Engineering Anti-EGFR Antibodies for Treatment of Breast Cancers with Poor Prognosis

Abstract

To enhance in vivo efficacy of anti-EGFR full length IgG for treatment of basal breast cancers, the most aggressive subtypes, we have successfully employed a molecular evolution approach to improve Fc binding affinity to Fc receptors that activate ADCC. In detail, both human and murine Fc domains have been functionally displayed on the surface of yeast. The Fc activating receptors, human Fc(Gamma)RIIIa and murine Fc(Gamma)RIV, were expressed in a transient 293E system and used for evaluating and sorting the affinity improved Fc domains. Libraries of Fc domains with random mutations were constructed and sorted. Several Fc domain variants were identified to bind human Fc(Gamma)RIIIa with enhanced affinity compared to wild-type Fc. We also found that the binding increase of Fc domain to human Fc(Gamma)RIIIa correlated with that to murine Fc(Gamma)RIV, indicating that the Fc domain with improved affinity to human Fc(Gamma)RIIIa should show enhanced in vivo efficacy in murine breast tumor model.

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Document Details

Document Type
Technical Report
Publication Date
Sep 01, 2008
Accession Number
ADA501070

Entities

People

  • James D. Marks
  • Yu Zhou

Organizations

  • University of California, San Francisco

Tags

DTIC Thesaurus Topics

  • Amino Acids
  • Antibodies
  • Biomedical Research
  • Breast Cancer
  • Cell Physiological Processes
  • Department Of Defense
  • Dna Sequence Analysis
  • Electronic Mail
  • Engineering
  • Genes
  • Genetic Phenomena
  • Growth Factors
  • Immune System
  • Mutations
  • Neoplasms
  • Personal Information Managers
  • Proteins

Fields of Study

  • Biology

Readers

  • Breast cancer cell signaling and growth regulation.
  • Immunology
  • Molecular Genetics