title: 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.forename: Daniel W
authors.initials: DW
authors.lastname: Sherbenou
authors.forename: Blake T
authors.initials: BT
authors.lastname: Aftab
authors.forename: Yang
authors.initials: Y
authors.lastname: Su
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Behrens
authors.forename: Arun
authors.initials: A
authors.lastname: Wiita
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Logan
authors.forename: Diego
authors.initials: D
authors.lastname: Acosta-Alvear
authors.forename: Byron C
authors.initials: BC
authors.lastname: Hann
authors.forename: Peter
authors.initials: P
authors.lastname: Walter
authors.forename: Marc A
authors.initials: MA
authors.lastname: Shuman
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Wu
authors.forename: John P
authors.initials: JP
authors.lastname: Atkinson
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wolf
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Martin
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000912:Antibodies, Neoplasm / Q000276:immunology / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics / Q000276:immunology; D018628:Gene Dosage / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates / Q000276:immunology / Q000494:pharmacology*; D051916:Membrane Cofactor Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; C497857:CD46 protein, human; D018796:Immunoconjugates; D051916:Membrane Cofactor Protein