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Cited by 55HER2/EGFR in Cancer ResearchMonoclonal and Polyclonal Antibodies ResearchGastric Cancer Management and Outcomes

A phase I study of a HER2/neu bispecific antibody with granulocyte-colony-stimulating factor in patients with metastatic breast cancer that overexpresses HER2/neu

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Pullarkat, V., Deo, Y., Link, J., Spears, L., Marty, V., Curnow, R., Groshen, S., Gee, C. +1 more·1999·Cancer Immunology, Immunotherapy
DOI 10.1007/s002620050543PMC PMC11037160
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Abstract

A phase I study of escalating doses of humanized bispecific antibody (bsAb) MDX-H210 with granulocyte-colony-stimulating factor (G-CSF) was conducted in patients with metastatic breast cancer that overexpressed HER2/neu. The main objectives of the study were to define the maximal tolerated dose (MTD) of MDX-H210 when combined with G-CSF, to measure the pharmacokinetics of MDX-H210 when administered with G-CSF, and to determine the toxicity, biological effects and possible therapeutic effect of MDX-H210 with G-CSF. MDX-H210 is a F(ab)' x F(ab)' humanized bispecific murine antibody that binds to both HER2/neu and the FcgammaR1 receptor (CD64), and was administered intravenously weekly for three doses followed by a 2-week break and then three more weekly doses. A total of 23 patients were treated, and doses were escalated from 1 mg/m2 to 40 mg/m2 with no MTD reached. The toxicity of the bsAb + G-CSF combination was modest, with no dose-limiting toxicity noted: 19 patients had fevers, 7 patients had diarrhea, and 3 patients had allergic reactions that did not limit therapy. The beta-elimination half-life varied from 4 h to 8 h at doses up to 20 mg/m2. Significant release of cytokines interleukin-6, G-CSF, and tumor necrosis factor alpha was observed after administration of bsAb. Circulating monocytes disappeared within 1 h of bsAb infusion, which correlated with binding of bsAb, noted by flow-cytometric analysis. Significant levels of human anti-(bispecific antibody) were measured in the plasma of most patients by the third infusion. No objective clinical responses were seen in this group of heavily pre-treated patients.

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  • Biological effects were seen in some clinical trials of MDX-210, MDX-H210 and MDX-447, but none of these treatments led to consistent antitumor activity.

    “Biological effects were seen in some clinical trials of bsAbs MDX-210 (targeting Her2 and CD64), MDX-H210 (humanized version of MDX-210) and MDX-447 (targeting EGFR and CD64), but none of these treatments led to consistent antitumor activity. [9][10]0][11][12]”

    From Bispecific antibodies for cancer therapy: The light at the end of the tunnel? (2009) · cites this paper as [9]

  • Chemically linked bispecific (Fab')2 molecules targeting HER2 or EGFR were tested in clinical trials; these antigens are overexpressed in many epithelial tumors such as colorectal, head and neck, bladder, renal, and non-small cell lung carcinoma.

    “A series of clinical trials were also performed with chemically linked bispecific (Fab')2 molecules targeting the breast and ovarian cancer tumor antigens HER2 or EGFR, [9][10][11][12] which are overexpressed in many epithelial tumors such as colorectal, head and neck, bladder, renal, non-small cell lung carcinoma.”

    From Bispecific antibodies for cancer therapy: The light at the end of the tunnel? (2009) · cites this paper as [9]

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Authors
Pullarkat, V., Deo, Y., Link, J., Spears, L., Marty, V., Curnow, R., Groshen, S., Gee, C., & Weber, J. S.
Affiliations
University of Southern California (US)
ORCID
Venue
Cancer Immunology, Immunotherapy
Publisher
Springer Science and Business Media LLC
Published
1999-03-12
Volume
48
Issue
1
Pages
9-21
ISSN
  • 0340-7004 (ISSN-L)
  • 1432-0851
DOI
10.1007/s002620050543
PMC
PMC11037160
OpenAlex
W2053167458
Cited by
55
References
25
Citations by year
2026: 1 · 2025: 1 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 4 · 2019: 1 · 2018: 2 · 2015: 2 · 2014: 1 · 2013: 3 · 2012: 2
FWCI
2.06
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Cancer Immunology Immunotherapy (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
USC Norris Comprehensive Cancer Center
Topics
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Gastric Cancer Management and Outcomes
Keywords
HER2/neu, bispecific antibodies, granulocyte colony-stimulating factor, metastatic breast cancer, Fc gamma receptor I, maximum tolerated dose, pharmacokinetics, cytokine production, monocyte depletion, dose-limiting toxicity
MeSH terms
Adult, Aged, Animals, Breast Neoplasms, Dose-Response Relationship, Drug, Female, Humans, Middle Aged, Tumor Necrosis Factor-alpha, Interleukin-6, Granulocyte Colony-Stimulating Factor, Antibodies, Bispecific, Erb-b2 Receptor Tyrosine Kinases, Mice

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