Emgality® (Galcanezumab)

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Galcanezumab: Human vs. Humanized Monoclonal Antibodies

Current evidence suggests designation of a monoclonal antibody as human or humanized does not have an impact on its overall efficacy and safety profile.

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Monoclonal Antibodies

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.1 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.2 Clinicians should individually assess each mAb for its clinical impact regarding safety and efficacy.1

Human mAbs

Generation of fully human mAbs can

  • start with either phage display technology or animal immunizations1
  • be developed in transgenic mice that have been genetically engineered with the human immunoglobulin locus,1 or
  • have mutations that have been introduced by the mouse somatic mutation machinery.3

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.1

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 ADAs, thereby potentially limiting clinical efficacy.1

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.1

Galcanezumab: a Humanized Monoclonal Antibody

Galcanezumab is

  • a humanized IgG4 mAb that binds to CGRP and blocks its binding to the receptor, and 
  • produced in Chinese Hamster Ovary cells by recombinant DNA technology.4

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

With 12 months of treatment, up to 12.5% of galcanezumab-treated patients developed ADAs, most of which were low titer and tested positive for neutralizing activity in vitro. 4

The presence of ADAs did not affect the pharmacokinetics, efficacy, or safety of galcanezumab. 4

Referencias

1Mallbris 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/

2World 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

3Di 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

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

Glossary

ADA = anti-drug antibody

CDR =  complementarity determining regions 

CGRP = calcitonin gene-related peptide

DNA = deoxyribonucleic acid

IgG4 = immunoglobulin G (subclass) 4

mAb = monoclonal antibody

Fecha de la última revisión: 2020 M04 14


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