Extended stability of the trastuzumab biosimilar ABP 980 (KANJINTI™) in polyolefin bags and elastomeric devices

Study Objectives: To investigate the quality and in-use stability of the trastuzumab biosimilar ABP 980 (KANJINTI™) in both concentrated multi-dose bags and following dilution and extended storage in intravenous (IV) bags and elastomeric devices, to address the stability requirements of diff erent global pharmacy practices. Methods: The eff ect of extended refrigerated storage plus exposure to in-use temperature conditions on KANJINTI™ (trastuzumab) solutions was assessed using a range of stability-indicating analytical methods, including appearance, pH, SEC, nonreducing CGE, reducing-CGE, CZE, sub-visible particle counting and potency by a cell-based proliferation inhibition assay. Stability of reconstituted 21 mg/mL solution stored in multi-dose bags and diluted samples at 0.3 mg/mL, 0.8 mg/mL and 4 mg/ mL in 0.9% w/v NaCl solutions stored in IV bags and elastomeric devices was determined over diff erent storage durations. Forced degraded samples exposed to room temperature and natural daylight were used to demonstrate the stability-indicating abilities of the methods. Results: No signifi cant changes were observed in the appearance, pH, monomer concentration, purity, charge heterogeneity, sub-visible particle counts or bioactivity, regardless of initial concentration, container or storage duration. Discussion: There was no indication of signifi cant changes to the physicochemical stability or bioactivity of any of the solutions following extended storage when compared to the initial results acquired on the day of preparation. Conclusion: The data presented has demonstrated the physicochemical stability and bioactivity of a range of KANJINTI™ (trastuzumab) solutions when prepared using controlled and validated aseptic processes, stored protected from light for extended periods at 2°C–8°C and subjected to in-use temperatures. The stability demonstrated in multi-dose bags and elastomeric devices provides additional preparation options to address diff erent global pharmacy practices and requirements.

Using molecular dynamics simulation to study the polarization response of the liquid water interface to surface charge heterogeneity

The hydration shells of proteins mediate interactions, such as small molecule binding, that are vital to their biological function or in some cases their dysfunction. However, even when the structure of a protein is known, the properties of its hydration environment cannot be easily predicted due to the complex interplay between protein surface heterogeneity and the collective fluctuations of water's hydrogen bonding network. This manuscript presents a theoretical study of the influence of surface charge heterogeneity on the polarization response of the liquid water interface. We introduce a new computational method for analyzing simulation data that is capable of quantifying water's nonlinear polarization response and determining the effective surface charge distribution of hydrated surfaces over atomistic length scales. When applied to a protein, this method is capable of revealing new insight into the influence of conformational dynamics on hydration structure, as we highlight by illustrating how salt-bridge formation enhances the polarization of the local hydration shell. To illustrate the utility of this method, we present the results of molecular dynamics simulations of liquid water in contact with a heterogeneous model surface and the CheY protein.

Using molecular dynamics simulation to study the polarization response of the liquid water interface to surface charge heterogeneity

The hydration shells of proteins mediate interactions, such as small molecule binding, that are vital to their biological function or in some cases their dysfunction. However, even when the structure of a protein is known, the properties of its hydration environment cannot be easily predicted due to the complex interplay between protein surface heterogeneity and the collective fluctuations of water's hydrogen bonding network. This manuscript presents a theoretical study of the influence of surface charge heterogeneity on the polarization response of the liquid water interface. We introduce a new computational method for analyzing simulation data that is capable of quantifying water's nonlinear polarization response and determining the effective surface charge distribution of hydrated surfaces over atomistic length scales. When applied to a protein, this method is capable of revealing new insight into the influence of conformational dynamics on hydration structure, as we highlight by illustrating how salt-bridge formation enhances the polarization of the local hydration shell. To illustrate the utility of this method, we present the results of molecular dynamics simulations of liquid water in contact with a heterogeneous model surface and the CheY protein.

Physicochemical and functional characterization of trastuzumab-dkst, a trastuzumab biosimilar

Aims: Preclinical comparative similarity studies of trastuzumab-dkst, a Herceptin® biosimilar, are reported. Materials & methods: Primary sequence and higher-order structure and pharmacological mechanisms of action were compared using multiple techniques. Pharmacokinetics and repeat-dose toxicity were assessed in cynomolgus monkeys. Results: Primary structures were identical; secondary and tertiary structures were highly similar. Non-significant differences were observed for charge heterogeneity. Twelve of 13 glycan species were highly similar, with slightly higher total mannose levels in trastuzumab-dkst. FcγR and FcRn binding activity was highly similar. Each drug equally inhibited HER2+ cell proliferation, demonstrating equivalent relative potency in mediating HER2+ cell cytolysis by antibody-dependent cellular cytotoxicity. Pharmacokinetic and toxicological profiles in cynomolgus monkeys were similar. Conclusion: Trastuzumab-dkst, US-licensed trastuzumab and EU-approved trastuzumab demonstrate high structural and functional similarity.

Different Surface Charged Plastic Particles Have Different Cotransport Behaviors with Kaolinite Particles in Porous Media

<p>The wide utilization of plastic related products leads to the ubiquitous presence of plastic particles in natural environments. Plastic particles could interact with kaolinite (one type of typical clay particles abundant in environment) and form plastic-kaolinite heteroaggregates. The fate and transport of both plastic particles and kaolinite particles thus might be altered. The cotransport and deposition behaviors of micron-sized plastic particles (MPs) with different surface charge (both negative and positive surface charge) with kaolinite in porous media in both 5 and 25 mM NaCl solutions were investigated in present study. Both types of MPs (negatively charged carboxylate-modified MPs (CMPs) and positively charged amine-modified MPs (AMPs)) formed heteroaggregates with kaolinite particles under both solution conditions examined, however, CMPs and AMPs exhibited different cotransport behaviors with kaolinite. Specifically, the transport of both CMPs and kaolinite was increased under both ionic strength conditions when kaolinite and CMPs were copresent in suspensions. While, when kaolinite and positively charged AMPs were copresent in suspensions, negligible transport of both kaolinite and AMPs were observed under examined salt solution conditions. The competition deposition sites by kaolinite (the portion suspending in solution) with CMPs-kaolinite heteroaggregates led to the increased transport both CMPs and kaolinite when both types of colloids were copresent. In contrast, the formation of larger sized AMPs-kaolinite heteroaggregates with surface charge heterogeneity led to the negligible transport of both kaolinite and AMPs when they were copresent in suspensions. The results of this study show that when plastic particles and kaolinite particles are copresent in natural environments, their interaction with each other will affect their transport behaviors in porous media. The alteration in the transport of MPs or kaolinite (either increased or decreased transport) is highly correlated with the surface charge of MPs.</p>