Orally active peptide-drug conjugate targeting CD206+ macrophages for crohn's disease treatment

Overview

Dextrimu is a peptide-drug conjugate designed to selectively target and modulate CD206+ intestinal macrophages, which play a key role in the inflammatory profile of Crohn's disease. The platform builds on TrimUNO, a proprietary targeting peptide containing the CD206-binding motif CSPGAK combined with a trypsin/pepsin inhibiting moiety that enhances proteolytic stability. By conjugating TrimUNO to dexamethasone, Dextrimu delivers an established anti-inflammatory steroid directly to disease-associated macrophages. The conjugate is intended for oral administration, offering deeper tissue penetration than therapeutic antibodies such as anti-TNF agents and the potential for improved patient compliance compared to injectable biologics.

Technical specifications

Core targeting mechanism:

• TrimUNO binds recombinant CD206 with a KD of approximately 0.4 µM
• The peptide incorporates a protease-inhibiting moiety to resist degradation in the gastrointestinal tract
• Fluorescein-labeled TrimUNO has been shown to localize precisely to CD206+ macrophages in tumor-bearing mice following intravenous, intraperitoneal, or oral administration, with minimal off-target accumulation

Drug conjugation:

• Dexamethasone-hemisuccinate is conjugated to the N-terminus of TrimUNO, preserving targeting efficacy
• The conjugate is engineered to remain water-soluble, addressing a key limitation of hydrophobic steroid payloads
• The design follows validated strategies from prior antibody-drug conjugate work targeting macrophage markers

Functional effects demonstrated in tumor models:

• A related conjugate (VetrimUNO, coupling TrimUNO to Verteporfin) upregulated MHCII expression, stimulated inflammatory cytokine production, and increased cytosolic YAP in vitro
• In the 4T1.2 tumor model, VetrimUNO slowed primary tumor growth, suppressed pulmonary metastases, increased the MHCII+ macrophage population by 20%, and doubled the proportion of tumor-infiltrating T cells

Technology readiness level

The underlying TrimUNO targeting peptide has been validated in tumor-bearing mice, demonstrating binding to recombinant CD206, homing to CD206+ macrophages via multiple administration routes, and functional activity when coupled to a drug payload. The Dextrimu conjugate is at an earlier stage of development. Planned validation includes confirming oral homing of FAM-TrimUNO to CD206+ macrophages in Crohn's disease models and benchmarking against Infliximab, synthesizing the dexamethasone conjugate, evaluating in vitro effects on primary human and mouse macrophages, and assessing therapeutic efficacy and toxicity in chemically induced mouse colitis models. The underlying peptide platform has been patented and previously licensed.