Scripps VIVO scripps research logo

  • Index
  • Log in
  • Home
  • People
  • Organizations
  • Research
  • Events
Search form

Monoclonal antibody therapeutics with up to five specificities: Functional enhancement through fusion of target-specific peptides

Academic Article
uri icon
  • Overview
  • Research
  • Identity
  • Additional Document Info
  • View All
scroll to property group menus

Overview

authors

  • LaFleur, D. W.
  • Abramyan, D.
  • Kanakaraj, P.
  • Smith, R. G.
  • Shah, R. R.
  • Wang, G. P.
  • Yao, X. T.
  • Kankanala, S.
  • Boyd, E.
  • Zaritskaya, L.
  • Nam, V.
  • Puffer, B. A.
  • Buasen, P.
  • Kaithamana, S.
  • Burnette, A. F.
  • Krishnamurthy, R.
  • Patel, D.
  • Roschke, V. V.
  • Kiener, P. A.
  • Hilbert, D. M.
  • Barbas III, Carlos

publication date

  • 2013

journal

  • MAbs  Journal

abstract

  • The recognition that few human diseases are thoroughly addressed by mono-specific, monoclonal antibodies (mAbs) continues to drive the development of antibody therapeutics with additional specificities and enhanced activity. Historically, efforts to engineer additional antigen recognition into molecules have relied predominantly on the reformatting of immunoglobulin domains. In this report we describe a series of fully functional mAbs to which additional specificities have been imparted through the recombinant fusion of relatively short polypeptides sequences. The sequences are selected for binding to a particular target from combinatorial libraries that express linear, disulfide-constrained, or domain-based structures. The potential for fusion of peptides to the N- and C- termini of both the heavy and light chains affords the bivalent expression of up to four different peptides. The resulting molecules, called zybodies, can gain up to four additional specificities, while retaining the original functionality and specificity of the scaffold antibody. We explore the use of two clinically significant oncology antibodies, trastuzumab and cetuximab, as zybody scaffolds and demonstrate functional enhancements in each case. The affect of fusion position on both peptide and scaffold function is explored, and penta-specific zybodies are demonstrated to simultaneously engage five targets (ErbB2, EGFR, IGF-1R, Ang2 and integrin αvβ3). Bispecific, trastuzumab-based zybodies targeting ErbB2 and Ang2 are shown to exhibit superior efficacy to trastuzumab in an angiogenesis-dependent xenograft tumor model. A cetuximab-based bispecific zybody that targeting EGFR and ErbB3 simultaneously disrupted multiple intracellular signaling pathways; inhibited tumor cell proliferation; and showed efficacy superior to that of cetuximab in a xenograft tumor model.

subject areas

  • Amino Acid Sequence
  • Angiopoietin-2
  • Animals
  • Antibodies, Bispecific
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antibody Specificity
  • Cell Proliferation
  • Cetuximab
  • Female
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Molecular Sequence Data
  • Neoplasms
  • Neovascularization, Pathologic
  • Peptides
  • Protein Engineering
  • Receptor, ErbB-2
  • Recombinant Fusion Proteins
  • Signal Transduction
  • Trastuzumab
  • Treatment Outcome
  • Xenograft Model Antitumor Assays
scroll to property group menus

Research

keywords

  • antibody engineering
  • multi-specific antibody
scroll to property group menus

Identity

PubMed Central ID

  • PMC3893231

International Standard Serial Number (ISSN)

  • 1942-0862

Digital Object Identifier (DOI)

  • 10.4161/mabs.23043

PubMed ID

  • 23575268
scroll to property group menus

Additional Document Info

start page

  • 208

end page

  • 218

volume

  • 5

issue

  • 2

©2019 The Scripps Research Institute | Terms of Use | Powered by VIVO

  • About
  • Contact Us
  • Support