Small Amounts of Sub-Visible Aggregates Enhance the Immunogenic Potential of Monoclonal Antibody Therapeutics

Ahmadi, Maryam; Bryson, Christine J.; Cloake, Edward A.; Welch, Keasley; Filipe, Vasco; Romeijn, Stefan; Hawe, Andrea; Jiskoot, Wim; Baker, Matthew; Fogg, Mark H.

doi:10.1007/s11095-014-1541-x

Cited by 137 publications

(134 citation statements)

References 40 publications

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“…Numerous studies – including human clinical investigations, in animal models and with in vitro assays with human cells - have shown a link between subvisible particles and unwanted immunogenicity of therapeutic protein products. 9,10,23–26 …”

Section: Discussionmentioning

confidence: 99%

Microparticles and Nanoparticles Delivered in Intravenous Saline and in an Intravenous Solution of a Therapeutic Antibody Product

Pardeshi

Wei²,

Dahl³

et al. 2017

Journal of Pharmaceutical Sciences

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Intravenous (IV) infusion is used for administration of a large proportion of biologic therapeutics, including most monoclonal antibody (mAb) products. In this study, we determined the sub-visible particle levels in IV solutions and after the solutions were processed with an IV administration setup that mimicked the typical clinical method of administration. IV saline in bags manufactured by both Hospira and Baxter contained 1,600–8,000 microparticles/mL and 4–73×106 nanoparticles/mL in solution. When intravenous immunoglobulin (IVIG) was diluted into the IV saline, 3,700–23,000 microparticles/mL and 18–240×106 nanoparticles/mL were detected. During processing of the solution through the IV system, in-line filters removed most microparticles. However, there were still 1–21×106 nanoparticles/mL in IV saline and 7–83×106 nanoparticles/mL in IVIG diluted in saline. Finally, in samples processed through in-line filters, we found relatively large microparticles (20–60 μm) that were composed of protein or polycarbonate. These particles resulted from shedding of polycarbonate and sloughing off of protein films downstream from the filter membrane. Overall, the results document that even with in-line filters in place, high levels of subvisible particles are delivered to patients and there is a need for improved, more effective filters and IV solutions with lower particle levels.

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Section: Discussionmentioning

confidence: 99%

Microparticles and Nanoparticles Delivered in Intravenous Saline and in an Intravenous Solution of a Therapeutic Antibody Product

Pardeshi

Wei²,

Dahl³

et al. 2017

Journal of Pharmaceutical Sciences

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“…B-cell epitopes are challenging to predict and B-cell-only responses to biotherapeutics appear to be driven by protein aggregates (26). The key attributes to reduce antibody immunogenicity risk in the clinic appear to be: low T-cell epitope content, minimized non-germ-line amino acid content and low aggregation potential (27).…”

mentioning

confidence: 99%

Augmented Binary Substitution: Single-pass CDR germ-lining and stabilization of therapeutic antibodies

Townsend

Fennell

Apgar

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Although humanized antibodies have been highly successful in the clinic, all current humanization techniques have potential limitations, such as: reliance on rodent hosts, immunogenicity due to high non-germ-line amino acid content, v-domain destabilization, expression and formulation issues. This study presents a technology that generates stable, soluble, ultrahumanized antibodies via single-step complementarity-determining region (CDR) germ-lining. For three antibodies from three separate key immune host species, binary substitution CDR cassettes were inserted into preferred human frameworks to form libraries in which only the parental or human germ-line destination residue was encoded at each position. The CDR-H3 in each case was also augmented with 1 ± 1 random substitution per clone. Each library was then screened for clones with restored antigen binding capacity. Lead ultrahumanized clones demonstrated high stability, with affinity and specificity equivalent to, or better than, the parental IgG. Critically, this was mainly achieved on germ-line frameworks by simultaneously subtracting up to 19 redundant non-germ-line residues in the CDRs. This process significantly lowered non-germ-line sequence content, minimized immunogenicity risk in the final molecules and provided a heat map for the essential non-germ-line CDR residue content of each antibody. The ABS technology therefore fully optimizes the clinical potential of antibodies from rodents and alternative immune hosts, rendering them indistinguishable from fully human in a simple, single-pass process.antibody | paratope | plasticity | humanization | immunogenicity

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“…Although nowadays the use of humanized or fully-human biodrugs has greatly contributed to reduce this risk, immunogenicity associated to the aggregation of biodrug molecules and other factors is still a major concern for the optimum exploitation of these modern drugs [296,297]. The association between biodrug molecules upon injection has been thought to be a natural way to enhance antigen processing and presentation in the cells [298,299]. On the other hand, the presence of impurities could also be part of the problem.…”

Section: The Next Challenge In Immunomodulation: Overcoming Antidrmentioning

confidence: 99%

Modulating the immune system through nanotechnology

Dacoba

Ana

Torres

et al. 2017

Seminars in Immunology

100

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Nowadays, nanotechnology-based modulation of the immune system is presented as a cutting-edge strategy, which may lead to significant improvements in the treatment of severe diseases. In particular, efforts have been focused on the development of nanotechnology-based vaccines, which could be used for immunization or generation of tolerance. In this review, we highlight how different immune responses can be elicited by tuning nanosystems properties. In addition, we discuss specific formulation approaches designed for the development of anti-infectious and anti-autoimmune vaccines, as well as those intended to prevent the formation of antibodies against biologicals.

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Small Amounts of Sub-Visible Aggregates Enhance the Immunogenic Potential of Monoclonal Antibody Therapeutics

Cited by 137 publications

References 40 publications

Microparticles and Nanoparticles Delivered in Intravenous Saline and in an Intravenous Solution of a Therapeutic Antibody Product

Microparticles and Nanoparticles Delivered in Intravenous Saline and in an Intravenous Solution of a Therapeutic Antibody Product

Augmented Binary Substitution: Single-pass CDR germ-lining and stabilization of therapeutic antibodies

Modulating the immune system through nanotechnology

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