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Targeting CD46 for both adenocarcinoma and neuroendocrine prostate cancer
Yang Su, … , Eric J. Small, Bin Liu
Yang Su, … , Eric J. Small, Bin Liu
Published September 6, 2018
Citation Information: JCI Insight. 2018;3(17):e121497. https://doi.org/10.1172/jci.insight.121497.
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Research Article Oncology Therapeutics

Targeting CD46 for both adenocarcinoma and neuroendocrine prostate cancer

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Abstract

Although initially responsive to androgen signaling inhibitors (ASIs), metastatic castration-resistant prostate cancer (mCRPC) inevitably develops and is incurable. In addition to adenocarcinoma (adeno), neuroendocrine prostate cancer (NEPC) emerges to confer ASI resistance. We have previously combined laser capture microdissection and phage antibody display library selection on human cancer specimens and identified novel internalizing antibodies binding to tumor cells residing in their tissue microenvironment. We identified the target antigen for one of these antibodies as CD46, a multifunctional protein that is best known for negatively regulating the innate immune system. CD46 is overexpressed in primary tumor tissue and CRPC (localized and metastatic; adeno and NEPC), but expressed at low levels on normal tissues except for placental trophoblasts and prostate epithelium. Abiraterone- and enzalutamide-treated mCRPC cells upregulate cell surface CD46 expression. Genomic analysis showed that the CD46 gene is gained in 45% abiraterone-resistant mCRPC patients. We conjugated a tubulin inhibitor to our macropinocytosing anti-CD46 antibody and showed that the resulting antibody-drug conjugate (ADC) potently and selectively kills both adeno and NEPC cell lines in vitro (sub-nM EC50) but not normal cells. CD46 ADC regressed and eliminated an mCRPC cell line xenograft in vivo in both subcutaneous and intrafemoral models. Exploratory toxicology studies of the CD46 ADC in non-human primates demonstrated an acceptable safety profile. Thus, CD46 is an excellent target for antibody-based therapy development, which has potential to be applicable to both adenocarcinoma and neuroendocrine types of mCRPC that are resistant to current treatment.

Authors

Yang Su, Yue Liu, Christopher R. Behrens, Scott Bidlingmaier, Nam-Kyung Lee, Rahul Aggarwal, Daniel W. Sherbenou, Alma L. Burlingame, Byron C. Hann, Jeffry P. Simko, Gayatri Premasekharan, Pamela L. Paris, Marc A. Shuman, Youngho Seo, Eric J. Small, Bin Liu

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Figure 1

Identification of human CD46 as a target for prostate cancer.

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Identification of human CD46 as a target for prostate cancer.
(A) Verifi...
(A) Verification of CD46 as the target antigen by IP and Western blot analysis using validated anti–human CD46 antibody. Two bands characteristic of human CD46 were seen in IP products from tumor (DU145) but not control nontumorigenic cells (BPH-1). CD46 is known to migrate on SDS-PAGE as 2 bands (27). (B) Verification of target identification by antibody binding to cells ectopically expressing human CD46. CHO-HUCD46: control (Ctrl), CHO-K1 cells transiently transfected with human CD46 expression plasmid without antibody incubation. Ctrl IgG: a nonbinding antibody randomly picked from naive library was incubated with CHO-HUCD46. CD46IgG: UA20 IgG was incubated with CHO-HUCD46 cellsn. (C) Epitope mapping by ectopic expression of CD46 deletion constructions followed by FACS analysis. De1+2, CD46 with Sushi domains 1 and 2 deleted. De1, domain 1 deleted. De2, domain 2 deleted. De3, domain 3 deleted. De4, domain 4 deleted. WtCD46: full-length WT CD46 that was used for normalization of FACS binding data. ***P < 0.001 (P = 0.0002), ****P < 0.0001. One-way ANOVA, Bonferroni’s multiple comparisons test. The experiment was done in triplicate. (D) IHC study of formalin fixed, paraffin-embedded prostate cancer tissues and a normal human tissue array. Top row: primary tumor and mCRPC samples with strong positive staining signals. H score for primary tumor, 211; bone mets (Mets), 295; lymph node mets 202; and bladder mets 276. Bottom row: normal tissues staining. Placental trophoblasts showed positive signals, along with prostate epithelium. Weak staining was seen for kidney and liver. H score for placenta, 167; prostate epithelium, 142; kidney, 52; and liver 12. Scale bars: 150 μm.

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