Purpose: The characteristics of aberrant overexpression and distinct features of cancer-associated (CA)-MUC1 has been often considered as a promising target in most of the solid cancers. MUC1 is composed of α and β subunits to form a full length of MUC1, and α subunit is released and circulated into the blood in cancer, which is used as biomarkers such as CA 15-3 and CA 27-29. As those α subunit-targeting strategies were failed in the numerous clinical trials due to, at least in part, the diminished α subunit of MUC1 in cancer, we have developed a humanized Ab, PAb001 targeting the residual β subunit of MUC1, called as an onco-tethered (OT)-MUC1. To prove the concept of this strategy, an antibody-drug conjugate (ADC) and chimeric antigen receptor (CAR) T cells were applied to assess its efficacies. Methods: We produced a monoclonal antibody (mAb) against OT-MUC1 from mouse and sequentially generated its derivative humanized antibody, PAb001. Then, the target product profiles (TPP) were determined by SPR, ELISA, FACS, immunohistochemical analysis, pilot tissue cross-reactivity, and pharmacokinetics (PK) analysis. Then, to evaluate anti-cancer efficacies, we either conjugated PAb001 with Monomethyl auristatin E (MMAE) or generated the second-generation CAR T cells and then sequentially tested in vitro and in vivo cancer models. Results: Based on the TPP criteria, PAb001 antibody was chosen over a hundred of candidate antibodies tested. Next, it was conjugated with MMAE, treated and measured its cytotoxicity in ovarian and breast cancer cell lines, including triple-negative breast cancers (TNBC). As a result, PAb001-ADC selectively inhibited the growth of cancer cell lines, depending on the expression level of MUC1. Also, it showed 80-100 % tumor growth inhibition rates (TGI) in the cell lines- and patient-derived xenograft models. Lastly, OT-MUC1 Car-T cells showed significant and selective growth inhibition of cancer cells. Conclusion: Taken together, the preclinical studies of PAb001-ADC and Car-T indicate the high therapeutic potentials targeting OT-MUC1 in cancer, which further provided the rationale for clinical development. Citation Format: Jin G Jung, Min-Seok Kim, Hwa-Chul Jung, Hoil Choi, Kyung-Duk Moon. Old target, but new approach: Targeting cancer-associated MUC1 with ADC and Car-T [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6530.
The main objective of the study is to analyze the various cutting parameters to investigate the surface quality of the minor scale diameter of magnesium alloy in the dry turning process using a different tool nose radius (r). The surface roughness (Ra) was gauged, and micro-images produced by scanning electron microscopy (SEM) were reviewed to evaluate the machined surface topography. The analysis of variance (ANOVA), linear regression model and signal-to-noise (S/N) ratio were applied to investigate and optimize the experimental conditions for surface roughness. The study results imply that the feed rate and tool nose radius significantly affected the surface quality, but the spindle speed did not. The linear regression model is valid to forecast the surface roughness. The cutting parameters for optimum surface quality are a combination of a spindle speed of 710 rpm, a feed rate of 0.052 mm/rev and a tool nose radius of 1.2 mm. The machined surface topography contains the feed marks, micro-voids, material side and material debris, but they become smaller and decrease at a lower feed rate, larger tool nose radius and higher spindle speed. These results show the good surface quality of magnesium alloys in a dry turning process, which could be applied in implant, orthopedic and trauma surgery.
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