AGCM-22, a novel cetuximab-based EGFR-targeting antibody-drug-conjugate with highly selective anti-glioblastoma efficacy.
Bioorg Med Chem
; 102: 117657, 2024 Mar 15.
Article
in En
| MEDLINE
| ID: mdl-38428068
ABSTRACT
The epidermal growth factor receptor (EGFR) has received significant attention as a potential target for glioblastoma (GBM) therapeutics in the past two decades. However, although cetuximab, an antibody that specifically targets EGFR, exhibits a high affinity for EGFR, it has not yet been applied in the treatment of GBM. Antibody-drug conjugates (ADCs) utilize tumor-targeting antibodies for the selective delivery of cytotoxic drugs, resulting in improved efficacy compared to conventional chemotherapy drugs. However, the effectiveness of cetuximab as a targeted antibody for ADCs in the treatment of GBM remains uncertain. In this study, we synthesized AGCM-22, an EGFR-targeted ADC derived from cetuximab, by conjugating it with the tubulin inhibitor monomethyl auristatin E (MMAE) using our Valine-Alanine Cathepsin B cleavable linker. In vitro experiments demonstrated that AGCM-22 effectively inhibited GBM cell proliferation through increased levels of apoptosis and autophagy-related cell death, whereas cetuximab alone had no anti-GBM effects. Additionally, both mouse and human orthotopic tumor models exhibited the selective tumor-targeting efficacy of AGCM-22, along with favorable metabolic properties and superior anti-GBM activity compared to temozolomide (TMZ). In summary, this study presents a novel ADC for GBM therapy that utilizes cetuximab as the tumor-targeting antibody, resulting in effective delivery of the cytotoxic drug payload.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Glioblastoma
/
Immunoconjugates
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Antineoplastic Agents
Limits:
Animals
/
Humans
Language:
En
Year:
2024
Type:
Article