1.
Recent Advances in Studying Interfacial Adsorption of Bioengineered Monoclonal Antibodies.
Hollowell, P, Li, Z, Hu, X, Ruane, S, Kalonia, C, van der Walle, CF, Lu, JR
Molecules (Basel, Switzerland). 2020;(9)
Abstract
Monoclonal antibodies (mAbs) are an important class of biotherapeutics; as of 2020, dozens are commercialized medicines, over a hundred are in clinical trials, and many more are in preclinical developmental stages. Therapeutic mAbs are sequence modified from the wild type IgG isoforms to varying extents and can have different intrinsic structural stability. For chronic treatments in particular, high concentration (≥ 100 mg/mL) aqueous formulations are often preferred for at-home administration with a syringe-based device. MAbs, like any globular protein, are amphiphilic and readily adsorb to interfaces, potentially causing structural deformation and even unfolding. Desorption of structurally perturbed mAbs is often hypothesized to promote aggregation, potentially leading to the formation of subvisible particles and visible precipitates. Since mAbs are exposed to numerous interfaces during biomanufacturing, storage and administration, many studies have examined mAb adsorption to different interfaces under various mitigation strategies. This review examines recent published literature focusing on adsorption of bioengineered mAbs under well-defined solution and surface conditions. The focus of this review is on understanding adsorption features driven by distinct antibody domains and on recent advances in establishing model interfaces suitable for high resolution surface measurements. Our summary highlights the need to further understand the relationship between mAb interfacial adsorption and desorption, solution aggregation, and product instability during fill-finish, transport, storage and administration.
2.
Interfacial Adsorption of a Monoclonal Antibody and Its Fab and Fc Fragments at the Oil/Water Interface.
Ruane, S, Li, Z, Campana, M, Hu, X, Gong, H, Webster, JRP, Uddin, F, Kalonia, C, Bishop, SM, van der Walle, CF, et al
Langmuir : the ACS journal of surfaces and colloids. 2019;(42):13543-13552
Abstract
The physical stability of a monoclonal antibody (mAb) solution for injection in a prefilled syringe may in part depend on its behavior at the silicone oil/water interface. Here, the adsorption of a mAb (termed COE-3) and its fragment antigen-binding (Fab) and crystallizable (Fc) at the oil/water interface was measured using neutron reflection. A 1.4 ± 0.1 μm hexadecane oil film was formed on a sapphire block by a spin-freeze-thaw process, retaining its integrity upon contact with the protein solutions. Measurements revealed that adsorbed COE-3 and its Fab and Fc fragments retained their globular structure, forming layers that did not penetrate substantially into the oil phase. COE-3 and Fc were found to adsorb flat-on to the interface, with denser 45 and 42 Å inner layers, respectively, in contact with the oil and a more diffuse 17-21 Å outer layer caused by fragments adsorbing in a tilted manner. In contrast, Fab fragments formed a uniform 60 Å monolayer. Monolayers were formed under all conditions studied (10-200 ppm, using three isotopic contrasts), although changes in packing density across the COE-3 and Fc layers were observed. COE-3 had a higher affinity to the interface than either of its constituent fragments, while Fab had a lower interfacial affinity consistent with its higher net surface charge. This study extends the application of high-resolution neutron reflection measurements to the study of protein adsorption at the oil/water interface using an experimental setup mimicking the protein drug product in a siliconized prefilled syringe.
3.
[Clinical value of iodine [131I] metuximab infusion combined with TACE for treatment of patients with post-intervention relapse of mid or advanced stage hepatocellular carcinoma].
Li, Z, Zhou, JX, Ren, JZ, Zhang, WJ, Han, XW
Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology. 2013;(10):728-33
Abstract
OBJECTIVE To evaluate the clinical value of iodine[131I] metuximab infusion combined with transcatheter arterial chemoembolization (TACE) for treating cases of post-intervention relapse of mid or advanced stage hepatocellular carcinoma (HCC). METHODS Sixty patients who were diagnosed between March 2009 and June 2010 with relapse of mid or advanced stage HCC following previous intervention with various standard clinical methods were recruited for study. The patients were randomly and equally divided into a control treatment group (CG; receiving TACE therapy alone) and an experimental treatment group (TG; receiving TACE combined with iodine [131I] metuximab injection). For all patients, licartin was first perfused into the tumor feeding artery and then the TACE procedure was performed 20 min later. Liver function markers and routine blood parameters, including alpha-fetoprotein (AFP) and clotting time, were examined at one week and one month after the treatment. Enhanced computed tomography or magnetic resonance imaging of the liver was performed at one month after treatment and thereafter on a bi-monthly follow-up schedule. The World Health Organization's tumor evaluation standard was used to assess the therapeutic effects in each group. Results of laboratory tests (pre- and post-treatment), reported complications, and side-effects were evaluated for their contributions to time of tumor progression (TTP) and survival time. RESULTS Patients in the TG and CG groups had similar blood cell counts at pre-operative and 1-week postoperative time points. The TG group showed a significantly reduced level of AFP following treatment, but it was not significantly different from the level in the CG group. The TG group did however show significantly different levels of liver functional parameters (all P less than 0.05) and significantly higher TTP (4.84+/-4.11 vs. CG: 2.54+/-2.08 months; t = -2.13, P less than 0.05) and average survival time (7.05 vs. 5.15 months; x2 = 4.24, P = 0.039). The rates of partial response (PR), slight remission (MR), unchanged status (SD) and progressive disease (PD) were 16.7%, 37.5%, 25.0% and 20.8% in the TG group, and 8.7%, 17.4%, 21.7% and 52.2% in the CG group. The therapeutic effect rate (CR + PR + MR) and reaction rate (CR + PR + MR + SD) was significantly different between the two groups (P = 0.048). No serious adverse effects were reported. CONCLUSION TACE combined with iodine [131I] metuximab injection is a safe and effective procedure for prolonging the survival and TTP of patients with HCC relapse following prior therapeutic intervention.