High Concentration Formulation Feasibility of Human Immunoglubulin G for Subcutaneous Administration

Dani, Bhas A.; Platz, Robert; Tzannis, Stelios T.

doi:10.1002/jps.20508

Cited by 83 publications

(61 citation statements)

References 46 publications

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“…This could be attributed to the relatively higher concentration of IgG in the precipitating solution. These results are consistent with the report previously published by Dani and coworkers (21). Due to the increased proximity due to increased concentration, partially unfolded IgG molecules would have increased tendency to aggregate.…”

Section: Discussionsupporting

confidence: 94%

“…Figure 10 reveals that the far-UV CD spectrum of the unprocessed IgG was characterized by a negative maximum at a wavelength of 218 nm and a positive maximum at 202 nm. These are characteristics typical for IgG because of their high β-sheet content (20)(21)(22)(23). All the precipitated particles retained a β-sheet structure similar to the unprocessed IgG as seen in Fig.…”

Section: Far-uv Circular Dichroism Spectroscopymentioning

confidence: 61%

“…It is also expected that these particles would go into dissolution at an acidic pH due to its isoelectric point (pI). It is well established that major perturbations in the conformational structure of a protein often lead to a reduction or even a loss of the biological activity of the protein (5,21,30,31). Further, soluble aggregates in protein formulations are undesirable (15,16).…”

Section: Discussionmentioning

confidence: 99%

“…This procedure was adapted from a previously described method by Dani et al (21). Figures 6,7, and 8 show the percentage specific binding activity retained by the IgG in the particles as fraction of the unprocessed IgG.…”

Section: Igg Specific Binding Activitymentioning

confidence: 99%

See 3 more Smart Citations

Self-Associated Submicron IgG1 Particles for Pulmonary Delivery: Effects of Non-ionic Surfactants on Size, Shape, Stability, and Aerosol Performance

Srinivasan

Shoyele

2012

AAPS PharmSciTech

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Abstract. The ability to produce submicron particles of monoclonal antibodies of different sizes and shapes would enhance their application to pulmonary delivery. Although non-ionic surfactants are widely used as stabilizers in protein formulations, we hypothesized that non-ionic surfactants will affect the shape and size of submicron IgG particles manufactured through precipitation. Submicron particles of IgG1 were produced by a precipitation process which explores the fact that proteins have minimum solubility but maximum precipitation at the isoelectric point. Non-ionic surfactants were used for size and shape control, and as stabilizing agents. Aerosol performance of the antibody nanoparticles was assessed using Andersen Cascade Impactor. Spinhaler® and Handihaler® were used as model DPI devices. SEM micrographs revealed that the shape of the submicron particles was altered by varying the type of surfactant added to the precipitating medium. Particle size as measured by dynamic light scattering was also varied based on the type and concentration of the surfactant. The surfactants were able to stabilize the IgG during the precipitation process. Polyhedral, sponge-like, and spherical nanoparticles demonstrated improved aerosolization properties compared to irregularly shaped (>20 μm) unprocessed particles. Stable antibody submicron particles of different shapes and sizes were prepared. Careful control of the shape of such particles is critical to ensuring optimized lung delivery by dry powder inhalation.

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Section: Discussionsupporting

confidence: 94%

Section: Far-uv Circular Dichroism Spectroscopymentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Igg Specific Binding Activitymentioning

confidence: 99%

See 2 more Smart Citations

Self-Associated Submicron IgG1 Particles for Pulmonary Delivery: Effects of Non-ionic Surfactants on Size, Shape, Stability, and Aerosol Performance

Srinivasan

Shoyele

2012

AAPS PharmSciTech

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“…In addition, for subcutaneous applications (due to the constraints of low dosage volume), it should be capable of being formulated at very high concentrations under conditions that maintain low viscosity, and homogeneity. [13][14][15] Thus, solubility and stability are 2 important biophysical properties for the success of any antibody development program. In the past, however, most discovery programs have been focused on finding high affinity antibodies against targets of interest, and little attention was paid early on to other developability attributes.…”

Section: Introductionmentioning

confidence: 99%

A novel screening method to assess developability of antibody-like molecules

Kohli

Jain²,

Geddie³

et al. 2015

mAbs

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Monoclonal antibodies and antibody-like molecules represent a fast-growing class of bio-therapeutics that has rapidly transformed patient care in a variety of disease indications. The discovery of antibodies that bind to particular targets with high affinity is now a routine exercise and a variety of in vitro and in vivo techniques are available for this purpose. However, it is still challenging to identify antibodies that, in addition to having the desired biological effect, also express well, remain soluble at different pH levels, remain stable at high concentrations, can withstand high shear stress, and have minimal non-specific interactions. Many promising antibody programs have ultimately failed in development due to the problems associated with one of these factors. Here, we present a simple high-performance liquid chromatography (HPLC)-based screening method to assess these developability factors earlier in discovery process. This method is robust and requires only microgram quantities of proteins. Briefly, we show that for antibodies injected on a commercially available pre-packed Zenix HPLC column, the retention times are inversely related to their colloidal stability with antibodies prone to precipitation or aggregation retained longer on the column with broader peaks. By simply varying the salt content of running buffer, we were also able to estimate the nature of interactions between the antibodies and the column. We believe this approach should generally be applicable to assessment of the developability of other classes of bio-therapeutic molecules, and that the addition of this simple tool early in the discovery process will lead to selection of molecules with improved developability characteristics.

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LC/MSversus Immune‐Based Bioanalytical Methods in Quantitation of Therapeutic Biologics in Biological Matrices

Zhang

2015

Pharmaceutical Sciences Encyclopedia

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This chapter reviews the main characteristics of liquid chromatography/mass spectrometry (LC/MS) and ligand‐binding assay (LBA) methods. If an LBA method for biotherapeutics quantification is well established, it usually provides sufficient sensitivity and selectivity and is considered the method of choice. The LC/MS method emerged as an alternative strategy for quantification of proteins of interest in complex biological matrices. Multiplexed capacity and selectivity are critical features determining the applicability of a bioanalytical method. Well‐established LBA methods usually provide adequate sensitivity for quantification analysis of biotherapeutics in preclinical/clinical pharmacokinetic (PK)/pharmacodynamic (PD) study. LC/MS with high resolution analyzer has become a promising technology for characterization of antibody‐drug conjugate (ADC) in the recent years. An affinity capture capillary LC coupled to quadrupole‐time‐of‐flight (TOF) MS has been employed to analyze anti‐MUC16 TDC, which obtained both in vitro and in vivo drug‐to‐antibody ratios (DARs) information.

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High Concentration Formulation Feasibility of Human Immunoglubulin G for Subcutaneous Administration

Cited by 83 publications

References 46 publications

Self-Associated Submicron IgG1 Particles for Pulmonary Delivery: Effects of Non-ionic Surfactants on Size, Shape, Stability, and Aerosol Performance

Self-Associated Submicron IgG1 Particles for Pulmonary Delivery: Effects of Non-ionic Surfactants on Size, Shape, Stability, and Aerosol Performance

A novel screening method to assess developability of antibody-like molecules

LC/MSversus Immune‐Based Bioanalytical Methods in Quantitation of Therapeutic Biologics in Biological Matrices

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