1560P - Quantitative evaluation of HER2-mediated cellular uptake of the HER2-targeted antibody-liposomal doxorubicin conjugate MM-302 suggests potential fo...

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Translational Research
Presenter Elena Geretti
Citation Annals of Oncology (2016) 27 (6): 526-544. 10.1093/annonc/mdw392
Authors E. Geretti1, C. Espelin1, B. Adiwijaya1, N. Dumont1, S. Coma1, Z. Koncki1, G. Garcia1, T. Bloom1, V. Rimkunas1, J. Reynolds1, K. Campbell1, V. Moyo1, I. Molnar1, P. Lorusso2, K. Miller3, C. Ma4, I.E. Krop5, P. Munster6, T. Wickham1
  • 1Development, Merrimack Pharmaceuticals, Inc., 02139 - Cambridge/US
  • 2Yale School Of Medicine, Yale Cancer Center, New Haven/US
  • 3Oncology, Indiana University Melvin and Bren Simon Cancer Center, 46202 - Indianapolis/US
  • 4Washington University, Washington University School of Medicine, St. Louis/US
  • 5Breast Cancer Treatment Center, Dana Farber Cancer Institute, Boston/US
  • 6Helen Diller Family Comprehensive Cancer Center, Helen Diller Family Comprehensive Cancer Center, San Francisco/US

Abstract

Background

MM-302 is a HER2-targeted antibody–liposomal doxorubicin conjugate designed to target doxorubicin to HER2-expressing tumor cells. MM-302 showed an acceptable safety profile and promising activity in a Phase I study in HER2-positive metastatic breast cancer (NCT01304797), and it is now being evaluated in a Phase II trial in the same setting (NCT02213744). The goal of this work is to determine the correlation between single-cell HER2 expression and liposome uptake on MM-302 patient biopsies as well as on preclinical tumor models.

Methods

Frozen biopsies were collected 3 days post infusion of MM-302 (8-50 mg/m2; alone or in combination with trastuzumab, with or without cyclophosphamide), and stained for PEG (surrogate for MM-302), HER2 and cytokeratin, side-by-side with two cell standard arrays: A PEG array, obtained by cell incubation with increasing amounts of MM-302, and a HER2 array, containing a panel of cell lines at various HER2 levels. The HER2 expression and liposome uptake in individual tumor cells of the human samples was quantified based on the PEG and HER2 fluorescent intensities of the standards. MM-302 cellular delivery was investigated in vivo in IHC 0, 1 + , 2+ and 3+ tumor models.

Results

Uptake of MM-302 into HER2-expressing cells was detected in ∼80% of patient biopsies. Interestingly, HER2 expression within individual samples was found to be heterogeneous, ranging from ∼1 X 105 to over 1 X 106 HER2 receptors per cell. Evaluation of cellular HER2 expression and MM-302 uptake within the same sample revealed that the magnitude of MM-302 tumor cell uptake was comparable across the range of HER2 expression from ∼1 X 105 to over 1 X 106 HER2 receptors per cell. These findings were in line with preclinical in vivo studies showing HER2-mediated delivery of MM-302 to IHC 1 + , 2 + , and 3+ tumors but not to IHC 0 tumors.

Conclusions

Our data suggest that MM-302 effectively targets tumor cells expressing various levels of HER2 in patients' tumors. Hence, in addition to treating HER2-positive patients, MM-302 may be a promising agent for treating patients with intermediate HER2 expression (HER2 IHC 1 + /2 + , FISH-negative).

Clinical trial identification

NCT01304797

Legal entity responsible for the study

Merrimack Pharmaceuticals, Inc.

Funding

Merrimack Pharmaceuticals, Inc.

Disclosure

E. Geretti, C. Espelin, B. Adiwijaya, N. Dumont, S. Coma, G. Garcia, T. Bloom, V. Rimkunas, J. Reynolds, K. Campbell, V. Moyo, I. Molnar, T. Wickham: Stocks ownership from Merrimack Pharmaceuticals, Inc. I.E. Krop: Employment, Leadership, Stock and Other Ownership Interests: immediate family member (Vertex) Consulting or Advisory Role: Amgen Research Funding: Genentech Travel, Accomodations, Expenses: Bayer. All other authors have declared no conflicts of interest.