A pilot trial of GM-CSF and MDX-H210 in patients with erbB-2-positive advanced malignancies

James A. Posey, Regina Raspet, Udit Verma, Yashwant M. Deo, Tibor Keller, John L. Marshall, Jennifer Hodgson, Amitabha Mazumder, Michael J. Hawkins

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28 Scopus citations

Abstract

MDX-H210 is a chemically, cross-linked, half-humanized bispecific antibody composed of F(ab’) fragment from monoclonal antibody (mAb) H22 that binds to the high-affinity receptor FcγRI and F(ab’) of mAb 520C9 that recognizes the erbB-2 (HER2/neu) oncoprotein. In a previous trial, the murine bispecific, MDX-210 at a dose of 7 mg/m2, was well tolerated and activated monocytes and macrophages in vivo in doses as low as 0.35 mg/m2. In our multidose trial, granulocyte-macrophage colony-stimulating factor, which increases and activates potential effector cells, was given on days 1-4 at 250 µg/m2 s.c. and MDX-H210 was given on day 4 weekly for 4 consecutive weeks. Thirteen patients were treated at dose levels of 1, 3.5, 7, 10, 15, and 20 mg/m2 without dose-limiting toxicity. Fever, chills, and rigors occurred during and up to 2 h postinfusion and correlated with the time to peak levels of tumor necrosis factor-α (median 88.2 pg/ml; range 15.6-887 pg/ml) and interleukin-6 (median 371 pg/ml; range 175-2,149 pg/ml). By the fourth consecutive week of treatment the side effects and cytokine levels decreased significantly. Human antibispecific antibody (HABA) levels were increased by 200- to 500-fold above pretreatment levels in 5 of 11 evaluable patients after 3 weeks of treatment. The monocyte and granulocyte population increased on days 4 and 11 (median 44%; range 18-68% and 42%; 19-71%), respectively, for monocytes and (60%; 43-75% and 74%; 54-82%) on days 4 and 11 for granulocytes. There was a significant decrease in the monocyte populations immediately after MDX-H210 administration (median decrease 73%; range 42-94%) and (52%; 12-72%) on days 4 and 11, respectively. Ten patients completed 4 weeks of treatment. One patient had a 48% reduction in an index lesions and six patients had stable disease at the time of evaluation. Three patients progressed before the fourth week. The therapy was generally well tolerated with toxicity, primarily, limited to the days of treatment.

Original languageEnglish (US)
Pages (from-to)371-379
Number of pages9
JournalJournal of Immunotherapy
Volume22
Issue number4
DOIs
StatePublished - Jan 1 1999

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Keywords

  • Antibody fragments
  • Antibody-dependent cytotoxicity
  • Bispecific antibody
  • Fc (fragment, crystalline) receptor
  • HER 2/neu

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology
  • Cancer Research

Cite this

Posey, J. A., Raspet, R., Verma, U., Deo, Y. M., Keller, T., Marshall, J. L., Hodgson, J., Mazumder, A., & Hawkins, M. J. (1999). A pilot trial of GM-CSF and MDX-H210 in patients with erbB-2-positive advanced malignancies. Journal of Immunotherapy, 22(4), 371-379. https://doi.org/10.1097/00002371-199907000-00011