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Treatment parameters modulating regression of human melanoma xenografts by an antibody–drug conjugate (CR011-vcMMAE) targeting GPNMB.
- Source :
-
Cancer Chemotherapy & Pharmacology . Sep2007, Vol. 60 Issue 3, p423-435. 13p. 2 Charts, 6 Graphs. - Publication Year :
- 2007
-
Abstract
- To investigate the pharmacological properties of the CR011-vcMMAE fully human antibody–drug conjugate (ADC), such as dose titrations, quantitation of the time (days) to complete regression, pharmacokinetics, and schedule dependency. Our prior study characterized a fully human antibody to GPNMB covalently linked to monomethylauristatin E, CR011-vcMMAE, and further demonstrated cell surface staining of melanoma lines susceptible to the immunoconjugate’s cytotoxicity (Clin Cancer Res 2005; 12(4): 1373–1382). The human SK-MEL-2 and SK-MEL-5 melanoma xenografts were used in athymic mice to assess anti-tumor efficacy. After s.c. implantation, tumors became established (60–100 mg), and treatment commenced by i.v. injection of the immunoconjugate or vinblastine or paclitaxel. Short-term anti-tumor effects (inhibition of tumor growth) and long-term effects (complete regression) were observed. CR011-vcMMAE induced regression of established human SK-MEL-2 and SK-MEL-5 xenografts at doses from 1.25 to 80 mg/kg treatment when administered intravenously every 4 days (4 treatments); strikingly, regressions were not associated with re-growth during the observation period (200 days). The disappearance rate of implants was dose dependent (minimum time, 18.5 days). Detectable serum CR011-vcMMAE ≥1 μg/mL (∼0.01 μM) was observed for >30 days post-dose; CR011-vcMMAE showed an elimination half-life of 10.3 days. A low volume of distribution suggested that CR011-vcMMAE was confined to blood and interstitial fluid. CR011-vcMMAE could be delivered by either a single bolus dose or by intermittent dosing (i.e., every 1, 2, 4, 8, or 16 days) with no discernible differences in the proportion of tumor-free survivors, indicating a lack of schedule dependency. The antibody–drug conjugate produced complete regressions, but the equivalent doses of free monomethylauristatin E or unconjugated antibody did not show anti-tumor effects. In addition, decreases in plasma tumor-derived human interleukin-8 coincided with tumor nodule disappearance. Short-term anti-tumor effects and long-term effects (complete regression) were observed with CR011-vcMMAE, but not with the reference agents. These results suggest that CR011-vcMMAE may provide therapeutic benefit in malignant melanoma. [ABSTRACT FROM AUTHOR]
- Subjects :
- *TUMORS
*XENOGRAFTS
*MELANOMA
*PHARMACOKINETICS
*PACLITAXEL
*IMMUNOGLOBULINS
Subjects
Details
- Language :
- English
- ISSN :
- 03445704
- Volume :
- 60
- Issue :
- 3
- Database :
- Academic Search Index
- Journal :
- Cancer Chemotherapy & Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 25382257
- Full Text :
- https://doi.org/10.1007/s00280-007-0490-z