Authors: Sherbenou DW [1], Aftab BT [1][2], Su Y, Behrens CR [3], Wiita A, Logan AC [2][4], Acosta-Alvear D, [5][6] Hann BC [2], Walter P [5][6], Shuman MA [1][2], Wu X [7], Atkinson JP [7], Wolf JL [1][2], Martin TG [1][2], Liu B [2][3].
Title: Antibody-drug conjugate targeting CD46 eliminates multiple myeloma cells.
Published in: J Clin Invest. 2016 Nov 14. pii: 85856. doi: 10.1172/JCI85856. [Epub ahead of print]
Keywords: Hematology, Original Research, Therapeutics, Multiple Myeloma
Multiple myeloma is incurable by standard approaches because of inevitable relapse and development of treatment resistance in all patients. In our prior work, we identified a panel of macropinocytosing human monoclonal antibodies against CD46, a negative regulator of the innate immune system, and constructed antibody-drug conjugates (ADCs).
In this report, we show that an anti-CD46 ADC (CD46-ADC) potently inhibited proliferation in myeloma cell lines with little effect on normal cells. CD46-ADC also potently eliminated myeloma growth in orthometastatic xenograft models.
In primary myeloma cells derived from bone marrow aspirates, CD46-ADC induced apoptosis and cell death, but did not affect the viability of nontumor mononuclear cells. It is of clinical interest that the CD46 gene resides on chromosome 1q, which undergoes genomic amplification in the majority of relapsed myeloma patients. We found that the cell surface expression level of CD46 was markedly higher in patient myeloma cells with 1q gain than in those with normal 1q copy number.
Thus, genomic amplification of CD46 may serve as a surrogate for target amplification that could allow patient stratification for tailored CD46-targeted therapy. Overall, these findings indicate that CD46 is a promising target for antibody-based treatment of multiple myeloma, especially in patients with gain of chromosome 1q.
Author affiliation:
[1] Department of Medicine, UCSF, San Francisco, California, USA.
[2] UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.
[3] Department of Anesthesia, [4] Department of Laboratory Medicine, and [5] Department of Biochemistry and Biophysics, UCSF, San Francisco, California, USA.
[6] The Howard Hughes Medical Institute, UCSF, California, USA.
[7] Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
Conflict of interest:
B. Liu, Y. Su, and C.R. Behrens hold patents (PCT/US2015/049492) on novel internalizing anti-CD46 human monoclonal antibodies and therapeutic targeting of cancers overexpressing CD46. B. Liu holds stocks in a biotech company that licensed the patented technology from the University of California. The company did not sponsor this study.
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