Understanding and Mimicking TCR Recognition with Therapeutic Monoclonal Antibodies.

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Abstract The goals of my research since 1978 have been to distinguish the features of cancer cells from healthy cells in order to be able to discover and develop safe and selective, innovative immunotherapies. Here, we leverage my past body of work that has evolved from native mouse antibodies, to humanized mAb, to various potent conjugates of these mAb, to TCRm antibodies, and ultimately to BiTE forms and CAR forms to create the latest generation of agents and experiments now proposed. This scientific progression has been sustained for more than 3 decades. This work is innovative, as noted by our numerous therapeutic firsts and more than 3 dozen patents, including: human antibodies for the treatment of acute leukemia, targeted alpha- particle therapies, in vivo alpha-particle isotope generators, oncogenic fusion point vaccines, human TCR mimic antibodies to intracellular oncogenic proteins, and most recently, various innovative CAR technologies, now in progress. Several of the antibodies and vaccines reached late stage, national clinical trials such as a WT1 vaccine, Galenpepimut, and our alpha generator-Lintuzumab. But now, how do we achieve true cancer specificity? The immune system has evolved the T cell and TCR as a highly efficient and truly selective system capable of recognizing viral and mutated intracellular proteins derived from inside the cell. Therefore, in this OIA the questions are: Is it possible to make truly cancer selective monoclonal antibodies, and various derived molecular platforms, that will be effective therapeutically by mimicking a TCR? What are the obstacles and cancer resistance mechanisms to this approach and how will they be overcome? How do we select the right target epitopes and also avoid inevitable off- targets that may cause toxicity? The following issues will be addressed: A. Target choices: What are the best epitopes from a biochemical, biophysical, or immunological point of view? Are certain classes of proteins or structures of peptides preferred? How do we design screens for TCRm? B. Can we modulate the expression of the epitopes or the antigen presentation machinery? How is the MHC ligandome generally affected by these drugs and is this important? C. Predictive tools: Can we develop proteomic and genetic tools to create general rules and to help guide us to picking epitopes and predicting which may be safe? D. What cancer therapeutic platform for the TCRm makes the most sense in light of what we have learned about the biology and immunology of the epitope, as well as the predictions of specificity from the tool sets?