Engineered Bivalent Ligands for Cardiac Protection and Regeneration

Applications

The invention describes methods and compositions for cardioprotection and regeneration using bivalent ligands from the epidermal growth factor (EGF) family. These methods have applications in anticancer therapeutics with dose-dependent cardiotoxic effects. Additionally, the invention serves to treat cardiotoxicity from compounds associated with alcohol and cocaine use.

Problem Addressed

Anticancer treatment cardiotoxicity limits the efficacy of cancer therapies. A common therapeutic of the anthracycline family is doxorubicin (DOX). Prior attempts to prevent DOX-induced cardiotoxicity include total dose limitation, liposomal delivery, and pharmacologic prevention; however, these tactics are confined by various factors. They can weaken the antitumor potency of treatment, are not easily controlled or thoroughly understood, and are not validated in randomized clinical trials. In another method, such as DOX-encapsulating, polymeric nanoparticles, difficulties in optimization of drug loading and tissue targeting for local delivery have arisen. Furthermore, monomeric ligands used to inhibit HER-initiated intracellular signaling pathways — including small molecule kinase inhibitors, ligand binding blocking antibodies, and sterically-oriented dimerization inhibiting antibodies — are not as cardioprotective as ligand dimers. The invention provides bivalent ligand compositions and controlled methods for reducing, preventing, and reversing cardiotoxicity effects while improving the efficacy of the therapeutic agents. It has also been found to treat heart dysfunction and reverse the effects of myocardial infarctions.

Technology

The technology is a set of ligand dimers, comprised of two ligands and a linker with a coiled coil domain. The dimer can bind with higher affinity to HER receptors, and subsequently cause selective homo- and hetero- dimerization, oligomerization, or aggregation of these receptors. The ligand dimers modulate interactions between these receptors, thus biasing or inhibiting downstream signaling transduction. For example, the neuregulin-1β (NRG1) homodimer has high affinity for the HER4/ErbB4 receptor and promotes HER4 homodimerization on cardiomyocytes. This leads to initiation of the PI3 kinase signaling cascade which plays a prominent role in cell survival, and, more specifically, in the cardiomyocyte response to toxic stimulus. This technology exhibits greater control with these selective abilities and provides a safer, more effective, and more cardioprotective addition to anticancer therapy treatment.

Advantages

  • Increases efficacy of anthracycline therapy
  • Mitigates future costs for cardiological damage
  • Reduces and prevents further cardiotoxicity, heart dysfunction
  • May be coupled with existing cardioprotective drugs