Suppression of human prostate tumor growth by a unique prostate-specific monoclonal antibody F77 targeting a glycolipid marker

Abstract

In our effort to find diagnostic markers and to develop therapeutic approaches for prostate cancer, we have identified an mAb that is capable of binding to a cell surface antigen specifically expressed on both androgen-dependent and androgen-independent prostate cancer cells. Immunohistological studies revealed that this mAb, called F77, stained 112 of 116 primary and 29 of 34 metastatic human prostate cancer specimens. Although the mAb F77 alone directly promotes prostate cancer cell death, it also mediates complementdependent cytotoxicity and antibody-dependent cellular cytotoxicity. In addition, mAb F77 can significantly inhibit androgenindependent PC3 and Du145 tumor growth in nude mice. Antigen characterization revealed that mAb F77 recognizes a very small molecular species with glycolipid properties. F77 antigen is concentrated in the lipid-raft microdomains, which serve as platforms for the assembly of associating protein complexes. Thus, the present study indicates that mAb F77 defines a unique prostate cancer marker and shows promising potential for diagnosis and treatment of prostate cancer, especially for androgen-independent metastatic prostate cancer.androgen-independent tumor | antibody therapy | prostate cancer lipid antigen (PCLA) | antibody-dependent cellular toxicity | lipid rafts P rostate cancer is the second leading cause of cancer-related death in men in the United States. Thirty percent to 45% of patients with clinically localized disease are found to have extracapsular extension (1), and cancer may relapse and metastasize after local therapy. Despite the effectiveness of hormone therapy, most patients with metastatic disease eventually progress to an androgen-independent state, at which time the disease is incurable. The 5-y survival rate for metastatic prostate cancer is only 34% (2). New therapeutic approaches are clearly needed for the treatment of advanced and metastatic prostate cancer.Targeted monoclonal antibody therapy has proven efficacious in clinical cancer treatment. Certain mAbs, such as the anti-CD20 mAb (rituximab) used to treat B cell lymphoma and the antip185Her2/neu mAb (trastuzumab) for metastatic breast cancer, have been reasonably efficacious on their own (3, 4). Our laboratory showed that mAbs to p185Her2/neu can reverse the malignant phenotype and render tumors more susceptible to concomitant genotoxic therapies (5).The antibodies currently available for detection and treatment of prostate cancers are limited. The mAb 7E11-C5.3, which binds to prostate-specific membrane antigen (PSMA), has been developed for clinical trials (6). The ProstaScint scan (Cytogen), based on 111

Determination of Carbohydrate Structure Recognized by Prostate-specific F77 Monoclonal Antibody through Expression Analysis of Glycosyltransferase Genes

“…The mAb F77, which was produced by immunizing mice with the prostate cancer cell line PC-3 (20), is one such cytotoxic antibody. F77 preferentially binds to prostate cancer versus normal prostate tissue in a manner correlating with tumor grade.…”

Glycobiology Modifications in Intratumoral Hypoxia: The Breathless Side of Glycans Interaction

“…PCLA is a glycolipid that is restricted to the prostate cancer cell surface, specifically recognized by monoclonal antibody (mAb) F77. mAb F77 is an antibody produced by immunizing mice with the prostate cancer cells line PC-3, which directly promotes cell death, showing potential for diagnosis and therapy [85]. These studies show that the hypoxic modulation is tumor-dependent, and that each tumor cell has a different behavior.…”

“…Disruption of Gal1- N -glycan interactions promoted transient regularization of tumor-associated vasculature in vivo , and facilitated the influx of immune cells into the tumor microenvironment. This offers a novel alternative to evade resistance to VEGF-targeted therapies [85, 204]. …”

Glycan changes: cancer metastasis and anti-cancer vaccines

“…The mAb F77 is defi ned as a unique prostate cancer marker as well (Zhang et al 2010). Furthermore, Yi et al (2009) and Rose et al (2010) suggest that α2-HS glycoprotein (AHSG), anti-AHSG autoantibody and nonmetastatic B may be useful biomarkers for breast cancer screening and diagnosis.…”