Specific Targeting, Biodistribution, and Lack of Immunogenicity of Chimeric Anti-GD3 Monoclonal Antibody KM871 in Patients With Metastatic Melanoma: Results of a Phase I Trial

Scott, Andrew M.; Lee, Fook-Thean; Hopkins, Wendie; Cebon, Jonathan; Wheatley, Jennifer M.; Liu, Zhanqi; Smyth, Fiona E; Murone, Carmel; Sturrock, Susan; MacGregor, Duncan; Hanai, Nobuo; Inoue, Kengo; Yamasaki, Motoo; Brechbiel, Martin W.; Davis, Ian D.; Murphy, Roger; Hannah, Anthony; Lim-Joon, Michael; Chan, Tsung-Han; Chong, Geoffrey; Ritter, Gerd; Hoffman, Eric W.; Burgess, Antony W.; Old, Lloyd J.

doi:10.1200/jco.2001.19.19.3976

Cited by 73 publications

(34 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Whereas this difference may be explained by the small number of patients studied, the longer sampling time points for the ch806 ELISA would support this value as being more representative of true ch806 clearance. The pharmacokinetic values for ch806 are comparable with other chimeric antibodies reported to date (9,11), and supports a weekly dosing schedule of ch806.…”

Section: Discussionsupporting

confidence: 62%

“…Linear relationships also were observed for AUC, C max , and C min , with dose levels Ͼ10 mg/m 2 achieving trough serum concentrations Ͼ1 g/ml. The V1, CL, t 1/2 ␣, and t 1/2 ␤ values were consistent between dose levels and in keeping with typical IgG1 human antibodies (8,9,11). The clearance of ch806 was also determined to be slower when ELISA ch806 calculations were compared with 111 In-ch806 measurements.…”

Section: Discussionmentioning

confidence: 81%

“…Clinical grade ch806 was produced in the Biological Production Facility of the Ludwig Institute for Cancer Research. The antibody ch806 was labeled with 111 In (MDS Nordion, Ottawa, ON, Canada) via the bifunctional metal ion chelate CHX-AЉ-DTPA according to methods described previously (10,11).…”

Section: Methodsmentioning

confidence: 99%

“…For this reason, our first-in-human clinical trials has emphasized the following endpoints: tumor targeting, biodistribution, and pharmacokinetics of trace-radiolabeled antibody. Determining these parameters has been our approach in the clinical evaluation in five antigenic systems: A33 (7,8), G250 (9), Le y (10), GD3 (11), and FAP␣ (12,13). In our opinion, information gained in this way from in vivo specificity analysis is essential for rational development of monoclonal antibodies for therapy, particularly therapies based on monoclonal antibodies as delivery systems for radioisotopes, toxins, or other cytotoxic strategies.…”

mentioning

confidence: 99%

See 3 more Smart Citations

A phase I clinical trial with monoclonal antibody ch806 targeting transitional state and mutant epidermal growth factor receptors

Scott

Lee

Tebbutt

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

201

136

View full text Add to dashboard Cite

An array of cell-surface antigens expressed by human cancers have been identified as targets for antibody-based therapies. The great majority of these antibodies do not have specificity for cancer but recognize antigens expressed on a range of normal cell types (differentiation antigens). Over the past two decades, our group has analyzed thousands of mouse monoclonal antibodies for cancer specificity and identified a battery of antibodies with limited representation on normal human cells. The most tumor-specific of these antibodies is 806, an antibody that detects a unique epitope on the epidermal growth factor receptor (EGFR) that is exposed only on overexpressed, mutant, or ligand-activated forms of the receptor in cancer. In vitro immunohistochemical specificity analysis shows little or no detectable 806 reactivity with normal tissues, even those with high levels of wild-type (wt)EGFR expression. Preclinical studies have demonstrated that 806 specifically targets a subset of EGFR expressed on tumor cells, and has significant anti-tumor effects on human tumor xenografts, primarily through abrogation of signaling pathways. The present clinical study was designed to examine the in vivo specificity of a chimeric form of mAb 806 (ch806) in a tumor targeting/biodistribution/pharmacokinetic analysis in patients with diverse tumor types. ch806 showed excellent targeting of tumor sites in all patients, no evidence of normal tissue uptake, and no significant toxicity. These in vitro and in vivo characteristics of ch806 distinguish it from all other antibodies targeting EGFR.

show abstract

Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 81%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

A phase I clinical trial with monoclonal antibody ch806 targeting transitional state and mutant epidermal growth factor receptors

Scott

Lee

Tebbutt

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

201

136

View full text Add to dashboard Cite

show abstract

“…This antibody, KM871, has enhanced antitumor activities and more favorable immune properties. In a preclinical study, intravenous injection of KM871 markedly suppressed tumor growth and radiolabeled KM871 efficiently targeted the tumor site in a nude mouse model (22). Recent preliminary clinical data indicate that KM871 has potential for the treatment of metastatic melanoma (23).…”

Section: Gd3 In Cancer Therapymentioning

confidence: 99%

The Ganglioside GD3 as the Greek Goddess Hecate: Several Faces Turned Towards as Many Directions

Malisan

Testi

2005

IUBMB Life (International Union of Biochemistry and Molecular B

View full text Add to dashboard Cite

SummaryThe disialoganglioside GD3 can mediate biological functions as diverse as proliferation, differentiation, and apoptosis. Since intracellular level of GD3 is crucial for the cell, understanding the mechanisms by which GD3 metabolism is tightly regulated seems of particular importance. GD3 can be enlisted among the most potent natural inducers of mitochondrial damage and apoptosis. However, some cell types resist GD3-mediated mitochondrial damage through complex mechanisms which are beginning to be unveiled. IUBMB Life, 57: 477 -482, 2005

show abstract

Treatment of Melanoma

Hofmann¹,

Sterry²,

Schwartz³

2008

Skin Cancer

View full text Add to dashboard Cite

Specific Targeting, Biodistribution, and Lack of Immunogenicity of Chimeric Anti-GD3 Monoclonal Antibody KM871 in Patients With Metastatic Melanoma: Results of a Phase I Trial

Abstract: This study is the first to demonstrate the biodistribution and specific targeting of an anti-GD3 antibody to metastatic melanoma in patients. The long half-life and lack of immunogenicity of KM871 makes this antibody an attractive potential therapy for patients with metastatic melanoma.

Cited by 73 publications

References 23 publications

A phase I clinical trial with monoclonal antibody ch806 targeting transitional state and mutant epidermal growth factor receptors

A phase I clinical trial with monoclonal antibody ch806 targeting transitional state and mutant epidermal growth factor receptors

The Ganglioside GD3 as the Greek Goddess Hecate: Several Faces Turned Towards as Many Directions

Treatment of Melanoma

Contact Info

Product

Resources

About