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

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• 作者：Maryam Ahmadi (1)
  Christine J. Bryson (1) (4)
  Edward A. Cloake (1)
  Katie Welch (1)
  Vasco Filipe (2) (5)
  Stefan Romeijn (2)
  Andrea Hawe (3)
  Wim Jiskoot (2)
  Matthew P. Baker (1)
  Mark H. Fogg (1)
  
  1. Antitope Ltd ; Babraham Research Campus ; Babraham ; Cambridge ; CB22 3AT ; UK
  4. Department of Haematology ; Cambridge University Hospitals ; Hills Road ; Cambridge ; CB2 0QQ ; UK
  2. Division of Drug Delivery Technology ; Leiden Academic Centre for Drug Research ; Leiden University ; Leiden ; The Netherlands
  5. Adocia ; 115 Avenue Lacassagne ; 69003 ; Lyon ; France
  3. Coriolis Pharma ; Am Klopferspitz 19 ; 82152 ; Martinsried ; Germany
  
• 关键词：anti ; drug antibodies ; biotherapeutics ; CD4+ T cell responses ; humanized antibodies ; immunogenicity
• 刊名：Pharmaceutical Research
• 出版年：2015
• 出版时间：April 2015
• 年：2015
• 卷：32
• 期：4
• 页码：1383-1394
• 全文大小：3,862 KB
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• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Pharmacology and Toxicology
  Pharmacy
  Biochemistry
  Medical Law
  Biomedical Engineering
  
• 出版者：Springer Netherlands
• ISSN：1573-904X

文摘

Purpose Determine the effect of minute quantities of sub-visible aggregates on the in vitro immunogenicity of clinically relevant protein therapeutics. Methods Monoclonal chimeric (rituximab) and humanized (trastuzumab) antibodies were subjected to fine-tuned stress conditions to achieve low levels (+ T cells with the aggregates was measured in vitro using cytokine secretion, proliferation and confocal microscopy. Results Due to its intrinsic high clinical immunogenicity, aggregation of rituximab had minimal effects on DC activation and T cell responses compared to monomeric rituximab. However, in the case of trastuzumab (low clinical immunogenicity) small quantities of aggregates led to potent CD4+ T cell proliferation as a result of strong cytokine and co-stimulatory signals derived from DC. Consistent with this, confocal studies showed that stir-stressed rituximab was rapidly internalised and associated with late endosomes of DC. Conclusions These data link minute amounts of aggregates with activation of the innate immune response, involving DC, resulting in T cell activation. Thus, when protein therapeutics with little or no clinical immunogenicity, such as trastuzumab, contain minute amounts of sub-visible aggregates, they are associated with significantly increased potential risk of clinical immunogenicity.