Treatment-induced antibodies to interleukin-2

Prümmer, Otto

doi:10.1007/978-94-011-5664-6_3

Cited by 6 publications

(8 citation statements)

References 49 publications

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“…Indeed, this product is highly immunogenic, inducing binding antibody responses in 80% to 100% of patients. 33 Of interest, neutralizing antibody to IL-2 largely arises in a group of patients treated with IL-2 in an immunologically provocative fashion (ie, SC administration or concomitant treatment with IFNa , a known immunomodulator, and extensive treatment over a prolonged time period). 33 Also intriguing is the time course in which the neutralizing response arises, as it is detected several months following detection of binding antibody, implicating epitope spreading as the likely route of development.…”

Section: Evidence For the Role Of Product Aggregates In Induction Of mentioning

confidence: 99%

Effects of protein aggregates: An immunologic perspective

Rosenberg

2006

AAPS J

1,205

854

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The capacity of protein aggregates to enhance immune responses to the monomeric form of the protein has been known for over a half-century. Despite the clear connection between protein aggregates and antibody mediated adverse events in treatment with early therapeutic protein products such as intravenous immune globulin (IVIG) and human growth hormone, surprisingly little is known about the nature of the aggregate species responsible for such effects. This review focuses on a framework for understanding how aggregate species potentially interact with the immune system to enhance immune responses, garnered from basic immunologic research. Thus, protein antigens presented in a highly arrayed structure, such as might be found in large nondenatured aggregate species, are highly potent in inducing antibody responses even in the absence of T-cell help. Their potency may relate to the ability of multivalent protein species to extensively cross-link B-cell receptor, which (1) activates B cells via Bt kinases to proliferate, and (2) targets protein to class II major histocompatibility complex (MHC)-loading compartments, efficiently eliciting T-cell help for antibody responses. The review further focuses on protein aggregates as they affect an immunogenicity risk assessment, the use of animal models and studies in uncovering effects of protein aggregates, and changes in product manufacture and packaging that may affect generation of protein aggregates.

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Section: Evidence For the Role Of Product Aggregates In Induction Of mentioning

confidence: 99%

Effects of protein aggregates: An immunologic perspective

Rosenberg

2006

AAPS J

1,205

854

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“…Drug immunogenicity is a well-known problem of biological agents [84], including IL-2. Both subcutaneous and intravenous administration of recombinant hIL-2 has been reported to cause anti-IL-2 antibodies in about 50% of patients; however, neutralizing anti-IL-2 antibodies were seen typically only in 5-10% of subjects treated [85][86][87]. However, the N88R IL-2 mutein BAY 50-4798 had already caused antidrug antibodies in 27% of treated patients after two cycles of intravenous infusion [76].…”

Section: Box 1 Limitations and Immunogenicity Of Il-2 Formulationsmentioning

confidence: 99%

“…However, the N88R IL-2 mutein BAY 50-4798 had already caused antidrug antibodies in 27% of treated patients after two cycles of intravenous infusion [76]. Hence, it is worth considering strategies to reduce the immunogenicity of IL-2 muteins; for example, by avoiding the formation of aggregates due to hydrophobicity and lack of glycosylation [85,87].…”

Section: Box 1 Limitations and Immunogenicity Of Il-2 Formulationsmentioning

confidence: 99%

Interleukin-2: Biology, Design and Application

Arenas-Ramirez

Woytschak

Boyman

2015

Trends in Immunology

306

283

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Interleukin-2 (IL-2) exerts crucial functions during immune homeostasis via its effects on regulatory T (Treg) cells, and the optimizing and fine-tuning of effector lymphocyte responses. Thus, somewhat paradoxically, low doses of recombinant IL-2 have been used for Treg cell-based immunosuppressive strategies against immune pathologies, while high-dose IL-2 has shown some success in stimulating antitumor immune responses. Recent studies of the functional, biophysical and structural characteristics of IL-2 have led to the generation of IL-2 formulations, including IL-2/mAb complexes and IL-2 variants (muteins) that selectively enhance IL-2's immune stimulatory versus inhibitory properties. Here, we review these findings, placing new mechanistic insights into improved next-generation IL-2 formulations within the broader context of IL-2 biology. We conclude by integrating these findings into a framework for understanding IL-2-mediated selective immune modulation.

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“…[13][14][15] Aggregation and chemical degradation of proteins have been reported to enhance their immunogenicity upon administration. [16][17][18][19][20][21][22][23][24][25][26][27][28][29] Neutralizing antibodies can reduce the efficacy of therapeutic proteins 7,[30][31][32][33] and sometimes cross-react with essential endogenous proteins to cause severe ADRs. 34 Physical aggregation and chemical degradation can occur throughout the life of a protein product, and even modest environmental stresses can cause extensive damage.…”

Section: Introductionmentioning

confidence: 99%

Postproduction Handling and Administration of Protein Pharmaceuticals and Potential Instability Issues

Nejadnik

Randolph

Volkin

et al. 2018

Journal of Pharmaceutical Sciences

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The safety and efficacy of protein pharmaceuticals depend not only on biological activity but also on purity levels. Impurities may be process related because of limitations in manufacturing or product related because of protein degradation occurring throughout the life history of a product. Although the pharmaceutical biotechnology industry has made great progress in improving bulk and drug product manufacturing as well as company-controlled storage and transportation conditions to minimize the level of degradation, there is less control over the many factors that may subsequently affect product quality after the protein pharmaceuticals are released and shipped by the manufacturer. Routine handling or unintentional mishandling of therapeutic protein products may cause protein degradation that remains unnoticed but can potentially compromise the clinical safety and efficacy of the product. In this commentary, we address some potential risks associated with (mis)handling of protein pharmaceuticals after release by the manufacturer. We summarize the environmental stress factors that have been shown to cause protein degradation and that may be encountered during typical handling procedures of protein pharmaceuticals in a hospital setting or during self-administration by patients. Moreover, we provide recommendations for improvements in product handling to help ensure the quality of protein pharmaceuticals during use.

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Treatment-induced antibodies to interleukin-2

Cited by 6 publications

References 49 publications

Effects of protein aggregates: An immunologic perspective

Effects of protein aggregates: An immunologic perspective

Interleukin-2: Biology, Design and Application

Postproduction Handling and Administration of Protein Pharmaceuticals and Potential Instability Issues

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