Cancer Chemotherapy and Pharmacology

, Volume 60, Issue 3, pp 423–435

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

  • Vincent A. Pollack
  • Enrique Alvarez
  • Kam Fai Tse
  • Michael Y. Torgov
  • Sam Xie
  • Suresh G. Shenoy
  • John R. MacDougall
  • Sharon Arrol
  • Haihong Zhong
  • Robert W. Gerwien
  • William F. Hahne
  • Peter D. Senter
  • Michael E. Jeffers
  • Henri S. Lichenstein
  • William J. LaRochelle
Original Article

DOI: 10.1007/s00280-007-0490-z

Cite this article as:
Pollack, V.A., Alvarez, E., Tse, K.F. et al. Cancer Chemother Pharmacol (2007) 60: 423. doi:10.1007/s00280-007-0490-z

Abstract

Purpose

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 ≥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.

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.

Keywords

GPNMB Melanoma CR011-vcMMAE Antibody–drug conjugate (ADC) Xenograft 

Abbreviations

CR

Complete regression

C.V.

Coefficient of variation

GPNMB

Glycoprotein NMB

MMAE

Monomethylauristatin E

MTD

Maximum tolerated dose

ROA

Route of administration

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Vincent A. Pollack
    • 1
  • Enrique Alvarez
    • 1
  • Kam Fai Tse
    • 1
  • Michael Y. Torgov
    • 1
  • Sam Xie
    • 1
  • Suresh G. Shenoy
    • 1
  • John R. MacDougall
    • 1
  • Sharon Arrol
    • 1
  • Haihong Zhong
    • 1
  • Robert W. Gerwien
    • 1
  • William F. Hahne
    • 1
  • Peter D. Senter
    • 2
  • Michael E. Jeffers
    • 1
  • Henri S. Lichenstein
    • 1
  • William J. LaRochelle
    • 1
  1. 1.Department of Preclinical DevelopmentCuraGen CorporationBranfordUSA
  2. 2.Seattle Genetics, IncBothellUSA

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