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Cited by 87Monoclonal and Polyclonal Antibodies ResearchHER2/EGFR in Cancer ResearchLung Cancer Treatments and Mutations

A phase-I trial of the epidermal growth factor receptor directed bispecific antibody MDX-447 without and with recombinant human granulocyte-colony stimulating factor in patients with advanced solid tumors

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Fury, Matthew G., Lipton, Allan, Smith, Katherine M., Winston, Corinne B., Pfister, David G.·2007·Cancer Immunology, Immunotherapy
DOI 10.1007/s00262-007-0357-5PMC PMC11030736
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Abstract

Introduction MDX-447 is a bispecific antibody directed against the epidermal growth factor receptor (EGFR) and the high affinity Fc receptor (FcgammaRI). Preclinical data suggest that co-administration of granulocyte-colony stimulating factor (G-CSF) may enhance the tumor cytotoxicity of bispecific antibodies.Methods In group 1, patients received MDX-447 intravenously (i.v.) weekly. Dose levels of MDX-447 evaluated in group 1 were 1, 3.5, 7, 10, 15, 20, 30, and 40 mg/m(2). In group 2, patients received MDX-447 IV weekly with G-CSF (3 mcg/kg/day) subcutaneously (days -3 to +2, 5-9, 12-16, etc.). Dose levels of MDX-447 evaluated in group 2 were 1, 3.5, 7, 10, and 15 mg/m(2).Results Sixty-four patients with advanced solid tumors were treated. Forty-one patients received MDX-447 alone (group 1); 23 patients received MDX-447 + G-CSF (group 2). Hypotension was the predominant dose-limiting toxicity (DLT) in both treatment groups, with seven patients experiencing >or= grade 3 events. MDX-447 half-life (T(1/2)) ranged from 1.9 to 8.4 h, with no obvious differences between the two treatment groups. MDX-447 binding to neutrophils and peak levels of circulating tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) were higher in group 2. The MTD for MDX-447 alone was 30 mg/m(2). When G-CSF was given with MDX-447, treatment was not well tolerated and group 2 was closed early because of safety concerns, with the last patient being treated at the 7 mg/m(2) dose level. There were no objective complete or partial responses in either group.Conclusion MDX-447 alone was generally well tolerated, but did not achieve objective tumor responses. The MTD for MDX-447 alone was 30 mg/m(2) weekly. Co-administration of G-CSF with MDX-447 precluded meaningful dose escalation.

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  • 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 [12]

  • 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 [12]

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Authors
Fury, M. G., Lipton, A., Smith, K. M., Winston, C. B., & Pfister, D. G.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • Penn State Milton S. Hershey Medical Center (US)
Corresponding author
Pfister, David G.
ORCID
Venue
Cancer Immunology, Immunotherapy
Publisher
Springer Science and Business Media LLC
Published
2007-06-30
Volume
57
Issue
2
Pages
155-163
ISSN
  • 0340-7004 (ISSN-L)
  • 1432-0851
DOI
10.1007/s00262-007-0357-5
PMC
PMC11030736
OpenAlex
W2006885022
Cited by
87
References
26
Citations by year
2026: 2 · 2025: 3 · 2024: 3 · 2023: 2 · 2022: 2 · 2021: 6 · 2020: 3 · 2019: 3 · 2018: 4 · 2017: 6 · 2016: 4 · 2015: 8 · 2014: 1 · 2013: 5 · 2012: 10
FWCI
4.25
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Cancer Immunology Immunotherapy (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords
bispecific antibodies, epidermal growth factor receptor, Fc gamma receptor I, granulocyte colony-stimulating factor, advanced solid tumors, dose-limiting toxicity, maximum tolerated dose, TNF-α, interleukin-6, antibody half-life, hypotension
MeSH terms
Adult, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Dose-Response Relationship, Drug, Female, Flow Cytometry, Humans, Male, Neoplasms, Recombinant Proteins, Granulocyte Colony-Stimulating Factor, Cytokines, Antibodies, Bispecific, Maximum Tolerated Dose, ErbB Receptors

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