A TIM3-IgG4 fusion protein was constructed to act as a TIM-3 ligand Trap. The T-cell immunoglobulin mucin-3 (TIM-3) receptor, and its main ligand galectin-9 (Gal-9), regulate self-renewal of human leukemic stem cells (LSCs) through co-activation of both NF-ÎºB and Î²-catenin signaling. The protein was designed to scavenge TIM-3 ligands in order to extinguish leukemic stem cell renewal in MDS and AML. Surprisingly, the TIM-3-IgG4 fusion protein induced the formation of non-cancerous hematopoietic progenitor colonies from primary MDS patient specimens by about 20 fold. These colonies were macroscopic with multilineage potential, suggesting that the TIM-3-IgG4 fusion protein could restore normal erythropoiesis while suppressing the malignant clone, thereby offering a novel therapeutic strategy for transfusion-dependent patients with low- or int-1-risk MDS.
- Medicare billing estimates that >50,000 new cases of myelodysplastic syndromes (MDS) are diagnosed annually in the US population 65 years of age or older. MDS patients are generally categorized into lower-risk (IPSS low or intermediate-1; LR) that accounts for roughly two-thirds or new cases, and higher-risk (IPSS high or intermediate-2; HR) groups that are subject to different treatments. MDS has an attendant risk of progression to acute myeloid leukemia, which is greatest in HR-disease.
- Survival is longest in LR-MDS where the priority is amelioration of symptoms by the treatment of cytopenias to improve quality in life. Erythropoiesis stimulating agents such as Epo are the first choice for treatment of anemia, however, the response rate in unselected patients is low. Lenalidomide is the treatment of choice for del(5q) MDS, with the only remaining FDA-approved alternatives represented by the hypomethylating agents.
- The TIM3-IgG4 fusion protein selectively promotes normal erythroid colony formation from primary MDS specimens treated ex vivo, thereby offering a potential novel anemia treatment. This treatment could therefore be used to treat LR-MDS patients with symptomatic anemia or a population similar to that approved by lenalidomide (Revlimid; Celgene), i.e., transfusion-dependent anemia due to low/int-1-risk MDS with a deletion 5q abnormality. Del(5q) MDS accounts for roughly 15% of all MDS patients, with Revlimid having generated $400M in US