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 4

Dose- and schedule-dependent in vivo activity of CD46-ADC in a disseminated MM xenograft model with MM1.S cell line.

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Dose- and schedule-dependent in vivo activity of CD46-ADC in a dissemina...
(A) Study treatment scheme. MM1.S-Luc cells were injected and established for 10 days. Starting on day 11 (treatment day 1), a total of 4 injections were given twice a week at the concentrations shown for all groups, except for the single-dose group. For each group, n= 5 mice per group. (B) BLI rapidly increased in negative control groups, but decreased to undetectable levels with all CD46-ADC treatment regimens (top views, dorsal; bottom views, ventral). Relapse of disease activity was observed progressively at single-dose 4-mg/kg and low-dose 0.8-mg/kg groups. No detectable BLI signal and no relapse after treatment was observed for the 4-mg/kg, 4-dose schedule, suggesting complete elimination of MM1.S xenografts in vivo. BLI in photons per second per cm2 per steradian (p/s/cm2/sr) was translated to color to indicate disease activity by the legend shown at far right. Tx, treatment; mAb, naked antibody. (C) Kaplan-Meier survival curves of NSG xenografts transplanted with MM1.S-Luc and treated with varying dose levels of CD46-ADC.