BMN 701-mediated receptor redistribution is responsible for increased uptake

Abstract

BMN 701 is a novel chimeric fusion protein of Insulin-like Growth Factor 2 (IGF-2) and acid alpha-glucosidase (GAA) that is now being tested in the clinic for the treatment of Pompe disease. BMN 701 was designed to improve delivery of GAA to the lysosome of muscle cells by fusing a high affinity ligand for the cation independent mannose-6phosphate receptor (CI-MPR) to GAA. In uptake experiments with rat L6 myoblasts, the Kuptake improvedmarkedly compared to untagged rhGAA, a predicted consequence of higher affinity binding to the CI-MPR. Additionally, the total amount of BMN 701 taken up by cells (system capacity) was doubled compared to rhGAA. This surprising observation could be explained by a phenomenon reported previously, namely that IGF-1 and IGF-2 can induce a signaling cascade resulting in redistribution of the CI-MPR so as to increase the quantity of the CI-MPR on the cell surface. We have investigated the ability of BMN 701 to do the same. In vitro, we find: i) BMN 701 can bind to the IGF-1 receptor; ii) BMN 701 can transduce a signaling cascade from the IGF-1 receptor; iii) the elevated system capacity of BMN701 is dependent on this signaling from the IGF-1 receptor; and iv) system capacity for uptake of untagged rhGAA can be increased by IGF-1. These results are consistent with the higher system capacity resulting from tag-dependent signaling. This novel attribute of BMN 701 may contribute to its enhanced ability to reverse glycogen storage in Pompe mice.