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

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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.

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Notes

  1. US National Institutes of Health, Physicians Data Query, PDQ http://www.cancer.gov

Abbreviations

CR:

Complete regression

C.V.:

Coefficient of variation

GPNMB:

Glycoprotein NMB

MMAE:

Monomethylauristatin E

MTD:

Maximum tolerated dose

ROA:

Route of administration

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Acknowledgments

We wish to thank Michael Gallo and Gadi Gazit-Bornstein (Abgenix Biopharma, Fremont, CA), and Damon Meyer (Seattle Genetics, Inc., Bothell, WA) who contributed significantly to design of the ADC. For expertise in animal experimentation, we are grateful to Donald Dykes and Murray Stackhouse of Southern Research Institute (Birmingham, AL), as well as Michael Wick, Jennifer Marty and Marla Lear of the Institute for Drug Development (San Antonio, TX). We are also indebted to Bruce Mico for pharmacokinetic analysis, Steven Henck for helpful discussions and to Traci Mansfield for program management.

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Authors and Affiliations

  1. Department of Preclinical Development, CuraGen Corporation, 322 E. Main St, Branford, CT, 06405, USA

    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, Michael E. Jeffers, Henri S. Lichenstein & William J. LaRochelle

  2. Seattle Genetics, Inc, Bothell, WA, USA

    Peter D. Senter

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  1. Vincent A. Pollack
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Correspondence to Vincent A. Pollack.

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Pollack, V.A., Alvarez, E., Tse, K.F. et al. Treatment parameters modulating regression of human melanoma xenografts by an antibody–drug conjugate (CR011-vcMMAE) targeting GPNMB. Cancer Chemother Pharmacol 60, 423–435 (2007). https://doi.org/10.1007/s00280-007-0490-z

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