ISSN:
0730-2312
Keywords:
Life and Medical Sciences
;
Cell & Developmental Biology
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
Notes:
A Phase I clinical trial with a bispecific monoclonal antibody (BsAb) (anti HER-2/neu × anti CD 64) is currently being conducted in patients with Stage IV breast carcinoma or Stage III/IV ovarian carcinoma who are refractory to standard therapy and who overexpress the HER-2/neu antigen as determined by immunohistochemistry. The trial is a hybrid Phase Ia/Ib trial in which the principal endpoints are toxicity, determination of the maximum tolerated dose, biological efficacy, and BsAb pharmacokinetics. Clinical efficacy will be assessed employing standard cancer and leukemia group B (CALGB) criteria to categorize tumor responses. The BsAb, designated MDX-210, is a Fab′ × Fab′ construct which is designed to enhance tumor penetration owing to its relatively small molecular size (approximately 100 kD). CD 64 (FcγRI) is a high affinity Fc receptor for IgG and potent cytotoxic trigger molecule for monocytes, macrophages, IFN-γ-activated neutrophils, and G-CSF-activated neutrophils. The anti CD 64 employed in this study is uniquely constructed to bind to an epitope outside the normal ligand binding site and thus should not be blocked in vivo by the relatively high levels of human IgG. Her-2/neu is overexpressed in human bresat carcinomas with poor prognosis. In vitro studies with MDX-210 have shown effective killing of tumor cell lines that express the HER-2/neu antigen. Eight patients have been treated to date. The dosage levels tested to date are 0.35, 1.0, and 3.5 mg/m2 infused intravenously at 6.0 mg/hour. Infusion of MDX-210 has been well-tolerated by all patients. The principal toxicities have been Grade I/II fevers and malaise that have fully resolved by 12 hours post infusion. Evidence of immunological activity has been observed even at the lowest dose tested. Plasma tumor necrosis factor alpha (TNFα) increased to as high as 500 picogram/ml in 5 of 6 patients tested. Peripheral blood monocytopenia, either preceding or concurrent with elevations of plasma TNFα, is consistent with binding of MDX-210 to both immune effector cells and target breast tumor cells. Significant dose-dependent in vivo binding of MDX-210 to CD 64 has been observed for more than 24 hours post infusion. It has been demonstrated in cell culture studies that MDX-210 triggers release of TNFα from immune effector cells in the presence, but not in the absence, of target tumor cells. The observation that MDX-210 is immunologically active at non-toxic doses forms the basis for considering MDX-210 as a candidate chemotherapeutic drug for recurrent or secondary breast cancers.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1002/jcb.240531157
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