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.

Manipulation of Cell-Type Selective Antibody Internalization by a Guide-Effector Bispecific Design

“…There are two limitations for those lineage markers: (i) they tend to show decreased or heterogeneous expression in late-stage cancers as they are not functionally required for tumor survival. For example, PSMA expression in late-stage prostate cancer is heterogeneous and is downregulated in androgen-signaling inhibitor-resistant small cell-type (10). (ii) They are often expressed in more than one normal tissue type.…”

“…9). The LNCap-C4-2B was originally obtained from UroCor Inc. and maintained in the laboratory (10). Cells were maintained in DMEM or RPMI1640 supplemented with 10% FBS (Thermo Fisher Scientific), 100 mg/mL penicillin/streptomycin (Axenia BioLogix) at 37 C 5% CO 2 .…”

Complementing the Cancer-Immunity Cycle

“…Upon opsonization of apoptotic cells, factor H induces an anti-inflammatory cytokine profile (61, 62) and a tolerogenic stage (63). CD46, a membrane-bound complement regulatory protein able to interact with C3 activation fragments and found at high levels in some cancer types (64, 65), has also been proposed as a negative regulator of immune recognition (66). Complement proteins are easily detectable in various types of cancer, consistent with complement activation by these tumors (32).…”

Adenovirus Receptor Expression in Cancer and Its Multifaceted Role in Oncolytic Adenovirus Therapy

“…CD46 expression is low or moderate in most normal tissues, but upregulated in many types of cancer [ 42 , 43 ]. One reason for the upregulation might be that CD46 can protect cancer cells from being killed by the complement system [ 44 ].…”

“…One reason for the upregulation might be that CD46 can protect cancer cells from being killed by the complement system [ 44 ]. Upregulation of CD46 for instance, is detected in primary and metastatic prostate cancer [ 43 ], as well as in bladder cancer [ 42 ]. In the latter, CD46 expression negatively correlated with the stage of the cancer.…”