A Phase II, Open Label, Multiple Center Study of huC242-DM4 Given as an Intravenous Infusion Once Every Three Weeks to Patients With Metastatic Gastric or Gastroesophageal Junction Carcinomas

To assess the response rate of huC242-DM4 given as an intravenous infusion to patients with metastatic or locally advanced gastric or gastroesophageal junction cancer.

Start Date01 May 2007

Sponsor / Collaborator

ImmunoGen, Inc.

NCT00352131

/ CompletedPhase 1

A Phase I Study to Assess the Safety and Pharmacokinetics of huC242-DM4 Administered as a Single Intravenous Infusion Once Every Three Weeks to Subjects With Solid Tumors

RATIONALE: Monoclonal antibodies, such as maytansinoid DM4-conjugated humanized monoclonal antibody huC242, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them.
PURPOSE: This phase I trial is studying the side effects and best dose of maytansinoid DM4-conjugated humanized monoclonal antibody huC242 in treating patients with solid tumors that cannot be removed by surgery or have spread to other parts of the body.

Start Date01 Feb 2005

Sponsor / Collaborator

ImmunoGen, Inc.

100 Clinical Results associated with CanAg

100 Translational Medicine associated with CanAg

0 Patents (Medical) associated with CanAg

Literatures (Medical) associated with CanAg

01 Jun 2015·Molecular PharmaceuticsQ2 · MEDICINE

Sensitive ELISA Method for the Measurement of Catabolites of Antibody–Drug Conjugates (ADCs) in Target Cancer Cells

Q2 · MEDICINE

Article

Author: Singh, Rajeeva ; Salomon, Paulin L.

A new, sensitive ELISA method has been developed which measures catabolites in cells and media upon processing of antibody-drug conjugates (ADCs) by target cancer cells. This ELISA method, exemplified for maytansinoid ADCs, uses competitive inhibition by a maytansinoid analyte of the binding of biotinylated antimaytansine antibody to an immobilized BSA-maytansinoid conjugate. Synthetic standards of several maytansinoid catabolites derived from ADCs with different linkers were tested and showed similar inhibition curves, with an EC50 of about 0.1 nM (0.03 pmol in an assay volume of 0.25 mL). This high sensitivity allowed quantification of catabolites from a methanolic cell extract and from the medium, generated from an ADC in 1 day using only about 1 million cells. The processing of anti-EpCAM and anti-CanAg ADCs with noncleavable linker (SMCC-DM1), disulfide linker (SPDB-DM4), and charged sulfonate-bearing disulfide linker (sulfo-SPDB-DM4), each containing an average of about four maytansinoid molecules per antibody, were compared in colon cancer cell lines (COLO 205 and HT-29). An 8-10-fold higher total level of catabolite was observed for anti-CanAg ADCs than for anti-EpCAM ADCs upon processing by COLO 205 cells, consistent with a higher cell-surface expression of CanAg. In a multidrug resistant HCT-15 colon cancer cell line, the anti-EpCAM-SPDB-DM4 linker conjugate was not cytotoxic and showed a significantly lower level of catabolite within cells compared to that in medium, presumably due to Pgp-mediated efflux of the nonpolar DM4 catabolite. In contrast, sulfo-SPDB-DM4 and SMCC-DM1 linker conjugates were cytotoxic, which correlated with higher amounts of catabolites found within the HCT-15 cells relative to amounts in medium. In a nonmultidrug resistant HT-29 cell line, the anti-EpCAM-SPDB-DM4 linker conjugate was cytotoxic, with most of the catabolite found in cells and little in the medium. In conclusion, this highly sensitive ELISA method for measurement of ADC catabolite is convenient for screening multiple ADC parameters such as linkers and antibodies in a number of cell lines, does not require concentration of sample or extraction of media, and is complementary to other reported methods such as radiolabeling of ADCs or mass spectrometry.

01 Nov 2011·Clinica Chimica ActaQ3 · MEDICINE

Comparison of three assays for quantifying S-100B in serum

Q3 · MEDICINE

Article

Author: David G. Grenache ; J. Alan Erickson

BACKGROUNDSerum S-100B has clinical value in monitoring malignant melanoma and in monitoring and predicting outcomes in patients with traumatic brain injury.METHODSAnalytical performance characteristic and split-sample method comparison studies for three commercial S-100B immunoassays (CanAg® S100, Sangtec® 100, YK150 Human S-100 β) were performed. Reference intervals (97.5th percentile) for each assay were established by non-parametric analysis of results from healthy volunteers.RESULTSLinearity results were slope=1.014, intercept=65.1, r(2)=0.999 for the Sangtec assay; slope=1.038, intercept=31.1, r(2)=0.999 for the CanAg assay; slope=1.123, intercept=-105.4, r(2)=0.997 for the YK150 assay. Within-run CVs were ≤5.7, ≤6.3 and ≤10.8 for the Sangtec, CanAg and YK150 ELISAs, respectively. Between-run CVs were ≤11.3, ≤5.9 and ≤9.5, respectively. Upper reference interval limits of 141, 96 and 735 ng/l S-100B were established for the Sangtec, CanAg and YK150 ELISAs, respectively. Deming regression generated the following: CanAg vs. Sangtec, slope=0.339, intercept=24.1, r(2)=0.932; YK150 vs. Sangtec, slope=0.266, intercept=-140.0, r(2)=0.690; YK150 vs. CanAg, slope=1.376, intercept=-13.1, r(2)=0.860.CONCLUSIONSThe configurations, procedures and performance characteristics of the Sangtec and CanAg S-100B ELISAs are comparable and better than those of the YK150 assay. Poor agreement and large biases prevent interchangeable use of results.

20 Jan 2010·Bioconjugate ChemistryQ2 · CHEMISTRY

Tumor Delivery and In Vivo Processing of Disulfide-Linked and Thioether-Linked Antibody−Maytansinoid Conjugates

Q2 · CHEMISTRY

Article

Author: Singh, Rajeeva ; Audette, Charlene ; Wilhelm, Sharon D. ; Whiteman, Kathleen ; Widdison, Wayne C. ; Erickson, Hans K. ; Mayo, Michele F.

Antibody-drug conjugates (ADCs) are designed to eradicate cancer cells that express the target antigen on their cell surface. A key component of an ADC is the linker that covalently connects the cytotoxic agent to the antibody. Several antibody-maytansinoid conjugates prepared with disulfide-based linkers such as those targeting the CanAg antigen have been shown to display more activity in preclinical mouse xenograft models than corresponding conjugates prepared with uncleavable thioether-based linkers. To investigate how the linker influences delivery and activation of antibody-maytansinoid conjugates, we isolated and characterized the [(3)H]maytansinoids from CanAg-positive tumor tissues following a single intravenous administration of 300 microg/kg (based on maytansinoid dose) of anti-CanAg antibody (huC242)-(3)H-maytansinoid conjugates prepared with cleavable disulfide linkers and an uncleavable thioether linker. We identified three target-dependent tumor metabolites of the disulfide-linked huC242-SPDB-DM4, namely, lysine-N(epsilon)-SPDB-DM4, DM4, and S-methyl-DM4. We found similar metabolites for the less hindered disulfide-linked huC242-SPP-DM1 conjugate with the exception that no S-methyl-DM1 was detected. The sole metabolite of the uncleavable thioether-linked huC242-SMCC-DM1 was lysine-N(epsilon)-SMCC-DM1. The AUC for the metabolites of huC242-SMCC-DM1 at the tumor over 7 d was about 2-fold greater than the corresponding AUC for the metabolites of the disulfide-linked conjugates. The lipophilic metabolites of the disulfide-linked conjugates were found to be nearly 1000 times more cytotoxic than the more hydrophilic lysine-N(epsilon)-linker-maytansinoids in cell-based viability assays when added extracellularly. The cell killing properties associated with the lipophilic metabolites of the disulfide-linked conjugates (DM4 and S-methyl-DM4, and DM1) provide an explanation for the superior in vivo efficacy that is often observed with antibody-maytansinoid conjugates prepared with disulfide-based linkers in xenograft mouse models.

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