Abstract: Analyzing anti-cancer immune responses is key to understanding cancer immunotherapy mechanisms. We used Immune Repertoire Capture (IRC) technology to sequence the full length variable regions of natively paired immunoglobulin heavy and light chain genes expressed by over 5000 blood plasmablasts (activated B cells) from a patient with Stage 4 lung adenocarcinoma during a period of long term non-progression (2+ years). There was extensive diversity of germline gene usage and elevated levels of somatic hypermutation (SHM) among the individual B cells. Sequences were grouped into putative clonal families based on immunoglobulin gene usage and other sequence features. Over 1500 putative antibody clonal families were identified, including families observed across blood collection time points and similar to families from another lung adenocarcinoma patient. The full length variable regions of IRC sequences were directly gene synthesized to generate recombinant antibodies representing over 150 large and small putative families. Antibodies showed a range of staining patterns on tumor and normal tissues, including some antibodies that bound tumor types other than lung tumor and some that bound tumor much better than normal tissue. Over one third of the antibodies bound lung cancer-derived cell lines. Some antibodies mediated ADCC killing in vitro. Human proteome arrays are being used to identify the targets of the antibodies. Analyses identified clones with differing SHM from the same putative family that bind the same target with varying potencies, indicating that the mutational differences between sibling antibodies reveal structure-activity information.
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