CD46–ADC Reduces the Engraftment of Multiple Myeloma Patient-Derived Xenografts

Abstract

An antibody–drug conjugate (ADC) targeting CD46 conjugated to monomethyl auristatin has a potent anti-myeloma effect in cell lines in vitro and in vivo, and patient samples treated ex vivo. Here, we tested if CD46–ADC may have the potential to target MM-initiating cells (MM-ICs). CD46 expression was measured on primary MM cells with a stem-like phenotype. A patient-derived xenograft (PDX) model was implemented utilizing implanted fetal bone fragments to provide a humanized microenvironment. Engraftment was monitored via serum human light chain ELISA, and at sacrifice via bone marrow and bone fragment flow cytometry. We then tested MM regeneration in PDX by treating mice with CD46–ADC or the nonbinding control–ADC. MM progenitor cells from patients that exhibit high aldehyde dehydrogenase activity also have a high expression of CD46. In PDX, newly diagnosed MM patient samples engrafted significantly more compared to relapsed/refractory samples. In mice transplanted with newly diagnosed samples, CD46–ADC treatment showed significantly decreased engraftment compared to control–ADC treatment. Our data further support the targeting of CD46 in MM. To our knowledge, this is the first study to show preclinical drug efficacy in a PDX model of MM. This is an important area for future study, as patient samples but not cell lines accurately represent intratumoral heterogeneity.

The complement regulatory protein CD46 serves as a novel biomarker for cervical cancer diagnosis and prognosis evaluation

“…However, the role of sCD46 forms in the development of cervical cancer, and its mechanism of action remains unknown. Currently, targeting CD46 as a therapeutic strategy in cancers has attracted increasing attention to overcome the poor therapeutic efficacy of conventional cancer treatments, including the inhibition of CD46 expression (11,(29)(30)(31), neutralizing (blocking) mAbs (30)(31)(32), anti-CD46 antibody−drug conjugates (CD46-ADCs) (21, [33][34][35][36], and oncolytic virotherapy (37-42). It has been demonstrated that targeted downregulation of CD46 expression by siRNA in vitro increases the sensitivity of cancer cells to CDC (11).…”

“…Sherbenou et al (34) suggested that CD46-ADC has the potential to be an effective treatment for multiple myeloma (MM), especially in patients with a gain of chromosome 1q. The curative potential of CD46-ADC has been confirmed in a patient-derived xenograft (PDX) model (35). In addition, exploratory toxicology studies of CD46-ADC in nonhuman primates have demonstrated an acceptable safety profile (21).…”

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“…However, the role of sCD46 forms in the development of cervical cancer, and its mechanism of action remains unknown. Currently, targeting CD46 as a therapeutic strategy in cancers has attracted increasing attention to overcome the poor therapeutic efficacy of conventional cancer treatments, including the inhibition of CD46 expression (11,(29)(30)(31), neutralizing (blocking) mAbs (30)(31)(32), anti-CD46 antibody−drug conjugates (CD46-ADCs) (21, [33][34][35][36], and oncolytic virotherapy (37-42). It has been demonstrated that targeted downregulation of CD46 expression by siRNA in vitro increases the sensitivity of cancer cells to CDC (11).…”

“…Sherbenou et al (34) suggested that CD46-ADC has the potential to be an effective treatment for multiple myeloma (MM), especially in patients with a gain of chromosome 1q. The curative potential of CD46-ADC has been confirmed in a patient-derived xenograft (PDX) model (35). In addition, exploratory toxicology studies of CD46-ADC in nonhuman primates have demonstrated an acceptable safety profile (21).…”