The most advanced drug candidate is APG101, a human, soluble fusion protein combining the extracellular domain of the CD95-receptor and the Fc-portion of IgG. CD95, a so-called death-receptor, is triggered by the CD95 ligand to initiate apoptosis. APG101 blocks CD95L-mediated apoptosis by binding to the ligand expressed on effector cells, thereby preventing apoptosis of healthy tissue.
Experimental evidence exists demonstrating that blockade of CD95L plays an important role in the pathophysiology of diseases characterized by an excess of apoptosis, such as myocardial infarction, acute “Graft-versus-Host Disease” (aGvHD), sepsis and stroke.
APG101 has demonstrated a dose-dependent effect in animal models of the above mentioned diseases and is in development for the prevention of aGvHD. GMP-material of APG101 is manufactured by the Jülich-based biotechnology company Celonic.
Apogenix has been granted orphan drug status for APG101 for the prevention of aGvHD by the European Commission in 2006 and plans to initiate clinical phase I studies for this indication in early 2008.
APG101 is covered by four different patent families claiming the composition of matter as well as its use for different indications.
Advantage over other approaches: Acute Graft-versus-Host Disease
In acute Graft-versus-Host Disease (aGvHD), grafted donor T-cells kill host cells by triggering apoptosis via CD95L, which binds to the CD95 receptor. APG101 exerts its therapeutic effect by binding CD95L, thereby blocking CD95L-mediated apoptosis. More specifically, it partly neutralizes the alloreactive cytotoxicity of donor T-cells, thus preventing the development of aGvHD. There is evidence that the desirable Graft-versus-Tumor (GvT) Effect whereby grafted donor T-cells attack residual tumor cells of the host, is mediated by yet another apoptotic pathway involving the apoptosis ligand TRAIL. This pathway is not affected by APG101.
Current therapeutic interventions such as, e.g. immunosuppressants show only a limited reduction of aGvHD occurrence. Moreover, there is a relatively high rate of opportunistic infections. More importantly, the treatment reduces the GvT Effect and therefore increases the leukaemia relapse rate. APG101 holds the promise to markedly reduce the severe complications associated with, e.g. allogeneic bone-marrow transplantations while maintaining the desired GvT Effect.
Advantage over other approaches: Myocardial Infarction
APG101 exerts its therapeutic effect by blocking CD95L-mediated apoptosis occurring in the pathogenesis of myocardial infarction (MI), reperfusion damage, post-MI remodelling and heart failure. Following a myocardial infarction, affected tissue, the so-called granulation tissue, overexpresses CD95, and it has been demonstrated that granulation tissue apoptosis is mediated via the CD95/CD95L system. Inhibition of this system by administration of soluble CD95 blocks maladaptive post-MI remodelling. This approach leads to an improvement in cardiac function and overall survival.
Thus, the therapeutic interference with pro-apoptotic stimuli such as CD95L in the context of heart failure development following MI represents an additional attractive indication to be treated with APG101.
Selected Publications