Trends in Nephrology: From nihilism to targeted treatment of antibody-mediated rejection

Antibody-mediated rejection (AMR) is among the leading causes of kidney transplant attrition. Traditional AMR therapy consisted of interventional studies that were small and often uncontrolled. Although a blockade of the interleukin-6 pathway failed to prevent allograft loss in a phase 3 trial, anecdotal evidence had previously suggested potential benefit. Likewise, anti-CD20 antibodies have not been shown to improve AMR outcomes in terms of graft survival. Imlifidase, which cleaves all IgGs, and hence also all donor specific antibodies, showed a higher rate of graft loss in the experimental group of an AMR study. Terminal complement inhibitors showed inconsistent efficacy in underpowered trials; currently, C3 inhibitors are a promising focus for complement-targeted strategies against AMR. Anti-CD38 antibodies currently represent the most promising novel therapy option for AMR based on encouraging phase 2 study results. We furthermore discuss genetically engineered CD38 knock-out multitarget natural killer cells, expressing anti-B cell maturation antigen (BCMA) CAR, IL-15RF and hnCD16, administered in combination with daratumumab (anti-CD38) in this context. This approach represents a cheaper and safer alternative to chimeric HLA antigen receptor (CHAR) T cell therapy. CHAR T cells showed a high specificity in recognizing their respective target anti-HLA class I B cell receptors in-vitro. Quantitative results from in-vivo trials are pending. Likewise, we hypothesize the use of bi-specific T cell engagers such as CD19 blinatumomab or BCMA teclistamab for the treatment of AMR. In addition, clinical studies investigating conversion from calcineurin inhibitors to co-stimulation therapies such as anti-CD40L antibodies may reduce dnDSAs and AMR. In summary, anti-CD38 antibodies currently constitute the drug class with the strongest evidence for AMR treatment. To date, most CD38 antibodies have been shown to be safe, even after several years of administration in patients with multiple myeloma.