Exploring APG101: A CD95/CD95L Inhibitor for Graft-Versus-Host Disease Prevention and T Cell Function Preservation

Allogeneic bone marrow transplantation (BMT) is a potential cure for blood cancers, utilizing the ability of T cells to destroy remaining cancer cells through a graft-versus-tumor (GVT) response. However, these same T cells can cause graft-versus-host disease (GVHD), which attacks the recipient's tissues and leads to severe health issues. The CD95/CD95L system is a key factor in the tissue damage associated with GVHD, suggesting that targeting this pathway could reduce GVHD without affecting the GVT response.

APG101 is a fusion protein that blocks the interaction between CD95 and CD95L, potentially mitigating GVHD. In a study using a mouse model of allogeneic BMT, APG101 was found to inhibit CD95L-induced apoptosis in T cells without impacting their ability to proliferate or exert cytotoxic effects. The treatment was administered prophylactically or therapeutically, starting either before transplantation or several days after.

Both prophylactic and early therapeutic administration of APG101 were found to protect against clinical GVHD and improve survival rates. The treatment did not alter the migration and proliferation of T cells to lymphoid or target organs. Despite its potential to affect T cell activation due to CD95L's role as a co-stimulatory signal, APG101 did not change the phenotype, proliferation, or cytokine expression of the transplanted T cells. Importantly, the GVT effect remained intact in treated mice, and the anti-tumor cytotoxicity of the T cells was not compromised, regardless of the cell line used.

The study's results indicate that early treatment with APG101 is a promising strategy to prevent GVHD while maintaining T cell functions and preserving the GVT effect post-BMT. The disclosures section notes that several authors have affiliations with Apogenix, including research funding, employment, and equity ownership, as well as patents and royalties.