AVID200: A Novel TGF-β Inhibitor for the Treatment of Anemia Associated with Myelodysplastic Syndromes

Abstract

AVID200 is an engineered TGF-β ligand trap comprised of TGF-β receptor ectodomains fused to a human Fc domain. AVID200 has antibody-like properties and is 1,000 times more selective for neutralizing TGF-β1 and TGF-β3 (pM potency), compared to TGF-b2. Since TGF-β1 and TGF-β3 are negative regulators of hematopoiesis, while TGF-b2 is a positive regulator of hematopoiesis, the unique isoform selectivity profile of AVID200 makes it an attractive agent for the treatment of Myelodysplastic syndrome (MDS) associated anemia. As TGF-β2 is implicated in normal cardiovascular function and tumor cell dormancy, the specificity profile of AVID200 also minimizes the potential for cardiotoxicity and promotion of metastasis, which have been observed with pan-neutralizing TGF- β agents.MDS consist of a group of disorders that lead to cytopenia through ineffective hematopoiesis. One critical factor that is commonly associated with the occurrence of these disorders is the pathological overproduction of TGF-β. Increased TGF-β results in the arrest of myeloprogenitor cells preventing hematopoiesis. This disruption of the differentiation program and resulting cytopenia can lead to development of acute myeloid leukemia (AML) in one-third of MDS patients.A critical feature of MDS is an increased level of non-homologous end-joining (NHEJ) activity, a low fidelity form of DNA damage repair, as compared to high-fidelity homologous recombination (HR) repair. The increased level of NHEJ repair in MDS cells results in a hypersensitivity to DNA damaging agents such as mitomycin C (MMC). Previously, in a model of MDS, treatment with TGF-β inhibitors was shown to restore the ratio of NHEJ:HR repair to normal, resulting in more accurate DNA repair. Therefore, the effect of increased TGF-β in patients with MDS is deleterious in two ways. First, elevated levels of TGF-β suppress erythropoiesis leading to anemia. Second, the shift from HR to NHEJ allows for less precise DNA repair and the development of mutations which could result in AML formation.Using a TGF-β responsive AML line, we have shown that AVID200 prevents the growth inhibition induced by TGF-β1. Additionally, AVID200 reversed the hypersensitivity to MMC, implying an improvement in DNA damage repair. Currently, we are investigating the effectiveness of treating two MDS cell lines (MDS-92 and MDS-L) with AVID200 to determine its ability to not only prevent the growth inhibition associated with TGF-β1, but also to enhance DNA damage repair.The safety of AVID200 has been evaluated in several preclinical models. In a chick embryo model of metastasis, AVID200 did not promote the growth of metastatic foci, whereas a pan-neutralizing TGF-β inhibitor did. This result is important since a significant percentage of patients with MDS go on to develop AML and other cancers. The cardiac safety of AVID200 was evaluated in a single-dose pilot non-human primate study. No adverse cardiovascular events were observed at doses of up to 30 mg/kg, the highest dose tested.These results indicate that AVID200 is a promising new agent for the safe and effective treatment for MDS associated anemia.(MJT is a Mitacs Accelerate Program Postdoctoral Fellow) DisclosuresThwaites:Formation Biologics: Employment, Research Funding. Koropatnick:Formation Biologics, Inc.: Research Funding. Tremblay:Formation Biologics: Employment. O'Connor-McCourt:Formation Biologics: Employment.