The costimulatory pathway bridges the activation of T cell responses to the amplification and activation of the innate immune response via the monocyte lineage.
Two signals are required for T-cell activation:
Signal 1: The MHC molecule, located on the surface of antigen-presenting cells (APCs), presents antigen to the TCR on the surface of the T cell. This signal alone is insufficient to generate T-cell activation and effector functions.
Signal 2: A costimulatory signal present on the surface of T cells interacts with its ligand present on the surface of APCs (including macrophages, dendritic cells, and B cells). The synergism of signal 1 with signal 2 is sufficient to induce T-cell activation and effector functions, including proliferation, differentiation, and cytokine production by T cells.
CD28 is constitutively expressed on CD4+ and CD8+ T cells. It has two ligands, B7-1 and B7-2. B7-1 expression is inducible on APCs and B7-2 is constitutively expressed on APCs. Their expression is upregulated after activation. B7-1 and B7-2 have their high-affinity inhibitory receptor named CTLA-4 whose expression is induced on activated T cells. The blocking effect of CTLA4-Ig fusion protein is not complete, probably because of redundant roles of CD28 with other costimulatory molecules.
CD40 is expressed on DCs and B cells and CD40L on activated CD4+ T cells. CD40 signals activate DCs and activated DCs in turn promote the activity of CD8+ T cells as well as CD4+ T cells. CD40 plays a critical role in Ab class switch.
AT-1501 is an anti CD40L antibody with high affinity to CD40L. AT-1501 lacks effector function due to point mutations induced into the FC portion of the antibody.
AT-1501 has an excellent safety profile in multiple dose escalating IND enabling safety studies.
We have completed a phase 1 safety and tolerability study of AT-1501 in healthy subject and patients with ALS.