Directing Lymphokines to the desired cells.

I was looking for an earlier article when I found this hot off of the presses Engineered cytokine/antibody fusion proteins improve IL-2 delivery to pro-inflammatory cells and promote antitumor activity

The earlier article discusses an antibody which binds to IL-2, does not block its action and, for some reason, causes it to bind more to inflammatory cells and less to TREGs

I am interested in other ways to direct IL-2 and IL-15 to CD8 killer cells and NK cells. I propose starting with bifunctional antibodies – a 1960s technology which yields an gamma globulin with 2 different Fab components by breaking and remaking the disulfide bonds between Fc components. Here one Fab could be from the Leonard and bind to IL-2. Another possibility is a non blocking antibody to the sushi domain of IL-15 R alpha with IL-15 irreversibly bound to that or a non blocking antibody to IL-15 itself.

In each case the Fab binds to an interleukin and does not block its action The other Fab (in the very preliminary 60s tech experiment) is either anti CD8, anti cd56, or anti NKG2A.

The logic of anti-CD8 is clear. It would direct that IL-2 or IL15 to CD8 killer cells as opposed to the (most common) CD4 TREGs. Also importantly it would direct them to lymphocytes and not the walls of capillaries reducing the dose limiting capillary leak toxicity for a given level of stimulation of the lymphocytes.

Similarly cd56 is characteristic of NK cells (and IL15 has a very dramatic effect on NK cell proliferation).

The case for anti NKG2A is a bit more complicated and interesting. NKG2A is found on NK cells and some CD8 cells. It is an inhibitory receptor which responds to HLA-e. Monalizumab is an FDA approved monoclonal which blocks NKG2A .