ESM™ Technology

The foundation of Macrophage Pharma’s approach is its proprietary Esterase Sensitive Motif (ESM™) technology. The technology involves the use of specifically designed amino acid ester motifs that are selectively hydrolysed intracellularly by human carboxylesterase-1 (hCE-1) to charged amino acid derivatives which accumulate only in monocytes and macrophages.

Intracellularly targeted drugs are coupled to a small library of amino acid esters through a variety of chemical linkers such that:

  • the resulting ester is readily hydrolysed by intracellular carboxylesterases but is stable in human plasma
  • the acid product retains the pharmacological activity of the parent drug
  • the acid product accumulates to high levels inside the cell

The schematic below based on our lead p38 programme outlines the principle of our technology.

These motifs can be incorporated into a range of agents and a series of drug types have been synthesised targeting enzymes such as histone deacetylase, p38 MAP kinase, Hsp90 and IKappaB-2 kinase. Qualitatively similar data, in terms of macrophage-targeting, are found irrespective of the parent molecule. In many cases, the amino acid ester derivative is significantly less effective (<100-fold) against the target enzyme than the acid derivative that accumulates intracellularly, making it feasible to inhibit the activity of the target enzyme only within hCE-1 expressing cells.

ESM Technology

These motifs can be incorporated into a range of agents and a series of drug types have been synthesised targeting enzymes such as histone deacetylase, p38 MAP kinase, PI3 kinase and IKappaB-2 kinase. Qualitatively similar data, in terms of macrophage-targeting, are found irrespective of the parent molecule. In many cases, the amino acid ester derivative is significantly less effective (<100-fold) against the target enzyme than the acid derivative that accumulates intracellularly, making it feasible to inhibit the activity of the target enzyme only within hCE-1 expressing cells.

Observed benefits of ESM™ technology are:

  • Increased potency through intracellular accumulation
  • Longer cell residence time
  • Improved tolerability compared to non-targeted analogues
  • Improved PK/PD relationships