Diabody-based recombinant formats of humanized IgG-like bispecific antibody with effective retargeting of lymphocytes to tumor cells

Ryutaro Asano, Hiroko Kawaguchi, Yasuhiro Watanabe, Takeshi Nakanishi, Mitsuo Umetsu, Hiroki Hayashi, Yu Katayose, Michiaki Unno, Toshio Kudo, Izumi Kumagai

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

Abstract

Recently, recombinant antibodies have been dissected into antigen-binding regions and rebuilt into multivalent high-avidity formats. These new structural designs are expected to improve in vivo pharmacokinetics and efficacy in clinical use. Here, we designed effective recombinant bispecific antibody (BsAb) formats based on hEx3, a humanized bispecific diabody with epidermal growth factor receptor and CD3 retargeting. The bispecific and bivalent IgG-like antibodies engineered from hEx3 (or its single-chain form, hEx3-scDb) and the human Fc region showed stronger binding to each target cell than did monovalent diabody formats, and their affinity was identical to that of the corresponding parent IgG. The bivalent effect of the constructed IgG-like BsAbs resulted in cell cytotoxicity 10 times that of monovalent diabodies, and further, the fusion of Fc portion contributed intense cytotoxicity in peripheral blood mononuclear cells by the induction of the antibody-dependent cellular cytotoxicity. The growth-inhibition effects of IgG-like BsAbs were superior to those of the approved therapeutic antibody cetuximab, which recognizes the same epidermal growth factor receptor antigen, even when peripheral blood mononuclear cells were used as effector cells. We thus demonstrated a critical improvement in the effect of hEx3 by the bottom-up construction of IgG-like BsAbs; in adoptive immunotherapy, monotherapy without supplemental molecules may be able to induce antibody-dependent cellular cytotoxicity.

Original languageEnglish
Pages (from-to)752-761
Number of pages10
JournalJournal of Immunotherapy
Volume31
Issue number8
DOIs
Publication statusPublished - 2008 Oct

Keywords

  • Bispecific IgG-like antibody
  • Bispecific diabody
  • Cancer immunotherapy
  • EGFR
  • Effective recombinant formats

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology
  • Cancer Research

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