A Mechanistic Understanding of Monoclonal Antibody Interfacial Protection by Hydrolytically Degraded Polysorbate 20 and 80 under IV Bag Conditions

Kannan, Aadithya; Giddings, Jamie; Mehta, Shrenik; Lin, Tiffany; Tomlinson, A. A. G.; Ritchie, Kyle; Shieh, Ian C.; Saggu, Miguel; Doshi, Nidhi

doi:10.1007/s11095-022-03217-x

Cited by 11 publications

(3 citation statements)

References 55 publications

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“…However, structurally different surfactants are foreseen to exhibit intrinsically different surface activity, which makes the comparison between surfactants a difficult task when solely employing this technique. Moreover, a strong correlation between ST and protein stabilization potential is still being debated in the field . For the above reasons, we coupled ST characterization to a subsequent agitation-induced aggregation assay to set up the screening gate 2.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Not the Usual Suspects: Alternative Surfactants for Biopharmaceuticals

Brosig,

Cucuzza,

Serno

et al. 2023

ACS Appl. Mater. Interfaces

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Therapeutically relevant proteins naturally adsorb to interfaces, causing aggregation which in turn potentially leads to numerous adverse consequences such as loss of activity or unwanted immunogenic reactions. Surfactants are ubiquitously used in biotherapeutics drug development to oppose interfacial stress, yet, the choice of the surfactant is extremely limited: to date, only polysorbates (PS20/80) and poloxamer 188 are used in commercial products. However, both surfactant families suffer from severe degradation and impurities of the raw material, which frequently increases the risk of particle generation, chemical protein degradation, and potential adverse immune reactions. Herein, we assessed a total of 40 suitable alternative surfactant candidates and subsequently performed a selection through a three-gate screening process employing four protein modalities encompassing six different formulations. The screening is based on short-term agitation-induced aggregation studies coupled to particle analysis and surface tension characterization, followed by long-term quiescence stability studies connected to protein purity measurements and particle analysis. The study concludes by assessing the surfactant’s chemical and enzymatic degradation propensity. The candidates emerging from the screening are de novo α-tocopherol-derivatives named VEDG-2.2 and VEDS, produced ad hoc for this study. They display protein stabilization potential comparable or better than polysorbates together with an increased resistance to chemical and enzymatic degradation, thus representing valuable alternative surfactants for biotherapeutics.

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Section: Resultsmentioning

confidence: 99%

“…Moreover, a strong correlation between ST and protein stabilization potential is still being debated in the field. 50 For the above reasons, we coupled ST characterization to a subsequent agitation-induced aggregation assay to set up the screening gate 2.…”

Section: Screening Gate 1: Biophysical Matrixmentioning

confidence: 99%

Not the Usual Suspects: Alternative Surfactants for Biopharmaceuticals

Brosig,

Cucuzza,

Serno

et al. 2023

ACS Appl. Mater. Interfaces

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show abstract

“…During the measurement process, the data was collected for an average of four/5 seconds, and the laser power auto-attenuated after each acquisition was beginning. The distribution fit of the preset general-purpose analysis model was used to conduct size analysis (Kannan et al., 2022 ).…”

Section: Methodsmentioning

confidence: 99%

Guanidine-modified albumin-MMAE conjugates with enhanced endocytosis ability

Xie²,

Xu³

et al. 2023

Drug Delivery

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Aiming to address the insufficient endocytosis ability of traditional albumin drug conjugates, this paper reports elegant guanidine modification to improve efficacy for the first time. A series of modified albumin drug conjugates were designed and synthesized with different structures, including guanidine (GA), biguanides (BGA) and phenyl (BA), and different quantities of modifications. Then, the endocytosis ability and in vitro / vivo potency of albumin drug conjugates were systematically studied. Finally, a preferred conjugate A4 was screened, which contained 15 BGA modifications. Conjugate A4 maintains spatial stability similar to that of the unmodified conjugate AVM and could significantly enhance endocytosis ability ( p *** = 0.0009) compared with the unmodified conjugate AVM. Additionally, the in vitro potency of conjugate A4 (EC 50 = 71.78 nmol in SKOV3 cells) was greatly enhanced (approximately 4 times) compared with that of the unmodified conjugate AVM (EC 50 = 286.00 nmol in SKOV3 cells). The in vivo efficacy of conjugate A4 completely eliminated 50% of tumors at 33 mg/kg, which was significantly better than the efficacy of conjugate AVM at the same dose ( P ** = 0.0026). In addition, theranostic albumin drug conjugate A8 was designed to intuitively realize drug release and maintain antitumor activity similar to conjugate A4. In summary, the guanidine modification strategy could provide new ideas for the development of new generational albumin drug conjugates.

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A thermodynamic investigation into protein–excipient interactions involving different grades of polysorbate 20 and 80

Whiteley,

Waters,

Humphrey

et al. 2024

J Therm Anal Calorim

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Developing stable biopharmaceutical formulations is of paramount importance and is typically achieved by incorporating surfactants as stabilising agents, such as polysorbate 20 and 80. However, little is known about the effect surfactant grade has on formulation stability. This study evaluates the effect of regular grade and Super-refined™ polysorbates 20 and 80 and their interaction with model proteins, namely β-lactoglobulin (β-Ig), human serum albumin (HSA) and immunoglobulin gamma (IgG), using isothermal titration calorimetry (ITC) and differential scanning calorimetry (DSC). ITC results indicated that all four polysorbates underwent binding interactions with β-Ig and HSA, yet no interaction was observed with IgG this is postulated to be a consequence of differences in secondary structure composition. Surfactant binding to β-Ig occurred at ratios of ~ 3:2 regardless of the surfactant used with dissociation constants ranging from 284 to 388 µM, whereas HSA bound at ratios of ~ 3:1 and dissociation constants ranging from 429 to 653 µM. Changes in enthalpy were larger for the surfactant interactions with HSA compared with β-Ig implying the former produced a greater binding interaction than the latter. DSC facilitated measurement of the temperature of unfolding of each protein with the presence of each polysorbate where results further confirmed interactions had occurred for β-Ig and HSA with an increased unfolding temperature between 4 and 6 K implying improved protein stability, yet again, no interaction was observed with IgG. This study thermodynamically characterised the role of polysorbates in protein stabilisation for biopharmaceutical formulations.

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A Mechanistic Understanding of Monoclonal Antibody Interfacial Protection by Hydrolytically Degraded Polysorbate 20 and 80 under IV Bag Conditions

Cited by 11 publications

References 55 publications

Not the Usual Suspects: Alternative Surfactants for Biopharmaceuticals

Not the Usual Suspects: Alternative Surfactants for Biopharmaceuticals

Guanidine-modified albumin-MMAE conjugates with enhanced endocytosis ability

A thermodynamic investigation into protein–excipient interactions involving different grades of polysorbate 20 and 80

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