A team from the Innsbruck University Clinic for Internal Medicine II (Director: Günter Weiss) at the Medical University of Innsbruck has co-developed an innovative antibody for the therapy of chronic anemia in dialysis patients. The added value of the new approach lies in the lower erythropoietin (EPO) dose required and the associated minimization of the cardiovascular risk to which kidney patients are particularly exposed. Following the promising results in mouse and rat models, the antibody is expected to enter clinical trials soon.
Anemia of chronic disease (ACD) is a common problem in dialysis patients. In addition to the functional iron deficiency caused by chronic inflammation, the damaged kidneys of these patients do not produce enough of the most important hormone for blood formation, erythropoietin (EPO). The administration of EPO is therefore a therapeutic cornerstone to correct anemia. However, despite the maximum dosage, the formation of the oxygen transport protein hemoglobin remains limited in dialysis patients due to the development of EPO resistance.
A recent "black box warning" also links EPO to increased cardiovascular mortality. "This warning poses an additional dilemma for dialysis patients since renal failure is in itself associated with an increased cardiovascular risk," emphasizes Igor Theurl, who has been researching ACDs for many years at the Innsbruck University Clinic for Internal Medicine II together with Director Günter Weiss.
The research team around Theurl now tested the new human monoclonal antibody KY1070. Its effectiveness was demonstrated in an animal model that can be transferred to patients with kidney damage requiring dialysis. "In animals that did not respond adequately to EPO, it was possible to achieve a sufficient increase in hemoglobin by combining the antibody with the antibody. In addition, a lower EPO dose was sufficient to combat anemia, which, considering the side effects of EPO, is an important basis for its use in dialysis patients," said main author Verena Petzer (from the University Clinic for Internal Medicine V. The results were published in the renowned journal BLOOD.
The therapeutic potential of the new antibody can be exploited as a monotherapy as well as in combination with EPO. The antibody influences the signal transduction for the formation of hepcidin. As a monotherapy, it leads to long-term inhibition of hepcidin production and therefore to the high availability of iron, which is essential for the formation of red blood cells.
"The effects of combination therapy are multifactorial. The advantage of the combined treatment is the reduction of the EPO dose so that the cardiovascular risk is not additionally increased and at the same time sufficient iron availability is ensured. In addition, we have been able to demonstrate that the inhibition of hepcidin increases the expression of the iron transport protein ferroportin on the hematopoietic cells in the bone marrow and, together with EPO, leads to more effective blood formation," said Igor Theurl.
A fully human anti-BMP6 antibody reduces the need for erythropoietin in rodent models of the Anemia of Chronic Disease. https://doi.org/10.1182/blood.2019004653