Antibody-drug conjugate targeting CD46 eliminates multiple myeloma cells
Daniel W. Sherbenou, … , Thomas G. Martin, Bin Liu
Daniel W. Sherbenou, … , Thomas G. Martin, Bin Liu
Published November 14, 2016
Citation Information: J Clin Invest. 2016;126(12):4640-4653. https://doi.org/10.1172/JCI85856.
View: Text | PDF
Research Article Hematology

Antibody-drug conjugate targeting CD46 eliminates multiple myeloma cells

Abstract

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.

Authors

Daniel W. Sherbenou, Blake T. Aftab, Yang Su, Christopher R. Behrens, Arun Wiita, Aaron C. Logan, Diego Acosta-Alvear, Byron C. Hann, Peter Walter, Marc A. Shuman, Xiaobo Wu, John P. Atkinson, Jeffrey L. Wolf, Thomas G. Martin, Bin Liu

×

Figure 7

Ex vivo evaluation of CD46-ADC in patient sample MM cells.

Options: View larger image (or click on image) Download as PowerPoint
Ex vivo evaluation of CD46-ADC in patient sample MM cells. (A) Internali...
(A) Internalization of CD46 antibody (red) into MM patient cells ex vivo. CD138 positively selected cells from a patient with MM were incubated with CD46 antibody for 18 hours and costained with anti-LAMP1 antibody (green) and Hoechst dye (blue). Representative cell illustrates the intracellular localization of CD46 antibody, partially colocalizing with the late lysosomal marker LAMP1 (left). CD138-negative cells were treated in the same fashion and showed minimal binding of CD46 antibody without discernible internalization (right). Images were taken using a digital confocal microscope (FluoView, Olympus) at ×60 magnification. (B) CD46-ADC depletes the number of CD138-positive, CD38-positive MM cells more potently in patients with amp1q21. Mean values with SEM are shown for CD46-ADC treatment of 2 patient samples with amp1q21 (red lines) and 2 patient samples with normal 1q21 (blue lines), compared with cells treated with nonbinding control ADC (black). (C) CD46-ADC does not affect the number of NPCs up to a concentration of 100 nM (n = 4) (data represent mean ± SEM).