160 Evaluation and development of dual and triple antigen targeting CAR-T Engager proteins for Her2-positive CNS metastases and solid tumors

Background Solid tumors display pronounced antigen heterogeneity and clinical studies have shown that escape from therapy occurs rapidly, limiting the persistence efficacy of CAR T cells. Here we present dual triple-antigen binding proteins bridge cells to multiple antigens, allowing a simultaneous attack on tumor antigens by single antibody domain. We call these Engager proteins. can be encoded into lentiviral vectors for secretion cells, oncolytic viral transduced or engineered as biologics injection. Methods Engagers contain protein target cell, eg. an anti-CD19 cell. previously presented Her2-binding with potent in vivo activity against solid tumors. used this basis building triple Specifically, mapped expression Her2-positive tumors, metastases, primary CNS Our analysis identified patterns two three would essentially saturate cellular composition specific greatly reducing chance therapy. created corresponding developed single, lines model potency novel proteins, administered alongside Results plus recognize Her2 B7H3 demonstrate cytotoxicity either alone, synergistic (2 pM) if both are expressed. Similarly, CART show which is enhanced when expressed All mediated through one domain pre-loaded multi-antigen retain cytotoxic activity. Because underlying CAR, cell fitness further presence normal B Conclusions The platform robust modular solution targeting Diverse readily targeted diverse indications. Examples other functional modalities added will presented. Acknowledgements thank Cancer Research UK their ongoing support.