The Effect of Small Oligomeric Protein Aggregates on the Immunogenicity of Intravenous and Subcutaneous Administered Antibodies

Fathallah, Anas M.; Chiang, Manting; Mishra, Anshul; Kumar, Sandeep; Xue, Lijun; Middaugh, C. Russell; Balu‐Iyer, Sathy V.

doi:10.1002/jps.24592

Cited by 37 publications

(30 citation statements)

References 31 publications

(74 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The sample was excited at 355 nm and the emission monitored at 430 nm. Fluorescence polarization and anisotropy were calculated as described previously (24). The phase behavior and transition was monitored using fluorescence anisotropy as a function of temperature over a temperature range of 4°C to 50°C.…”

Section: Methodsmentioning

confidence: 99%

Exosomes Associated with Human Ovarian Tumors Harbor a Reversible Checkpoint of T-cell Responses

Shenoy

Loyall

Maguire

et al. 2018

Cancer Immunology Research

Self Cite

View full text Add to dashboard Cite

Nano-sized membrane-encapsulated extracellular vesicles isolated from the ascites fluids of ovarian cancer patients are identified as exosomes based on their biophysical and compositional characteristics. We report here that T cells pulsed with these tumor-associated exosomes during TCR-dependent activation inhibit various activation endpoints including translocation of NFκB and NFAT into the nucleus, upregulation of CD69 and CD107a, production of cytokines and cell proliferation. Additionally, the activation of virus-specific CD8+ T cells that are stimulated with the cognate viral peptides presented in the context of class I MHC is also suppressed by the exosomes. The inhibition occurs without loss of cell viability, and coincidentally with the binding and internalization of these exosomes. This exosome-mediated inhibition of T cells was transient and reversible: T cells exposed to exosomes can be reactivated once exosomes are removed. We conclude that tumor-associated exosomes are immunosuppressive, and represent a therapeutic target blockade of which would enhance the antitumor response of quiescent tumor-associated T cells and prevent the functional arrest of adoptively transferred tumor-specific T cells or chimeric antigen receptor (CAR) T cells.

show abstract

Section: Methodsmentioning

confidence: 99%

Exosomes Associated with Human Ovarian Tumors Harbor a Reversible Checkpoint of T-cell Responses

Shenoy

Loyall

Maguire

et al. 2018

Cancer Immunology Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Several studies have shown that under accelerated stress conditions, proteins can give mixtures of soluble aggregates that are submicron species including oligomers or multimers, mostly detected with dynamic light scattering method, and insoluble aggregates that are above the micrometer range (37). This was the case for human growth hormone submitted to a stir stress that gave homogenous aggregates around 892 nm (38), or antibody preparations that underwent stir stress (39), or thermal stress (40, 41). Another study showed the appearance of nanosized antibody aggregates upon heat or pH-shift stress that persisted when preparations were diluted in human serum, highlighting the interactions of aggregated proteins with biological fluids (42).…”

Section: Protein Aggregates As Nps Can Drive Immune Responsesmentioning

confidence: 99%

“…Such transgenic mice models have been developed for interferons (50, 51), and a recent paper showed that recombinant interferon beta aggregates induced a break of immune tolerance in transgenic mice, related with the size and structure of the generated aggregates (52). Using a conventional murine model, another study highlighted that oligomeric antibody aggregates were more immunogenic than larger highly aggregated particles (41), suggesting that protein aggregation that maintains some native epitopes is more immunogenic. However, the use of in vitro models is more convenient to test the effect of aggregated proteins on immune cells.…”

Section: Protein Aggregates As Nps Can Drive Immune Responsesmentioning

confidence: 99%

Why the Immune System Should Be Concerned by Nanomaterials?

2017

View full text Add to dashboard Cite

Particles possess huge specific surface area and therefore nanomaterials exhibit unique characteristics, such as special physical properties and chemical hyper-reactivity, which make them particularly attractive but also raise numerous questions concerning their safety. Interactions of nanomaterials with the immune system can potentially lead to immunosuppression, hypersensitivity (allergy), immunogenicity and autoimmunity, involving both innate and adaptive immune responses. Inherent physical and chemical NP characteristics may influence their immunotoxicity, i.e., the adverse effects that can result from exposure. This review will focus on the possible interaction of nanomaterials including protein aggregates with the innate immune system with specific emphasis on antigen-presenting cells, i.e., dendritic cells, macrophages and monocytes.

show abstract

“…[5][6][7][8][9][10][11] This cascade of interfacial molecular events may cause loss of bioactivity, anti-drug antibody response and, potentially, immunogenicity. 12,13 Addition of nonionic surfactants into mAb formulations is widely thought to inhibit protein adsorption. Many studies including our work have already shown that nonionic surfactants can prevent protein adsorption at the air/water interface when their concentrations are sufficiently high, 14,15 but it is also important to understand how they can influence mAb adsorption at the solid/water interface.…”

Section: Introductionmentioning

confidence: 99%

Coadsorption of a Monoclonal Antibody and Nonionic Surfactant at the SiO₂/Water Interface

Pan

et al. 2018

ACS Appl. Mater. Interfaces

View full text Add to dashboard Cite

ZL and FP made equal contributions AbstractDuring the formulation of therapeutic monoclonal antibodies (mAbs), nonionic surfactants are commonly added to attenuate structural rearrangement caused by adsorption/desorption at interfaces during processing, shipping and storage. We examined the adsorption of a mAb (COE-3) at the SiO 2 /water interface in the presence of pentaethylene glycol monododecyl ether (C 12 E 5 ), polysorbate 80 (PS80-20EO) and a polysorbate 80 analogue with 7 ethoxylates (PS80-7EO). Spectroscopic ellipsometry (SE) was used to follow COE-3 dynamic adsorption and neutron reflection (NR) was used to determine interfacial structure and composition.Neither PS80-20EO nor C 12 E 5 had a notable affinity for COE-3 or the interface under the conditions studied, and thus did not prevent COE-3 adsorption. In contrast, PS80-7EO did coadsorb but did not influence the dynamic process or the equilibrated amount of absorbed COE-3. Near equilibration, COE-3 underwent structural rearrangement and PS80-7EO started to bind the COE-3 interfacial layer and subsequently formed a well-defined surfactant bilayer via self-assembly. The resultant interfacial layer was comprised of an inner mAb layer of some 70 Å thick and an outer surfactant layer of a further 70 Å, with distinct transitional regions across the mAb-surfactant and surfactant-bulk water boundaries. Once formed, such interfacial layers were very robust and worked to prevent further mAb adsorption, desorption and structural rearrangement. Such robust interfacial layers could be anticipated to exist for formulated mAbs stored in type II glass vials; further research is required to understand the behaviour of these layers for siliconized glass syringes.

show abstract

The Effect of Small Oligomeric Protein Aggregates on the Immunogenicity of Intravenous and Subcutaneous Administered Antibodies

Cited by 37 publications

References 31 publications

Exosomes Associated with Human Ovarian Tumors Harbor a Reversible Checkpoint of T-cell Responses

Exosomes Associated with Human Ovarian Tumors Harbor a Reversible Checkpoint of T-cell Responses

Why the Immune System Should Be Concerned by Nanomaterials?

Coadsorption of a Monoclonal Antibody and Nonionic Surfactant at the SiO₂/Water Interface

Contact Info

Product

Resources

About

The Effect of Small Oligomeric Protein Aggregates on the Immunogenicity of Intravenous and Subcutaneous Administered Antibodies

Cited by 37 publications

References 31 publications

Exosomes Associated with Human Ovarian Tumors Harbor a Reversible Checkpoint of T-cell Responses

Exosomes Associated with Human Ovarian Tumors Harbor a Reversible Checkpoint of T-cell Responses

Why the Immune System Should Be Concerned by Nanomaterials?

Coadsorption of a Monoclonal Antibody and Nonionic Surfactant at the SiO2/Water Interface

Contact Info

Product

Resources

About

Coadsorption of a Monoclonal Antibody and Nonionic Surfactant at the SiO₂/Water Interface