Nonclinical Efficacy and Safety of CX-2029, an Anti-CD71 Probody-Drug Conjugate.

Probody therapeutics (Pb-Txs) are conditionally activated antibody-drug conjugates (ADCs) designed to remain inactive until proteolytically activated in the tumor microenvironment, enabling safer targeting of antigens expressed in both tumor and normal tissue. Previous attempts to target CD71, a highly expressed tumor antigen, have failed to establish an acceptable therapeutic window due to widespread normal tissue expression. This study evaluated whether a probody-drug conjugate targeting CD71 can demonstrate a favorable efficacy and tolerability profile in preclinical studies for the treatment of cancer. CX-2029, a Pb-Tx conjugated to maleimido-caproyl-valine-citrulline-p-aminobenzyloxycarbonyl-monomethyl auristatin E, was developed as a novel cancer therapeutic targeting CD71. Preclinical studies were performed to evaluate the efficacy and safety of this anti-CD71 PDC in patient-derived xenograft (PDX) mouse models and cynomolgus monkeys, respectively. CD71 expression was detected at high levels by IHC across a broad range of tumor and normal tissues. In vitro, the masked Pb-Tx form of the anti-CD71 PDC displayed a >50-fold reduced affinity for binding to CD71 on cells compared with protease-activated, unmasked anti-CD71 PDC. Potent in vivo tumor growth inhibition (stasis or regression) was observed in >80% of PDX models (28/34) at 3 or 6 mg/kg. Anti-CD71 PDC remained mostly masked (>80%) in circulation throughout dosing in cynomolgus monkeys at 2, 6, and 12 mg/kg and displayed a 10-fold improvement in tolerability compared with an anti-CD71 ADC, which was lethal. Preclinically, anti-CD71 PDC exhibits a highly efficacious and acceptable safety profile that demonstrates the utility of the Pb-Tx platform to target CD71, an otherwise undruggable target. These data support further clinical development of the anti-CD71 PDC CX-2029 as a novel cancer therapeutic.

Comparison of the Effect for Fracture Resistance of Different Coronally Extended Post Length with Two Different Post Materials.

AIMS AND OBJECTIVES: To compare the effect for fracture resistance of different coronally extended post length with two different post materials. MATERIALS AND METHODS: One hundred and sixty endodontically treated maxillary central incisors embedded in acrylic resin with decoronated root portion were taken for the study. The postspaces were prepared according to standard protocol. The samples were divided into two groups according to the post material: glass-fiber post and Quartz fiber post. These groups were further subdivided on the basis of coronal extension of 4 and 6 mm for glass fiber and Quartz fiber posts, respectively. The posts were then luted with dual-polymerizing resin cement followed by core buildup. Samples were subjected to increasing compressive oblique load until fracture occurred in a universal testing machine. Data were analyzed with one-way ANOVA and independent Student's t-test. Analysis was done using SPSS version 15 (SPSS Inc., Chicago, IL, USA) Windows software program. RESULTS: Glass fiber post with coronal extension of 4 mm (182.8 N) showed better results than with 6-mm length (124.1 N). Similarly, in quartz fiber posts group, 4-mm postlength (314 N) was better when compared with 6 mm (160 N). The 4-mm coronal extension of quartz fiber post displayed superior fracture resistance. CONCLUSIONS: Glass fiber posts showed better fracture resistance than Quartz fiber posts. 4-mm coronal length showed more fracture resistance than 6 mm.

Assessment of Inhibition of Mineral Loss from Human Tooth Enamel by Carbon Dioxide Laser and 1.23% Acidulated Phosphate Fluoride.

AIMS AND OBJECTIVES: The efficacy of carbon dioxide (CO2) laser irradiation combined with fluoride in inhibiting enamel demineralization has been demonstrated by several laboratory investigations. However, there are very few reports about the in situ or in vivo caries preventive effect of CO2 laser combined with topical fluoride on dental enamel. Hence, an in situ study was designed and carried out to assess inhibition of mineral loss from human tooth enamel by CO2 laser and 1.23% acidulated phosphate fluoride (APF). MATERIAL AND METHODS: Impressions of upper and lower arch of the volunteers were made in alginate impression material. Study models were poured, duplicated, and duly labeled. On the working model, appliances were fabricated in acrylic resin to fit the upper dental arch of the volunteers. Four enamel slabs (one from each group) were fitted on the palatal surface of the appliance as close as possible to posterior teeth. Surfaces of slabs were kept below the outer surface of acrylic. The analysis was done using SPSS version 15 (SPSS Inc., Chicago, IL, USA) Windows software program. RESULTS: Statistically significant increase in inhibition of mineral loss of enamel slabs when treated individually or in a combination of low power CO2 laser and 1.23% APF solution. The application of 1.23% APF solution after low power CO2 laser treatment showed maximum inhibition of mineral loss. CONCLUSION: The combined use of this specific laser treatment plus fluoride was more successful than either laser treatment or fluoride alone in the inhibition of mineral loss in the mouth. The results of this study also suggest that the combination of low power laser treatment with fluoride therapy may be effective as a caries inhibition treatment.

Quantification of particle-conjugated or particle-encapsulated peptides on interfering reagent backgrounds.

Particle-based technologies are increasingly being used in diagnostics and therapeutics. The particles employed in these applications are usually composed of polymers such as poly(lactide-co-glycolide) (PLG) and functionalized with peptides or proteins. Peptide or protein conjugation to particles is frequently achieved using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), while dimethyl sulfoxide (DMSO) is used to retrieve surface-attached or encapsulated peptides or proteins by solubilizing the particles. We examined strategies based on bicinchoninic acid (BSA), Coomassie Plus, and 3-(4-carboxybenzoyl)quinoline-2-carboxaldehyde (CBQCA) assays for the quantification of surface-attached or encapsulated peptides or proteins. We determined that the CBQCA assay is a highly sensitive and accurate substitute for radioactivity-based assays that is suitable for measuring multiple particle-bound or particle-encapsulated peptides or proteins in the presence of EDC or PLG in DMSO, compounds that interfere with the more commonly used BSA and Coomassie Plus assays. Our strategy enables the accurate quantification of peptides or proteins loaded onto or into particles-an essential component of particle-based platform design for diagnostics and therapeutics.