The combination of trastuzumab and pertuzumab administered at approved doses may delay development of trastuzumab resistance by additively enhancing antibody-dependent cell-mediated cytotoxicity

Gábor Tóth, Árpád Szöőr, László Simon, Yosef Yarden, János Szöllősi, G. Vereb

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Although the recently concluded CLEOPATRA trial showed clinical benefits of combining trastuzumab and pertuzumab for treating HER2-positive metastatic breast cancer, trastuzumab monotherapy is still the mainstay in adjuvant settings. Since trastuzumab resistance occurs in over half of these cancers, we examined the mechanisms by which treatment of intrinsically trastuzumab-resistant and -sensitive tumors can benefit from the combination of these antibodies. F(ab′)2 of both trastuzumab and pertuzumab were generated and validated in order to separately analyze antibody-dependent cell-mediated cytotoxicity (ADCC)-based and direct biological effects of the antibodies. Compared to monotherapy, combination of the two antibodies at clinically permitted doses enhanced the recruitment of natural killer cells responsible for ADCC, and significantly delayed the outgrowth of xenografts from intrinsically trastuzumab-resistant JIMT-1 cells. Antibody dose-response curves of in vitro ADCC showed that antibody-mediated killing can be saturated, and the two antibodies exert an additive effect at sub-saturation doses. Thus, the additive effect in vivo indicates that therapeutic tissue levels likely do not saturate ADCC. Additionally, isobole studies with the in vitro trastuzumab-sensitive BT-474 cells showed that the direct biological effect of combined treatment is additive, and surpasses the maximum effect of either monotherapy. Our results suggest the combined therapy is expected to give results that are superior to monotherapy, whatever the type of HER2-positive tumor may be. The combination of both antibodies at maximum clinically approved doses should thus be administered to patients to recruit maximum ADCC and cause maximum direct biological growth inhibition.

Original languageEnglish
Pages (from-to)1-10
Number of pages10
JournalmAbs
DOIs
Publication statusAccepted/In press - Jul 28 2016

Fingerprint

Antibody-Dependent Cell Cytotoxicity
Blocking Antibodies
Antibodies
Neoplasms
Therapeutics
Trastuzumab
pertuzumab
Heterografts
Natural Killer Cells
Antibody Formation
Clinical Trials
Breast Neoplasms
Growth

Keywords

  • Antibody-dependent cell-mediated cytotoxicity (ADCC)
  • combination antibody therapy
  • HER2
  • Herceptin resistance
  • pertuzumab
  • resistance
  • trastuzumab

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

The combination of trastuzumab and pertuzumab administered at approved doses may delay development of trastuzumab resistance by additively enhancing antibody-dependent cell-mediated cytotoxicity. / Tóth, Gábor; Szöőr, Árpád; Simon, László; Yarden, Yosef; Szöllősi, János; Vereb, G.

In: mAbs, 28.07.2016, p. 1-10.

Research output: Contribution to journalArticle

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