# In Vitro and In Vivo Characterization of 40 kDa PEGylated Adrenomedullin in a DSS-Induced Colitis Model

## TL;DR

A new long-acting version of adrenomedullin shows promise in treating inflammatory bowel disease by reducing inflammation in mice.

## Contribution

The development and characterization of 40 kDa PEGylated adrenomedullin as a novel therapeutic for inflammatory bowel disease.

## Key findings

- PEG-AM showed greater plasma stability and similar cAMP stimulation compared to native AM.
- A single low dose of PEG-AM demonstrated therapeutic and preventive effects in a DSS-induced colitis model.
- AM receptor expression remained unchanged despite high plasma concentrations of PEG-AM.

## Abstract

Adrenomedullin (AM), a biologically active peptide, induces complete remission with mucosal healing in patients with refractory ulcerative colitis. We have developed 40 kDa PEGylated AM (PEG-AM), a long-acting AM derivative, as a potential therapeutic agent for inflammatory bowel disease (IBD). Both PEG-AM and native AM stimulated cyclic adenosine monophosphate (cAMP) production in HEK-293 cells stably expressing the AM1 receptor (CLR/RAMP2 complex), in a dose-dependent manner. The pEC50 values for PEG-AM and AM were 7.23 ± 0.05 and 8.42 ± 0.10, respectively. PEG-AM exhibited significantly greater stability in plasma and serum than native AM. We evaluated the in vivo anti-colitis effects of intravenously administered PEG-AM in a dextran sodium sulfate (DSS)-induced murine colitis model. A single intravenous dose of PEG-AM, as low as 25 nmol/kg, demonstrated therapeutic efficacy. Notably, AM receptor expression was not downregulated, despite sustained high plasma concentrations of PEG-AM. Additionally, PEG-AM exerted both therapeutic and preventive effects in a DSS colitis model. These findings suggest that PEG-AM is a promising therapeutic candidate for the treatment of patients with IBD.