Identification of
tumor-specific
cell surface antigens has proven challenging, as the vast majority of
tumor-associated
antigens are also expressed in normal tissues. In
mesothelioma, we identified a highly specific
tumor cell surface antigen that can be targeted for
therapy development.
Mesothelioma is caused by malignant transformation of the mesothelium, is incurable, and can be categorized into three histologic subtypes: epithelioid, biphasic, and sarcomatoid. To identity novel
mesothelioma cell surface antigens with broad subtype coverage and high tissue specificity, we have previously selected phage antibody display libraries on live
mesothelioma cells and tissues following counterselection on normal cells and identified a panel of human
antibodies that bind all subtypes of
mesothelioma, but not normal mesothelium. One of the
antibodies, M25, showed high specificity against an
antigen we identify here as ALPPL2. IHC on normal human tissues found that ALPPL2 is expressed only on placental trophoblasts, but not on any other normal tissues. This significant tissue specificity and broad
tumor type coverage suggest that ALPPL2 could be an excellent cell surface target for therapeutic development against
mesothelioma. To evaluate therapeutic potential of ALPPL2 targeting, an ALPPL2-targeted
antibody-drug conjugate was developed and demonstrated potent and specific
tumor killing in vitro and in vivo against both epithelioid and sarcomatoid
mesothelioma. Thus, ALPPL2 belongs to a rare class of
cell surface antigens classified as truly
tumor specific and is well suited for
therapy development against ALPPL2-expressing
tumors. SIGNIFICANCE: These findings identify ALPP2 as a true
tumor-specific
cell surface antigen whose tissue specificity enables the development of novel
therapies.