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  • Review Article
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Protein therapeutics: new applications for pharmacogenetics

Nature Reviews Drug Discovery volume 5, pages 507–521 (2006)Cite this article

Key Points

  • Recombinant protein therapeutics have uniquely targeted mechanisms that complement or block endogenous factors. Individual variability in a patient's disease state and genetic background can affect drug responses, which suggests a need to improve methods for patient selection and drug targeting.

  • A target-oriented pharmacogenetic approach is appropriate for highly selective protein drugs, as therapeutic activities, adverse responses and drug elimination are generally mediated through target engagement. However, factors upstream or downstream of the drug target can significantly alter each of these processes.

  • Many pharmacogenetic studies of protein therapeutics have focused on candidate genes within the pharmacological pathways of drug targets. Others have investigated candidate genes associated with disease susceptibility, sub-type or severity. Although exploratory studies have yielded many significant associations, few prospective studies have been performed for protein therapeutics.

  • Genotyping assays are widely available and relatively cheap, but acquiring the resources to develop assays for relevant phenotypic endpoints can be a challenge. In many cases, the functional relevance of (statistically significant) associations between candidate genes and drug response is unknown. A scientific basis for understanding pharmacogenetic associations must be developed, to promote the value of the genetic biomarker.

  • Therapeutics can be derived from endogenous proteins that are subject to genetic variation. Such drugs should be developed with an understanding of the major variants present in the treatment population, to minimize the risk of unintended consequences such as immunogenicity.

  • By integrating pharmacogenetic studies into the early development of new protein therapeutics, scientists can coincidently develop qualified assays for candidate genes and evidence for pharmacogenetic effects on the pharmacodynamic biomarkers typically measured in early-phase clinical studies. With these tools and information in hand, project teams will be poised to derive maximal value from later-phase pharmacogenetic investigations.

Abstract

Pharmacogenetic studies have traditionally focused on genes involved in processes that affect the pharmacokinetics of small-molecule drugs, such as drug metabolism. However, attention is shifting to the effects of genetic variations in drug targets and associated pathway components on drug responses. We describe how these variations are important for understanding differences in responses to the growing number of protein therapeutics that are entering clinical practice. Pharmacogenetic studies of these drugs are surveyed, and issues important to the success of such endeavours are discussed. As novel protein therapeutics are introduced, we anticipate that the use of pharmacogenetics will assume a key role in their development and clinical application.

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Figure 1: Time elapsed between FDA approval and first peer-reviewed publication of pharmacogenetic association.

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Acknowledgements

The authors wish to thank our colleagues for helpful discussion and critical review of this manuscript.

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Authors and Affiliations

  1. ZymoGenetics, Inc., 1201 Eastlake Avenue East, Seattle, 98102-3702, Washington, USA

    Cecile Krejsa & Mark Rogge

  2. Department of Pharmacology, College of Medicine, The Ohio State University, Columbus, 43210-1239, Ohio, USA

    Wolfgang Sadee

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  1. Cecile Krejsa
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  2. Mark Rogge
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  3. Wolfgang Sadee
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Correspondence to Cecile Krejsa.

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Competing interests

C.K. and M.R. are employees of ZymoGenetics, Inc. which is involved in the production and commercialization of therapeutic proteins for the prevention and treatment of human diseases.

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DATABASES

OMIM

Chronic lymphocytic leukaemia

Crohn's disease

follicular lymphoma

multiple sclerosis

psoriasis

rheumatoid arthritis

stroke

Waldrenstrom's macroglobulinaemia

FURTHER INFORMATION

Draft Guidance for Industry and FDA Staff-Pharmacogenetic Tests and Genetic Tests for Heritable Markers

EMEA Guideline on Pharmacogenetics Briefing Meetings

EMEA Position Paper on Terminology in Pharmacogenetics

US FDA Guidance for Industry Pharmacogenomic Data Submissions

US FDA Pharmacogenomic Data Submission

Glossary

Recombinant protein therapeutics

Include cytokines, growth factors, enzymes, coagulation factors, soluble receptors, monoclonal antibodies and engineered forms of these proteins.

Polymorphism

A genetic variation in the DNA sequence with a measurable frequency of detection above 1%. Any polymorphism in the chromosomal DNA (coding and non-coding) can affect mRNA processing, maturation and translation, as a result of changes in conformation. A subset of polymorphisms alters the translated protein.

Single nucleotide polymorphism (SNP)

A specific location in a DNA sequence at which different people can have a different DNA base. SNPs can occur in coding or non-coding regions of a gene; a coding SNP can be synonymous (the codon encodes the same amino acid), non-synonymous (an amino acid change) or nonsense (a premature stop results).

Microsatellite repeat

A class of repetitive DNA that is made up of repeats that are two to eight nucleotides in length. They can be highly polymorphic and are frequently used as molecular markers in population genetics studies.

Genotype

The set of two alleles carried by an individual at a given polymorphic site.

Haplotype

The composite of several alleles carried by an individual across a region of DNA. Haplotypes can be constructed from multiple polymorphic alleles observed in a single gene, or extended to incorporate polymorphic sites across several genes.

Diplotype

The combination of two haplotypes carried by an individual.

Phenotype

The physical manifestation of genetic traits, or general constitutional manifestation of health or disease in an individual. A patients phenotype can describe disease status, but phenotype can also relate to specific responses such as analytical test results.

Pharmacokinetics

Pharmacokinetics describes the absorption, distribution, metabolism and excretion of the drug, and yields an estimate of drug exposure.

Pharmacodynamics

Drug pharmacodynamics generally uses biomarkers to monitor the biological response to drug–target interaction.

Dominant model

In the dominant model, carriage of a single copy of the allele has the same functional outcome as carriage of two copies (the allele is dominant).

Recessive model

In the recessive model, carriage of a single copy of the allele has the same functional outcome as carriage of zero copies of the variant allele (the allele is recessive).

Additive model

In the additive model, carriage of a single copy of the allele has functional effects intermediate to carriage of zero or two copies (the alleles are additive and gene-dosage effects might apply).

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Krejsa, C., Rogge, M. & Sadee, W. Protein therapeutics: new applications for pharmacogenetics. Nat Rev Drug Discov 5, 507–521 (2006). https://doi.org/10.1038/nrd2039

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