Background Despite being approved for clinical use over a decade ago, CTLA-4 mAbs remain encumbered by a narrow therapeutic window and relatively severe adverse event (AE) profile. Increasing data support that CTLA-4 mAb efficacy is primarily driven by depletion of CTLA-4+ T regulatory cells (Tregs) in the tumor microenvironment (TME), while AEs have been linked to an overzealous peripheral T cell response mediated by prolonged CTLA-4 blockade. It has been postulated that a more selective approach directly targeting TME-associated Treg cell depletion, while reducing peripheral T cell effects, might improve the tolerability of this class of immune checkpoint inhibitors, yet no CTLA-4 targeted mAb has achieved this. MT-8421 is a potent CTLA-4-targeted engineered toxin body (ETB) that can preferentially deplete high CTLA-4 expressing Tregs in the TME while sparing low CTLA-4 expressing peripheral T cells. In addition, MT-8421 was well-tolerated in a non-GLP non-human primate (NHP) study at doses hundreds-fold higher (450ng/mL) than the IC50 on CTLA-4 expressing cells. Here we demonstrate that MT-8421 synergizes with αPD-1 mAb in a Treg/T cell primary cell co-culture to stimulate T cell proliferative responses through direct Treg cell depletion.1 Results from animal models including a GLP-NHP study will be described.
Methods T cells and Tregs were isolated from PBMCs of healthy donors and were stained to track T cell proliferation. T cells were co-cultured with autologous Tregs at various ratios. Anti-CD3/CD28 was used to drive proliferation of T cells in the presence of 4,000ng/mL of MT-8421, inactive MT-8421, or αPD-1 mAb (20µg/mL) to test for monotherapy activity. In addition, cells were treated with αPD-1 mAb followed by MT-8421 to evaluate combination effects. After 4 days, cells were stained with surface antibodies and analyzed by flow cytometry.
Results Co-cultures treated with MT-8421 alone demonstrated release of Treg-mediated CD8 T cell suppression compared to the untreated or inactive MT-8421. In addition, while αPD-1 treatment alone expectedly increased CD4+ and CD8+ T cell proliferation, when followed by MT-8421 treatment, the effects on T cell proliferation were greater than with either treatment alone.
Conclusions MT-8421 is a novel approach to CTLA-4 targeting: a potent depletion of TME CTLA-4+ Tregs without long-lasting CTLA-4 blockade in the periphery. This approach may allow for enhanced efficacy over current antibody approaches through the elimination of Tregs in the TME. The lack of prolonged peripheral CTLA-4 blockade may reduce toxicity as seen with antibody approaches to CTLA-4. Clinical studies are expected to start in 2023.
Sarkar A, Martin R, Byrne LR, Howard C, Khanna S, Rabia LA, Adhikari D, Sousares MM, Aldana A, Robinson GL, Zhao J, Moore CB, Iberg A. A CTLA-4 targeted ETB for Treg depletion shows favorable preclinical efficacy and safety. Cancer Research 2022; 82:12 supplement, 3538–3538.
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