March 2024: Organ Transplantation

This month heralded the release of groundbreaking news involving the monoclonal antibody tegoprubart, which facilitated the successful transplantation of a genetically edited pig kidney into a 62-year-old man grappling with end-stage kidney disease. Tegoprubart, an anti-CD40L antibody, blocks the CD40L signaling crucial for immune cell activation and function, thus offering a promising avenue for non-lymphocyte depleting immunomodulatory therapeutic interventions.

The successful transplantation using tegoprubart underscores a pivotal shift towards precision medicine in transplantation immunology. Traditional immunosuppressive therapies broadly suppress the immune system and come with a host of side effects. By specifically inhibiting pathways involved in organ rejection, new drugs can aim to minimize adverse effects while preventing the immune system from attacking the transplanted organ.

Xenotransplantation, or the transplantation of organs from one species to another, has long been seen as a potential solution to the chronic shortage of human organs available for transplantation. However, the human immune system's tendency to reject foreign tissue has been a significant barrier. The use of genetically edited pigs, designed to be more compatible with the human immune system, combined with sophisticated immunomodulatory drugs like tegoprubart, brings us closer than ever to making xenotransplantation a viable and routine option for patients in need.

Currently in development are several other antibody drugs which focus more broadly on preventing organ rejection overall. 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.

Just this week, HI-Bio’s felzartamab received FDA Orphan Drug Designation for the treatment of antibody-mediated rejection in kidney transplant recipients. Felzartamab is an investigational therapeutic human monoclonal antibody directed against CD38, a protein expressed on mature plasma cells. Felzartamab has been shown in clinical studies to selectively deplete CD38+ plasma cells, which may allow applications that ultimately improve clinical outcomes in a broad range of diseases driven by pathogenic antibodies.    

Other antibody drugs in development against organ rejection:

• Tocilizumab is 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 and is currently recruiting for a randomized control trial.

• 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.

• CSL’s clazakizumab is a humanized monoclonal IgG1 antibody that targets IL-6. It iis currently recruiting for a Phase 3 trial for the treatment of chronic active antibody-mediated rejection in kidney transplant recipients.

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.

Looking forward, the successful application of antibody drugs in transplantation could bring about a new era where organ shortages are significantly alleviated through the use of animal organs. It also raises important ethical, regulatory, and logistical questions that will need to be addressed as these technologies advance. How will regulatory bodies ensure the safety and efficacy of these new treatments? What ethical considerations arise from the use of animal organs for human transplantation? And how can we ensure equitable access to these potentially life-saving treatments? As research continues and these therapies enter clinical trials, it will be crucial to engage with these questions openly and collaboratively.