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.
Image credit: Eledon Pharmaceuticals
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.
DOI: 10.3390/jcm11102810
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.
DOI: 10.1097/MD.0000000000037242
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.
This report aims to explore the events and trends of the biopharmaceutical industry in Q2 (April, May, June). Besides crovalimab and Vyloy, two more novel antibody drugs have been approved this year
These past few weeks, several antibody drug startups have progressed from the pre-seed stage to final funding rounds. In the pre-seed stage, the focus is on early research, often funded by founders, grants, or angel investors. As the company progresses to the seed stage, it seeks additional funding to validate its scientific concept and develop initial prototypes, attracting early-stage venture capital.
In August, the US FDA approved Galderma’s Nemluvio (nemolizumab) for adult patients living with prurigo nodularis (PN). Nemluvio is the first approved monoclonal antibody specifically inhibiting the signaling of IL-31, a neuroimmune cytokine that drives multiple disease mechanisms in (PN). Prurigo nodularis is a chronic skin condition that affects approximately 181,000 patients in the United States
Anti-drug antibodies (ADAs) are immune system proteins that can develop in response to therapeutic drugs, particularly biologics like monoclonal antibodies. These biopharmaceuticals have significantly advanced therapies for cancer and autoimmune diseases, but their long-term use can elicit immunogenicity due to repeated administration. The host immune system may recognize epitopes in the biologic drug as foreign, triggering the production of ADAs. This can lead to the formation of drug–ADA immune complexes, which accelerate drug clearance and potentially neutralize the drug's efficacy.
