when CD4+ cell suspensions prepared from BALB/c nu/+ mice lymph nodes and spleens were depleted of CD25+ cells by specific mAb and C, and then inoculated into BALB/c athymic nude (nu/nu) mice, all recipients spontaneously developed histologically and serologically evident autoimmune diseases (such as thyroiditis, gastritis, insulitis, sialoadenitis, adrenalitis, oophoritis, glomerulonephritis, and polyarthritis); some mice also developed graft-vs-host-like wasting disease.²

When nu/nu mice were transplanted with allogeneic skins or immunized with xenogeneic proteins at the time of CD25- cell inoculation, they showed significantly heightened immune responses to the skins or proteins, and reconstitution of CD4+CD25+ cells normalized the responses. Taken together, the results indicated that CD4+CD25+ cells contribute to maintaining self-tolerance by down-regulating immune response and to self and non-self Ags in an Ag-nonspecific manner, presumably at the T cell activation stage; elimination/reduction of CD4+CD25+ cells was shown to relieve this general suppression, thereby not only enhancing immune responses to non-self Ags, but also eliciting autoimmune responses to certain self-Ags.

In the field of MS research, only 1 clinical trial testing the effect of a Treg-based therapy has been conducted. Published in 2021, the phase 1b/2a, open-label, two-arm trial included 145 patients with relapsing-remitting MS who received either expanded ex vivo Treg cells intravenously (intravenous [IV] group, n = 11; dose 40 × 10⁶ Treg cells/kg of body weight) or freshly isolated Treg cells intrathecally (intrathecal [IT] group, n = 3; dose 1.0 × 10⁶ Treg cells). No adverse events were observed in the study, and self-assessed quality of life did not change or differ significantly from the groups.³

Interestingly, in that study, disease progression was halted in patients who received Tregs intrathecally. More specifically, no patients in that group experienced a relapse or a deterioration of more than 1 point on Expanded Disability Status Scale score. Notably, Treg cells in all patients consisted of two different phenotypes: peripheral Treg cells Helios(-) (≈ 20%) and thymic Treg cells Helios(+) (≈ 80%). The analysis of the cytokine pattern revealed higher levels of transforming growth factor-α and proinflammatory factors MCP3, CXCL8, and IL-1RA in the IT group compared with the IV group.

REFERENCES
1. Abata Therapeutics receives FDA fast track designation for ABA-101 for the treatment of progressive multiple sclerosis. News release. August 22, 2024. Accessed August 28, 2024. https://www.globenewswire.com/news-release/2024/08/22/2934105/0/en/Abata-Therapeutics-Receives-FDA-Fast-Track-Designation-for-ABA-101-for-the-Treatment-of-Progressive-Multiple-Sclerosis.html
2. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155(3):1151-64.
3. Chwojnicki K, Iwaszkiewicz-Grzes D, Jankowska A, et al. Administration of CD4+CD25highCD127-FoxP3+ regulatory T cells for relapsing-remitting multiple sclerosis: a phase 1 study. BioDrugs. 2021;35(1):47-60. doi:10.1007/s40259-020-00462-7