Anti-Tubulin Monoclonal Antibody

A nonlinear molecular structural mechanics (MSM) model is proposed in this paper for studying the tensile properties of microtubules (MTs). In the nonlinear MSM models, the interactions between tubulin monomers in MTs are treated as nonlinear axial and torsional springs, whose stiffness coefficients are extracted from all-atom molecular dynamics simulations. The Young's modulus and fracture properties of MTs under tension extracted from the present nonlinear MSM models are found to agree well with the existing simulation and experiment results, which shows the efficiency and accuracy of the proposed nonlinear MSM models. In addition, the nonlinear MSM models are also extended to investigate the tensile properties including Young's modulus and fracture strain of MTs possessing lattice defects. The results obtained from nonlinear MSM models are utilized to develop a predictive equation for quickly predicting the tensile properties of MTs with different lattice defect levels. (C) 2020 Elsevier B.V. All rights reserved.

Background Osteosarcoma (OS), the most common bone tumor in children and adolescents, has high rates of metastasis leading to poor survival. Leucine-rich repeat containing 15 (LRRC15), a transmembrane protein whose expression is modulated by TGF beta, was recently shown to be highly expressed on the surface of OS tumor cells. Here, we evaluate a novel antibody-drug conjugate (ADC) targeting LRRC15 in OS human cell lines and murine xenografts. We compare this new ADC, which is conjugated to the anthracycline derivative PNU-159682 (PNU), to a previously studied LRRC15 ADC that is conjugated to the tubulin inhibitor monomethyl auristatin E (MMAE), since anthracyclines are standard of care in OS. Procedure We evaluated LRRC15 expression in OS cells using Western blots and flow cytometry, and analyzed the epigenetic landscape of the LRRC15 locus using chromatin immunoprecipitation. Efficacy of ADCs on cell growth was analyzed by IncuCyte live cell imaging. Intramuscular xenograft tumor growth was assessed by bioluminescence imaging and hematoxylin and eosin staining. Results LRRC15-PNU is more effective at inhibiting growthin vitroandin vivothan an isotype antibody control or the LRRC15-MMAE ADC in two high LRRC15 expressing OS cell lines. Low expressing cell lines are not sensitive to either ADC. Importantly, cells with low LRRC15 expression are amenable to re-expression after TGF beta treatment, suggesting a potential to sensitize insensitive OS cells to LRRC15 ADC treatment.In vivo, LRRC15-PNU had cure rates of 40-100% in OS xenograft models. Conclusions Overall, LRRC15-directed ADCs are a promising new avenue for OS treatment.