Treatment parameters modulating regression of human melanoma xenografts by an antibody-drug conjugate (CR011-vcMMAE) targeting GPNMB.
OBJECTIVE
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).


METHODS
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.


RESULTS
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 >or=1 microg/mL (approximately 0.01 microM) 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.


CONCLUSIONS
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.
Pollack
Vincent A
VA
Department of Preclinical Development, CuraGen Corporation, 322 E. Main St, Branford, CT 06405, USA. vpollack@curagen.com
Alvarez
Enrique
E
Tse
Kam Fai
KF
Torgov
Michael Y
MY
Xie
Sam
S
Shenoy
Suresh G
SG
MacDougall
John R
JR
Arrol
Sharon
S
Zhong
Haihong
H
Gerwien
Robert W
RW
Hahne
William F
WF
Senter
Peter D
PD
Jeffers
Michael E
ME
Lichenstein
Henri S
HS
LaRochelle
William J
WJ
D000328:Adult; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000187:drug effects*; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy; D014183:Transplantation, Heterologous
C503042:GPNMB protein, human; D000922:Immunotoxins; D008562:Membrane Glycoproteins