CD40/CD40L Pathway and Tegoprubart Site of Action. Image credit: Eledon Pharmaceuticals
This week, exciting news came out that Eledon Pharmaceuticals’ tegoprubart was successfully used to aid the first-ever transplant of a genetically-edited pig kidney into a 62-year-old man with end-stage kidney disease. Tegoprubart is an investigational anti-CD40L antibody that has a high affinity for CD40 ligand. CD40L signaling plays an important role in adaptive and innate immune cell activation and function, and is therefore a target for non-lymphocyte depleting, immunomodulatory therapeutic intervention.
Organ rejection poses a significant threat to the success of transplantation procedures, potentially endangering the recipient's life. This rejection stems from allorecognition, where the recipient's immune system perceives the transplanted organ as foreign material, prompting an immune reaction against it. Current therapies to mitigate rejection risks use calcineurin inhibitors (CNIs), but prolonged CNI usage can cause several complications. Thus, improving strategies for organ protection to prolong their functionality represents a pressing unmet need.
There are several potential antibody drugs in current development and ongoing clinical trials. One example is a recent trial studying the potential of tocilizumab, a recombinant humanized monoclonal antibody directed against the human interleukin-6 (IL-6) receptor. Tocilizumab has shown promise in the treatment of chronic active antibody-mediated rejection (caAMR) in kidney transplants. They hypothesize that inhibition of IL-6 receptor will reduce antibody production and antibody-mediated damage to then slow the decline in graft function in the long-term.
Another exciting antibody drug in development is Tonix Pharmaceuticals’ TNX-1500, an Fc-modified humanized anti-CD40L monoclonal antibody. A Phase 1 clinical stage has just been completed in healthy volunteers, with the aim of becoming a treatment for the prevention of rejection in solid organ and bone marrow transplant, in addition to treating autoimmune disorders.
In an informative review published this month, Park et al. describes the current use of antithymoglobulin as induction regimen in kidney transplantation. In Korea, antithymoglobulin accounts for 20% of all induction therapy. It is a purified gamma globulin used to treat human thymocytes in horses and rabbits, and for kidney transplantation, antithymoglobulin immunosuppressants attach to the T-cell surface to induce antibody-dependent cell-mediated cytotoxicity (ADCC), leading to apoptosis.
