Taltz ® (ixekizumab) injektion

För fullständig produktresumé för Taltz® se FASS.

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Taltz▼ (ixekizumab): humana kontra humaniserade monoklonala antikroppar

Aktuella bevis tyder på att beteckningen för en monoklonal antikropp som human eller humaniserad inte har någon inverkan på total effekt och säkerhetsprofil.

  • Ixekizumab is an IgG4 monoclonal antibody that binds with high affinity (< 3 pM) and specificity to interleukin 17A (both IL-17A and IL-17A/F). Elevated concentrations of IL-17A have been implicated in the pathogenesis of psoriasis by promoting keratinocyte proliferation and activation. Neutralization of IL17A by ixekizumab inhibits these actions (Taltz Summary of Product Characteristics).

  • The nomenclature assigned to a monoclonal antibody (mAb) (ie, human or humanized) is dependent on the variable region of the immunoglobulin. This is the site that confers binding specificity and affinity of a therapeutic antibody (Mallbris, 2016).

  • While there are a number of differences between human and humanized monoclonal antibodies (mAbs), current evidence indicates that this designation does not impart a measurable impact on overall efficacy and safety profiles of a given drug (Mallbris, 2016). This is reflected in the updated mAb nomenclature recommended by the International Nonproprietary Names Expert Group (World Health Organization, 2017).

  • Clinicians should individually assess each mAb for its clinical impact regarding safety and efficacy (Mallbris, 2016).

Human mAbs

Generation of Fully Human mAbs

    • can start with either phage display technology or animal immunizations (Mallbris, 2016)

    • can be developed in transgenic mice that have been genetically engineered with the human immunoglobulin locus (Mallbris, 2016)

    • can have mutations which have been introduced by the mouse somatic mutation machinery (Di Noia, 2007).

Humanized mAbs

Generation of Humanized Abs (Mallbris, 2016)

  • starts with animal immunizations typically utilizing mice.

  • are developed initially in wild type mice with a native genome bearing the mouse immunoglobulin locus.

  • involves grafting the mouse-derived variable region onto a human antibody sequence utilizing molecular engineering technology to generate a humanized mAb,

  • can result in mAbs that, in total, have high human amino acid sequence homology, with differences limited to complementarity determining regions (CDRs) within the variable region of the antibody, and

  • can be specifically engineered to have fully human frameworks with no mutations from germline in these areas

Impact on Safety or Efficacy

Changes in the amino acid sequence homology to human amino acid sequences of either fully human or humanized mAbs can contribute to the development of anti-drug antibodies (ADAs), thereby potentially limiting clinical efficacy (Mallbris, 2016; Jullien, 2015).

The distinction between fully human and humanized mAbs has no predictable impact on the development of ADAs. Rather, a number of intrinsic and extrinsic factors, including but not limited to the amino acid sequence of a mAb, are involved in the development of ADAs for a given therapeutic mAb (Mallbris, 2016).


References

Di Noia JM, Neuberger MS. Molecular mechanisms of antibody somatic hypermutation. Annu Rev Biochem 2007;76:1-22.

Jullien D, Prinz JC, Nestle FO. Immunogenecity of biotherapy used in psoriasis: the science behind the scenes. J Invest Dermatol 2015; 135(1):31-38.

Mallbris L, Davies J, Glasebrook R, et al. Molecular Insights into Fully Human and Humanized Monoclonal Antibodies: What are the differences and should dermatologists care? J Clin Aesthet Dermatol 2016; 9(7):13–15.

Taltz EU Summary of Product Characteristics, Utrecht, The Netherlands: Eli Lilly Nederland B.V.

World Health Organization Revised monoclonal antibody (mAb) nomenclature scheme. INN Working Doc. 17.4.16. May 2017. http://www.who.int/medicines/services/inn/Revised_mAb_nomenclature_scheme.pdf?uaD1

This medicine is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Datum fӧr senaste ӧversyn 2018 M02 19

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