Generation and Characterization of Cancer-Specific Monoclonal Antibodies for Immunotherapy
Open AccessMonoclonal antibody-based treatment for cancer has been shown to have significant clinical benefits. Identification of novel tumor antigens and generation of cancer-specific antibodies are critical needs. Cluster of differentiation 24 is a specific surface marker involved in the tumorigenesis and progression of up to 70% of all cancers. Overexpression of surface and intracellular CD24 has been associated with poor prognosis for cancer patients. While CD24 is expressed in many cancer types, it is also expressed on hematopoietic and terminally differentiated cells. Currently, there are no CD24 antibodies that exhibit preferential binding against cancer associated CD24 cells with minimal cross-reactivity against normal cell CD24. We have generated monoclonal antibodies against CD24, which has selective binding to cancer cells. PP6373 and its humanized version H3L3 recognizes CD24 on a wide range of cancer cell lines and tissues but not normal tissues nor peripheral blood. Antigenic epitope of PP6373 and H3L3 is the linear CD24 peptide and is spatially hindered by two O-glycans flanking the epitope. PP6373 and H3L3 induces antibody dependent cell-mediated cytotoxicity in vitro. PP6373 retards tumor growth in xenograft model. Additionally, using a CD24h/h mouse model, we also demonstrated the cancer immunotherapy effect of H3L3 in an immunocompetent host with minimal antibody-induced toxicity. Our data suggest that cancer specific monoclonal antibodies PP6373 and H3L3 against CD24 have great potential as diagnostic tool as well as therapeutic drug. We hereby also described a rapid and potentially en masse identification of cancer-specific antibodies directly from human cancer tissues. A computational framework was developed and successfully tested for antibody discovery by mining RNA-sequencing (RNAseq) data of The Cancer Genome Atlas (TCGA) from solid tumor samples. Synthetic recombinant antibody based on high-abundance complementarity-determining region 3 (CDR3) sequences from lung adenocarcinoma (LUAD) patients bound all lung cancer samples tested and was cross-reactive to other cancer types but rarely to normal tissues. Targeted DNA sequencing of the B cell receptor from 5 lung tumor tissues also allowed us to identify variable region sequences with somatic mutations. Antibodies based on predominant variable region sequences showed specific binding to autologous lung cancer samples. This platform dramatically reduces the barrier in developing human anti-cancer antibodies and paves the way for cancer treatment using patient-derived tumor-reactive monoclonal antibodies.
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