2. Academic Validation
  3. Peptide-Drug Conjugate for Therapeutic Reprogramming of Tumor-Associated Macrophages in Breast Cancer

Peptide-Drug Conjugate for Therapeutic Reprogramming of Tumor-Associated Macrophages in Breast Cancer

  • Adv Sci (Weinh). 2025 Mar;12(10):e2410288. doi: 10.1002/advs.202410288.
Anni Lepland 1,  Elisa Peranzoni 2,  Uku Haljasorg 3,  Eliana K Asciutto 4,  Maria Crespí-Amer 5,  Lorenzo Modesti 2,  Kalle Kilk 6,  Manuel Lombardia 7,  Gerardo Acosta 5 8,  Miriam Royo 5 8,  Pärt Peterson 3,  Ilaria Marigo 2 9,  Tambet Teesalu 1,  Pablo Scodeller 1 5
Affiliations

Affiliations

  • 1 Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14B, Tartu, 50411, Estonia.
  • 2 Immunology and Molecular Oncology Diagnostics, Veneto Institute of Oncology IOV - IRCCS, Padua, 35128, Italy.
  • 3 Molecular Pathology Research Group, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, 50411, Estonia.
  • 4 Instituto de Ciencias Físicas, Universidad Nacional de San Martin (UNSAM) and CONICET, Campus Migueletes, 25 de Mayo y Francia, Buenos Aires, CP 1650, Argentina.
  • 5 Institute for Advanced Chemistry of Catalonia, IQAC-CSIC, Jordi Girona 18-26, Barcelona, 08034, Spain.
  • 6 Department of biochemistry, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, Tartu, 50411, Estonia.
  • 7 Proteomics core facility, Centro Nacional de Biotecnologia, CNB-CSIC, Calle Darwin 3, Madrid, 28049, Spain.
  • 8 CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, IQAC-CSIC, Barcelona, 08034, Spain.
  • 9 Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padova, Padova, 35128, Italy.
PMID: 39840532 DOI: 10.1002/advs.202410288
Abstract

In triple-negative breast Cancer (TNBC), pro-tumoral macrophages promote metastasis and suppress the immune response. To target these cells, a previously identified CD206 (Mannose Receptor)-binding peptide, mUNO was engineered to enhance its affinity and proteolytic stability. The new rationally designed peptide, MACTIDE, includes a trypsin inhibitor loop, from the Sunflower Trypsin Inhibitor-I. Binding studies to recombinant CD206 revealed a 15-fold lower KD for MACTIDE compared to parental mUNO. Mass spectrometry further demonstrated a 5-fold increase in MACTIDE's half-life in tumor lysates compared to mUNO. Homing studies in TNBC-bearing mice shows that fluorescein (FAM)-MACTIDE precisely targeted CD206+ tumor-associated macrophages (TAM) upon intravenous, intraperitoneal, and even oral administration, with minimal liver accumulation. MACTIDE was conjugated to Verteporfin, an FDA-approved Photosensitizer and YAP/TAZ pathway inhibitor to create the conjugate MACTIDE-V. In the orthotopic 4T1 TNBC mouse model, non-irradiated MACTIDE-V-treated mice exhibited anti-tumoral effects comparable to those treated with irradiated MACTIDE-V, with fewer signs of toxicity, prompting further investigation into the laser-independent activity of the conjugate. In vitro studies using bone marrow-derived mouse macrophages showed that MACTIDE-V excluded YAP from the nucleus, increased phagocytic activity, and upregulated several genes associated with cytotoxic anti-tumoral macrophages. In mouse models of TNBC, MACTIDE-V slowed primary tumor growth, suppressed lung metastases, and increased markers of phagocytosis and antigen presentation in TAM and monocytes, increasing the tumor infiltration of several lymphocyte subsets. MACTIDE-V is proposed as a promising peptide-drug conjugate for modulating macrophage function in breast Cancer Immunotherapy.

Keywords

CD206; peptide‐drug conjugate; targeting peptides; triple negative breast cancer; tumor‐associated macrophages.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z