Emgality ® (galkanezumab)

För fullständig produktresumé för Emgality® se FASS.

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Emgality® ▼ (galcanezumab): 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.

Galcanezumab: a Humanized Monoclonal Antibody

Galcanezumab is a humanised IgG4 monoclonal antibody that binds CGRP thus preventing its biological activity.1

The nomenclature assigned to a mAb (ie, human or humanized) is dependent on the variable region of the immunoglobulin. This is the site that provides specificity and affinity for an antibody.2 While there are a number of differences between human and humanized mAbs, current evidence indicates that this designation does not impart a measurable impact on overall efficacy and safety profiles of a given drug. This is reflected in the updated mAb nomenclature recommended by the International Nonproprietary Names Expert Group.3 Clinicians should individually assess each mAb for its clinical impact regarding safety and efficacy.2

As with all therapeutic proteins there is the potential for immunogenicity with galcanezumab.4

Human mAbs

Generation of fully human mAbs can

  • start with either phage display technology or animal immunizations2

  • be developed in transgenic mice that have been genetically engineered with the human immunoglobulin locus,2 or

  • have mutations that have been introduced by the mouse somatic mutation machinery.5

Humanized mAbs

Generation of humanized mAbs

  • 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 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.2

Impact on Safety or Efficacy

In the clinical studies, the incidence of anti-drug antibody development during the double-blind treatment phase was 4.8 % in patients receiving galcanezumab once monthly (all but one of whom had in vitro neutralizing activity). With 12 months of treatment, up to 12.5 % of galcanezumab-treated patients developed anti-drug antibodies, most of which were of low titre and tested positive for neutralising activity in vitro. However, the presence of anti-drug antibodies did not affect the pharmacokinetics, efficacy, or safety of galcanezumab.1

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 ADAs, thereby potentially limiting clinical efficacy.2

Monoclonal antibodies can provoke neutralizing ADAs which may reduce clinical efficacy. The distinction between fully human and humanized mAbs has no generalizable impact on the development of ADAs based on nomenclature. 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.2

Therapeutic Indication

Galcanezumab is indicated for the prophylaxis of migraine in adults who have at least 4 migraine days per month.1

References

1. Emgality [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2. Mallbris L, Davies J, Glasebrook A, 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5022998/

3. World Health Organization. Revised monoclonal antibody (mAb) nomenclature scheme. INN Working Doc. 17.416. May 2017. http://www.who.int/medicines/services/inn/Revised_mAb_nomenclature_scheme.pdf?uaD1

4. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

5. Di Noia JM, Neuberger MS. Molecular mechanisms of antibody somatic hypermutation. Annu Rev Biochem. 2007;76:1-22. http://dx.doi.org/10.1146/annurev.biochem.76.061705.090740

Glossary

ADA = anti-drug antibody

CDR =  complementarity determining regions 

CGRP = calcitonin gene-related peptide

IgG4 = immunoglobulin G (subclass) 4

mAb = monoclonal antibody

This medicinal product 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 2020 M04 14


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