AGCM-22, a novel cetuximab-based EGFR-targeting antibody-drug-conjugate with highly selective anti-glioblastoma efficacy.

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.

Study of the influence of macro-structure and micro-structure on the mechanical properties of stag beetle upper jaw.

Macrostructural control of stress distribution and microstructural influence on crack propagation is one of the strategies for obtaining high mechanical properties in stag beetle upper jaws. The maximum bending fracture force of the stag beetle upper jaw is approximately 154, 000 times the weight of the upper jaw. Here, we explore the macro and micro-structural characteristics of two stag beetle upper jaws and reveal the resulting differences in mechanical properties and enhancement mechanisms. At the macroscopic level, the elliptic and triangular cross-sections of the upper jaw of the two species of stag beetles have significant effects on the formation of cracks. The crack generated by the upper jaws with a triangular section grows slowly and deflects easily. At the microscopic level, the upper jaw of the two species is a chitin cross-layered structure, but the difference between the two adjacent fiber layers at 45° and 50° leads to different deflection paths of the cracks on the exoskeleton. The mechanical properties of the upper jaw of the two species of stag beetle were significantly different due to the interaction of macro-structure and micro-structure. In addition, a series of bionic samples with different cross-section geometries and different fiber cross angles were designed, and mechanical tests were carried out according to the macro-structure and micro-structure characteristics of the stag beetle upper jaw. The effects of cross-section geometry and fiber cross angle on the mechanical properties of bionic samples are compared and analyzed. This study provides new ideas for designing and optimizing highly loaded components in engineering. STATEMENT OF SIGNIFICANCE: The upper jaw of the stag beetle is composed of a complex arrangement of chitin and protein fibers, providing both rigidity and flexibility. This structure is designed to withstand various mechanical stresses, including impacts and bending forces, encountered during its burrowing activities and interactions with its environment. The study of the upper jaw of the stag beetle can provide an efficient structural design for engineering components that are subjected to high loads. Understanding the relationship between structure and mechanical properties in the stag beetle upper jaw holds significant implications for biomimetic design and engineering.