Exploiting autoantibodies for cancer immunotherapy

Malignant tumors present a distinct challenge to the immune system as "altered self". Although there is a well-established crosstalk between the immune system and the tumor that has substantial implications for cancer therapy, the nature of the antigens that allow the immune system to distinguish cancer cells from non-cancer cells has long remained obscure. Recent findings provide an important scientific linkage between the cancer immunology and autoimmunity fields and suggest that targeted breakdown of self-tolerance to various tissue-specific antigens (which are highly expressed by the corresponding tumor) could potentially be exploited as the "magic bullet" to ultimately defeat cancer. It is well established that Aire-deficient mice on NOD genetic background develop severe autoimmune phenotype, characterized by generation of a plethora of autoantibodies against multiple tissues. Therefore, in this research project we aim at exploiting breakdown of immunological tolerance to hundreds of tumor-specific antigens, which occurs naturally in AIRE-deficient mice for cancer immunotherapy. Specifically, we aim at isolating autoantibodies from AIRE-deficient mice, targeting extracellular domains of various membrane-bound antigens associated with various solid tumors, including liver (ASGR1), ovarian (MUC16) and urinary bladder (UPK2) tumors. To this end, we build on our promising preliminary data and experimental platforms we have recently developed for isolation, cloning humanization and expression of autoantibodies against the desired targets. We have identified and isolated several promising autoantibody clones to the above tumor-associated antigens and are in the process of their validation and characterization. The most promising clones will then be used for generation of antibody drug conjugates (ADC), which will then be tested for their tumor cytotoxic capacity in both in vitro and in-vivo mouse xenograft models. So far, we have successfully generated and tested ADC derived from 2B5 mAb clones that specifically targets a unique epitope of MUC16. We hope to generate ADCs for ASGR1 and UPK2 in the near future.