Anti-CDR3 Therapy for B-Cell Malignancies.

摘要

Immunotherapy is rapidly becoming accepted as an effective way to treat human cancer. A large proportion of B-cell malignancies express the product of their rearranged immunoglobulin (IG) genes on the cell surface. Surface-expressed IG constitutes a de facto tumor-specific target antigen. Here we report that two B-cell tumor cell lines, JVM13 and Mec1, express surface IG. Therefore we cloned and sequenced the cDNA encoding the variable portions of these IGs. Specifically, we identified the CDR3 sequences of the heavy and light chain variable portions for each IG, which constitute the molecular target. We have now engineered the following CDR3 sequences "ARSQGVLTAIDY"/"QQYYSIPYT" for the Mec1 heavy and light chains respectively and "ASSYYDILTGYLYYYFDY "/"SSYTSSSTLMI" for the JVM13 heavy and light chains, into a model antibody 4D5 (see figures 1-5 in the report). The "Tomlinson" human antibody phage library will be used to pan for antibodies that bind these target CDR3s and not the parent 4D5 antibody. To confirm the utility of the Tomlinson library and gain experience with handling this complex selection system we have confirmed selection of phage to a test antigen. Successful expression will lead directly to the selection of CDR3-specific antibody-encoding phage: from which we will make our final immunotherapeutic agents.