Is Antibody-mediated Rejection a Roadblock to Organ Transplantation?

Over the last decades, organ transplantation has become the leading treatment option for patients with last-stage organ failure. However, although it has significantly reduced the mortality rate, specifically in life-threatening diseases such as end-stage kidney failure, recognition and eventual destruction of well-matched transplants by the host’s immune system have quashed its beneficial effects.

Antibody-mediated rejection (AMR), well-known as humoral or B-cell-mediated rejection, is a problematic post-transplant complication caused by anti-donor HLA antibodies. It plays a vital role in acute or chronic allograft dysfunction and is associated with graft loss. Allograft rejection can be hyperacute, late acute, or chronic, depending on the time of its occurrence after transplantation. Among all these, hyperacute AMR is a rare occurrence in transplantation, primarily bothering pre-sensitized patients who have undergone previous transplantation or blood transfusions or patients with pregnancy. Acute AMR accounts for approximately 5–7% of all kidney transplants and is accountable for 20–48% of acute rejection episodes among pre-sensitized positive cross-match patients. In the case of chronic AMR, progression could be prompt, especially with ongoing acute AMR, resulting in graft failure within months

According to DelveInsight’s estimates, the total AMR incident population in the 7MM was 5,283 cases in 2020. The condition’s rarity has led to the absence of widely accepted treatment guidelines and FDA-approved therapies for AMR. Consequently, the decisions regarding first-line and second-line treatment for managing refractory AMR rely on the assessment of the physician providing treatment. Various treatment choices for AMR have been acquired from other areas of medication without proper clinical studies in transplantation. Besides, a bias is evident toward developing drugs targeting antibodies for indications like oncology and rheumatology, other than transplantation.

The current treatment options in the Antibody-mediated rejection market include off-label use of plasmapheresis, intravenous immunoglobulin (IVIG), rituximab, proteasome inhibitors, anti-CD20, complement inhibitors, lymphocyte-depleting antibodies, corticosteroids, etc. Treatment of AMR with existing remedies has led to the diversification of results preventing the development of the standardized treatment protocol.

Nevertheless, the hunt for novel drugs is ongoing. Some of the most promising drugs in the Antibody-mediated rejection market include clazakizumab (CSL Behring), Imlifidase (Hansa Biopharma AB), and VIB4920 (Viela Bio). Clazakizumab is a powerful, monoclonal antibody that binds to IL-6 and inhibits it; IL-6 plays a vital role in transplant rejection and is a significant driver of the inflammatory response. While Imlifidase is an antibody-cleaving enzyme that mainly inhibits IgG-mediated immune response and originates from Streptococcus pyogenes, VIB4920 is a fusion protein intended to bind to CD40L on T-cells, thus obstructing their interaction with CD40-expressing B-cells and preventing B-cells from differentiating into plasma and memory cells. Besides these, the other drugs under development are Inebilizumab-cdon (Viela Bio) and Daratumumab (Janssen Biotech).

Novel and innovative technologies such as genomic studies, and assays for defining and detecting donor-specific antibodies have provided vital understanding concerning the diagnosis and pathophysiology associated with AMR have pushed the growth of the AMR market, however, to some extent. Unfortunately, these advancements have been unable to transform into concrete results, as present treatment can only decrease graft destruction, and there exists a paucity of a drug in the AMR market that can suppress antibody generation by plasma cells. Inevitably, there are several unmet needs associated with AMR, along with a requirement for clinical trials that are well designed and use standardized and contemporary diagnostic, monitoring, and therapeutic strategies for AMR. Meanwhile, the FDA has rigorous requirements for the approval and labeling of novel drugs and agents in the arena of transplantation. Until such studies and drugs become available, drugs with an exorbitant cost and extensive side effect profile can only be recommended as rescue therapy in nonresponding patients.