Characterization of Co-Formulated High-Concentration Broadly Neutralizing Anti-HIV-1 Monoclonal Antibodies for Subcutaneous Administration

Sharma, Vaneet K.; Misra, Bijay; McManus, Kevin T; Avula, Sreenivas; Nellaiappan, Kaliappanadar; Caskey, Marina; Horowitz, Jill; Nussenzweig, Michel C.; Seaman, Michael S.; Javeri, Indu; Dey, Antu

doi:10.3390/antib9030036

Cited by 12 publications

(12 citation statements)

References 30 publications

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“…Recent reports have demonstrated that protein sequence optimization of several clinically advanced bnAbs can improve expression levels, conformational stability, and downstream processing and formulation conditions, all while maintaining the neutralization profile of the parental antibody ( 70 , 71 ). A high concentration co-formulated drug product containing bnAbs 3BNC117-LS and 10-1074-LS that will allow for subcutaneous administration has also recently been described ( 72 ). As will be reviewed further below, the first 2- and 3-bnAb combinations have initiated clinical testing in HIV-infected and uninfected individuals.…”

Section: Combinations Of Bnabsmentioning

confidence: 99%

Broadly Neutralizing Antibodies for HIV-1 Prevention

Walsh

Seaman

2021

Front. Immunol.

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Given the absence of an effective vaccine for protection against HIV-1 infection, passive immunization strategies that utilize potent broadly neutralizing antibodies (bnAbs) to block acquisition of HIV-1 are being rigorously pursued in the clinical setting. bnAbs have demonstrated robust protection in preclinical animal models, and several leading bnAb candidates have shown favorable safety and pharmacokinetic profiles when tested individually or in combinations in early phase human clinical trials. Furthermore, passive administration of bnAbs in HIV-1 infected individuals has resulted in prolonged suppression of viral rebound following interruption of combination antiretroviral therapy, and robust antiviral activity when administered to viremic individuals. Recent results from the first efficacy trials testing repeated intravenous administrations of the anti-CD4 binding site bnAb VRC01 have demonstrated positive proof of concept that bnAb passive immunization can confer protection against HIV-1 infection in humans, but have also highlighted the considerable barriers that remain for such strategies to effectively contribute to control of the epidemic. In this review, we discuss the current status of clinical studies evaluating bnAbs for HIV-1 prevention, highlight lessons learned from the recent Antibody Mediated Prevention (AMP) efficacy trials, and provide an overview of strategies being employed to improve the breadth, potency, and durability of antiviral protection.

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Section: Combinations Of Bnabsmentioning

confidence: 99%

Broadly Neutralizing Antibodies for HIV-1 Prevention

Walsh

Seaman

2021

Front. Immunol.

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“…Although it is undesirable to have oligomers in mAb products, small fractions of such higher-order structures are present in mAb formulations [ 14 , 15 , 16 ]. The formation of oligomers initiates when two mAb molecules form dimers.…”

Section: Introductionmentioning

confidence: 99%

Effects of Monovalent Salt on Protein-Protein Interactions of Dilute and Concentrated Monoclonal Antibody Formulations

Clark

Pollastrini

et al. 2022

Antibodies

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In this study, we used sodium chloride (NaCl) to extensively modulate non-specific protein-protein interactions (PPI) of a humanized anti-streptavidin monoclonal antibody class 2 molecule (ASA-IgG2). The changes in PPI with varying NaCl (CNaCl) and monoclonal antibody (mAb) concentration (CmAb) were assessed using the diffusion interaction parameter kD and second virial coefficient B22 measured from solutions with low to moderate CmAb. The effective structure factor S(q)eff measured from concentrated mAb solutions using small-angle X-ray and neutron scattering (SAXS/SANS) was also used to characterize the PPI. Our results found that the nature of net PPI changed not only with CNaCl, but also with increasing CmAb. As a result, parameters measured from dilute and concentrated mAb samples could lead to different predictions on the stability of mAb formulations. We also compared experimentally determined viscosity results with those predicted from interaction parameters, including kD and S(q)eff. The lack of a clear correlation between interaction parameters and measured viscosity values indicates that the relationship between viscosity and PPI is concentration-dependent. Collectively, the behavior of flexible mAb molecules in concentrated solutions may not be correctly predicted using models where proteins are considered to be uniform colloid particles defined by parameters derived from low CmAb.

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“…Aimed at both coadministration and FDC products, enhanced analytical methods are needed to monitor product quality attributes for use-time studies and program life cycles [34,35]. The conventional iCIEF and IEX assays using UV detection lack the needed sensitivity [36] and dynamic range to simultaneously quantify charge variants of multiple components in wide ratios, such as FDC products with ratios ranging from 1:6 to 1:40.…”

Section: Introductionmentioning

confidence: 99%

Dual‐detection approach for a charge variant analysis of monoclonal antibody combination products using imaged capillary isoelectric focusing

Candreva

Esterman

et al. 2022

Electrophoresis

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The clinical benefits of treatments with a combination of two or more therapeutic monoclonal antibodies (mAbs) have emerged in recent years. Imaged capillary isoelectric focusing is a frequently used technology in the biopharmaceutical industry for charge variant analysis of protein therapeutics. However, with the wide concentration ranges of combination products, one component may fall within the linear detection range, whereas the other does not. Here, we report a novel methodology to explore charge variants of mAb mixtures using multiple detection techniques simultaneously. We use ultraviolet absorbance to monitor the charge variants of the high-concentration component and native fluorescence (FL) to monitor the variants of the low-concentration one. Charge variants of mixtures that span 40-fold in ratio differences can be accurately quantified with this approach. In contrast to the conventional methods, it is not necessary to prepare and analyze two samples at different concentrations and combine the results for combination product testing. Additionally, the use of FL detection enables the charge variant analysis of highly potent/low abundant mAbs in a mixture. This methodology is more quality-control friendly and efficient for the charge variant analysis of combination products with wide ratios.

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Characterization of Co-Formulated High-Concentration Broadly Neutralizing Anti-HIV-1 Monoclonal Antibodies for Subcutaneous Administration

Cited by 12 publications

References 30 publications

Broadly Neutralizing Antibodies for HIV-1 Prevention

Broadly Neutralizing Antibodies for HIV-1 Prevention

Effects of Monovalent Salt on Protein-Protein Interactions of Dilute and Concentrated Monoclonal Antibody Formulations

Dual‐detection approach for a charge variant analysis of monoclonal antibody combination products using imaged capillary isoelectric focusing

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