Treatment of Autoimmune Diseases

I have a thought so blindingly obvious that I don’t know why I haven’t read about it. First the thought then wondering why I haven’t found it written.

The idea is to treat with a chimera of an antibody to a tissue specific antigen and PDL1 (note how quickly it can be stated).

PDL1 (programmed death ligand 1) interacts with PD1 (programed death 1) On Kiler T cells and Natural Killer cells. The acronyms suggest that these cells then die. However, it is now known that they live on without killing the cell which displays PDL1. Blocking this “checkpoint” Is a very major dramatic Nobel Prize winning step towards effective immunotherapy of cancer.

Killing by lymphocytes is often a problem: Type 1 diabetes, Multiple sclerosis, Celiac Disease, Ulcerative Colitis and other less common disorders. It seems obvious that the PDL1/PD1interaction could be very useful. A problem with immunosuppressants is that they leave the patient vulnerable to infections. They are still used, however it clearly would be useful to focus the immunosuppression on the tissue where the immune response is causing trouble.

This should be easy if there is a monoclonal antibody which binds to that tissue. For example pancreatic Islet cells (beta cells) display a characteristic antigen Zinc Transporter-8 (ZnT8) cells There is a monoclonal antibody to this antigen . It seems to me that a chimera of that antibody and PDl1 is worth exploring.

It is possible that by the time Diabetes is diagnosed it is too late (there are beta cells in the pancreases of people with type 1 diabetes but they may have survived by becoming irreversibly dormant). Also Islet cells for transplant might usefully be decorated with the chimera.

For multiple sclerosis and related diseases a myelin specific might be useful. Such antibodies exist and create trouble when not attached with PDL1.

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 .