A Novel Class of Bifunctional Immunotherapeutic That Exploits a Universal Antibody Binding Terminus (uABT) to Recruit Endogenous Antibodies to Cell Expressing CD38 Demonstrate In Vivo efficacy in Three Distinct Animal Models

Background: Antibody recruiting molecules (ARM) represent a new modality in immunotherapy of cancer. These are bifunctional molecules composed of two active termini connected by a linker. One of the termini binds to a target molecule on a cancer cell. The other terminus can recruit endogenous IgG antibodies independent of their antigen binding specificity representing a breakthrough improvement to previous approaches (Murelli et al.J Am Chem Soc. 2009). We named this active moiety a universal antibody binding terminus (uABT). As a result of antibody recruitment to the cell surface, the target cell is “opsonized” by antibodies which then bring in the immune effector cells to eliminate the target through various antibody-dependent destruction mechanisms. Multiple myeloma is a neoplasm that arises from terminally differentiated immunoglobulin producing long-lived plasma cells with 32,000 new cases diagnosed each year. Kleo Pharmaceuticals has developed a series of compounds, CD38-ARM which target human CD38 highly expressed by multiple myeloma cells. CD38 -ARM compounds are therapeutically active in three distinct in vivo models without depleting CD38 expressing immune effector cells like existing therapeutic antibodies such as Daratumumab. Methods: CD38-ARM compounds were tested in three independent in vivo models. In the first model, intraperitoneal Daudi xenograft in SCID mice, 20x106 fluorescently labelled Burkitt lymphoma CD38-expressing Daudi cells were injected into SCID mice and treated with 3 mg/kg of compounds. Peritoneal exudates were examined 24 hours later for percentages and absolute numbers of Daudi cells recovered. Activity of compounds was further tested in a MOLP-8 multiple myeloma cell xenograft model in nude mice. Animals received 106 MOLP8 cells subcutaneously, and were treated with a daily dose of 10 mg/kg after tumor volumes of 150 mm3 were reached. Finally, CD38-ARM efficacy was examined in hu IL-15 transgenic NOG mice that have been preconditioned with busulfan and reconstituted i.p. with 2x106human NK cells. Three weeks after reconstitution, 5x106RAJI cells expressing CD38 were implanted s.c. and treatment commenced a week later with 10 mg/kg QDx14. Mice were monitored for NK cell levels and activation status in the blood during the whole study duration by flow cytometry. Results: CD38-uAbt compounds are able to induce clearance of Burkitt's lymphoma Daudi cells expressing high levels of CD38 in a SCID mouse intraperitoneal model. In