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.
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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

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Figure 5

CD46 locus is frequently coamplified with 1q21, and copy gain for either MCL1 or CD46 identifies patients with high CD46 expression.

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CD46 locus is frequently coamplified with 1q21, and copy gain for eithe...
(A) About 30% of newly diagnosed patients demonstrate 1q21 copy gain overlapping the MCL1 locus by array comparative genomic hybridization (CGH), defined as log2 copy number >0.3, and a similar proportion demonstrate amplification along the 1q arm, including CD46 (gray shaded histogram; left axis). High frequency of coamplification along the 1q arm with MCL1 amplification is shown by the purple line and quantified on the right axis (n = 322 patients). (B) Dot plot of log2 CGH values in patient samples indicates that copy numbers for CD46 and MCL1 loci are highly correlated and cluster in regular copy number intervals (n = 322 patients). (C) Mean CD46 transcript expression values (quantified as fragments per kilobase per million mapped reads [FPKM]) for CD46 or MCL1 copy-amplified cohorts, defined by ≥0.3 log2 CGH value, versus nonamplified cohorts indicate high CD46 expression in MCL1 or CD46 amplified patient samples, compared with total population or samples without copy gain (n = 260 patients). Data represent mean ± 95% CI. One-way ANOVA with Tukey’s multiple comparison correction, **P < 0.01, ***P < 0.001, ****P < 0.0001.