New Therapies for Highly Sensitized Patients on the Waiting List

Abstract

Purpose: Exposure to HLA alloantigens through pregnancy, blood products and previous transplantations induce powerful immunologic responses that create an immunologic barrier to successful transplantation. This is commonly detected through screening for HLA antibodies using Luminex beads coated with HLA antigens at transplant evaluation. Currently accepted approaches to desensitization include plasmapheresis (PLEX)/low or high dose IVIg plus anti-CD20. However, these approaches are often unsuccessful due to the inability to remove high titer circulating HLA antibodies and limit rebound responses by long-lived anti-HLA antibody secreting plasma cells (PCs) and memory B-cells (BMEM). This is especially significant for patients with cPRA 99-100%. Recent findings: Newer desensitization approaches such as imlifidase (IgG endopeptidase) rapidly inactivates IgG molecules and creates an “antibody-free zone” by cleaving IgG into F(ab’2) and Fc fragments, thus eliminating complement and cell-mediated injury to the graft. This represents an important advancement in desensitization. However, the efficacy of imlifidase is limited by pathogenic antibody rebound, increasing the potential for antibody-mediated rejection. Controlling antibody rebound requires new strategies that address the issues of antibody depletion and inhibition of BMEM & PC responses. This will likely require a combination of agents that effectively and rapidly deplete pathogenic antibodies and prevent immune cell activation pathways responsible for antibody rebound. Here, using anti-IL-6R (tocilizumab) or anti-IL-6 (clazakizumab) could offer long-term control of BMEM and PC DSA responses. Agents aimed at eliminating long-lived PCs (anti-CD38 & anti-BCMAxCD3) are likely to benefit HS patients. Complement inhibitors and novel agents aimed at inhibiting Fc neonatal receptor (FcRn) IgG recycling will be important in desensitization. Conclusions: Administering these agents alone or in combination will advance our ability to effectively desensitize patients and maintain durable suppression post-transplant. After many years of limited options, advanced therapeutics will likely improve efficacy of desensitization and improve access to kidney transplantation for highly-HLA sensitized patients.