Abstract
Anemia of chronic disease (ACD) is the most common cause of anemia in hospitalized patients. The underlying pathophysiological mechanisms are manifold, including reduced Erythropoietin (EPO) availability and sensitivity, direct negative effects of inflammatory cytokines on erythropoiesis and functional iron deficiency due to iron restriction mainly in the reticuloendothelial system (RES). The latter can be ascribed to increased hepcidin levels, a small liver derived peptide that has been found to be the key iron regulator.
Up to date, most patients suffering from ACD are treated with a combination of both ESA (Erythropoietin Stimulating Agent) and intravenous (i.v.) iron to maintain hemoglobin (Hb) levels. Despite this combination therapy a significant number of patients require increasing doses of i.v. iron and ESA during their medical history - often resulting in continuous, potential toxic iron overload and ESA doses that exceed the acceptable range. As hepcidin is central to the iron-restrictive phenotype in ACD, several therapeutic approaches of hepcidin modulation have been investigated to overcome iron overload and EPO resistance. Some of these therapies are currently investigated in early clinical trials.
We here report the effects of a fully human anti-BMP6 antibody on anemia, iron metabolism, erythropoiesis and ESA dosing in two different, well established rodent models of ACD.
As BMPs, mainly BMP2 and BMP6, have been reported to be involved in hepcidin control, with knock out mice showing very low hepcidin levels even in an inflammatory setting, a fully human anti-BMP6 antibody has been developed to suppress hepcidin levels.
We tested the antibody treatment in two distinct ACD animal models: First, a rat arthritis model (PG-APS in Lewis rats) and second, a Chronic Kidney Disease (CKD) mouse anemia model (Adenine model in C57BL/6 mice). Both models present with long-lasting anemia as seen in humans suffering from ACD. Mice and rats were treated with different doses of the anti-BMP6 antibody with and without ESA. Whole blood count, serum iron parameters (including hepcidin), bone marrow erythropoiesis determined by FACS analysis, cytokine expression and iron metabolism gene expression in spleen, liver and kidney were analyzed.
Anti-BMP6 as well as ESA monotherapy resulted in a net increase in Hb level but only anti-BMP6 treatment significantly increased MCV and MCH, which can be ascribed to effective iron mobilization. In contrast, ESA therapy raised Hb levels by increasing red blood cell numbers. Of note, mere i.v. iron supplementation (sodium ferric gluconate), even at high doses, was not able to restore Hb levels to the same extent as the anti-BMP6 monotherapy.
Strikingly, combination of both, ESA and anti-BMP6 treatment, had a synergistic effect on Hb levels, especially in the rat PG-APS model. Combination therapy of low ESA doses that only had a modest effect as a monotherapy, led to a dramatic increase in Hb levels, even exceeding those seen in healthy rats. Based on these results, additional experiments were performed to investigate the potential of this combination treatment to reduce ESA doses. Indeed, when anti-BMP6 was combined with a significantly reduced total ESA dose Hb levels were corrected to normal values in disease animals. Anti-BMP6 treatment also led to a significant decrease of iron deposition in the spleen with no iron deposition in parenchymal organs, indicating that the freed-up iron was effectively used for erythropoiesis and not just distributed elsewhere.
In summary, anti-BMP6 therapy worked synergistically with ESA treatment in two different models of ACD leading to significantly increased Hb levels, a reduced ESA need as well as reduced iron overload in the RES. Furthermore, these experiments clearly show that treatment of ACD, being a complex multifactorial disease, benefits from using a combination of diversified approaches to overcome anemia and significantly reduce the dose of each therapeutic.
Disclosures
Wake: Kymab Ltd.: Employment. Bayliss:Kymab Ltd.: Employment. Papworth:Kymab Ltd.: Employment. Carvalho:Kymab Ltd.: Employment. Deantonio:Kymab Ltd.: Employment. Weiss:Kymab Ltd.: Consultancy. Germaschewski:Kymab Ltd.: Employment. Theurl:Kymab Ltd.: Consultancy, Research Funding.
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