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

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 5

CD46 gene expression and genomic change in mCRPC.

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CD46 gene expression and genomic change in mCRPC. (A) Compared with prim...
(A) Compared with primary tumor, mCRPC patient samples show increased CD46 genomic gain/amplification (7.16% ± 2.83% for primary vs. 37.60% ± 7.70% for metastasis). Data are from a public database (http://www.cbioportal.org). Studies were conducted by multiple centers, as indicated. The number of patient samples in each dataset is indicated. MSKCC, Memorial Sloan Kettering Cancer Center; BROAD, Broad Institute; TCGA, The Cancer Genome Atlas; FHCRC, Fred Hutchinson Cancer Research Center; MICH, University of Michigan; SU2C, Stand Up To Cancer; WCM, Weill Cornell Medicine. (B) Prostate cancer patients who have undergone CD46 genomic gain/amplification show significantly higher levels of CD46 mRNA expression. ***P < 0.001 (P = 0.0005). Student’s t test, unpaired 2-tailed. (C) In mCRPC adenocarcinoma, CD46 is homogeneously overexpressed, and at a level significantly higher than that of PSMA. *P < 0.05 (P = 0.040). Student’s t test, paired, 2-tailed. The analysis was performed on the dataset generated by one center (41). Due to differences in data format, we could not perform a combined analysis using datasets from all centers. (D) CD46 mRNA is overexpressed across prostate cancer subtypes (adenocarcinoma [Adeno] and neuroendocrine-like subtypes; no significant difference). SCNC, small cell/neuroendocrine carcinoma. (E) Abiraterone-resistant patients maintained high CD46 mRNA expression (no significant difference between ASI-naive and -resistant). (F) In neuroendocrine mCRPC that is resistant to ASIs, CD46 mRNA level is significantly higher than PSMA. *P < 0.05 (P = 0.030). Student’s t test, paired, 2-tailed. (G) Cell surface CD46 level is upregulated in CTCs compared with WBC and is further upregulated in CTCs from ASI-resistant compared with -naive patients. Abi, abiraterone; Enza, enzalutamide; MFI, median fluorescence intensity. ***P < 0.001. One-way ANOVA, Bonferroni’s multiple comparisons test.