Monoclonal antibodies targeting tumor associated antigens (TAA's) have since 1997, provided safe and efficacious human cancer therapeutics. More recently, bispecific antibodies or bispecific antibody fragments that promote immunologic synapses between cells of the innate immune system and malignant cells have shown in clinical trials remarkable efficacy and potency against several leukemias and lymphomas. We propose in this Phase I SBIR study to determine whether it is feasible to develop a platform based on engineering a novel human scaffold, MICA, to target and promote killing of specific cancer cells by generating specific immunologic synapses. NK cells and certain T-cells of the innate immune system protect the host from the malignant enemy within by constant surveillance for cells expressing surface MICA or MICB, indicators that the cell is a threat to the health of the host. Once such effector cells of the innate immunity detect a cell decorated by a membrane-bound MIC protein, they attack and destroy the decorated, threatening cell. Such threats include malignancies; but many cancerous cells do not express a level of MICA sufficient to recruit the effector cells. Many high grade malignant cells trap MIC protein intracellularly or secrete proteases that cleave the MIC protein from their surface, clearing the distress signal and enabling escape from innate immunity. Thus, in spite of being dangerous and threatening host survival, cancer cells can break through the surveillance by manipulating surface expression of MIC proteins. We propose to overcome this escape of malignant cells by decorating their surfaces with MICA from outside. Soluble MICA targeted specifically to TAA's expressed uniquely on the malignant cell surface would be administered parenterally. Such a novel approach enables an adaptive use of Nature's potent innate immunity to override the evolved, nefarious mechanism of cancer escape---"innate immunotherapy". The innovation lies in the conversion of this human MICA scaffold naturally deployed by the innate immune system into an immune "adaptor" that specifically binds malignant cells and thereby recruits and activates innate immunity effector cells expressing the receptor for MICA, NKG2D, to promptly kill the targeted cell. We propose herein to focus these platform technologies and concepts on a prototypic and important TAA, Fibroblast Growth Factor Receptor-3 (FGFR3), an oncogenic protein over expressed on most human bladder cancers and many multiple myeloma cells. We intend to demonstrate in vitro specific killing of human cells expressing FGFR3.
Public Health Relevance Statement: Public Health Relevance: Killer cells of the innate arm of human immune system provide constant surveillance of their human host for cells expressing on their surface MICA or MICB protein molecules, indicators that the cell is dangerous. Once a cell decorated by a MIC protein is detected, it is attacked and killed by killer cells. In spite of being dangerous, many cancer cells do not express a level of MIC proteins sufficient to attract the attention of the killr cells. While this surveillance system has served mammals well, there are significant exceptions to its successful deployment. Those rare exceptions include the malignancies that eventually become symptomatic. For example, many high grade malignant cells don't express MICA or MICB on their surfaces; they trap MIC proteins inside the cell or secrete enzymes that cleave the MIC proteins from their surface, thereby clearing the distress signal and escaping from the innate immunity. Thus, in spite of being dangerous and threatening host survival, cancer cells can break through the surveillance by keeping MIC proteins off their surface. We propose to overcome this escape by decorating cancer cells from outside by administering MICA protein engineered to target specific molecules uniquely present on the surface of the malignant cell. Such a novel approach enables the adaptive use of Nature's potent innate immunity to override the evolved, nefarious mechanism of cancer escape. Our proposed first target of this platform is Fibroblast Growth Factor Receptor-3 (FGFR3), an oncogenic ("cancer-causing") protein which is overly abundant on most human bladder cancer cells and many multiple myeloma cells. We intend to demonstrate in vitro the specific killing of human cells expressing FGFR3.
NIH Spending Category: Biotechnology; Cancer
Project Terms: Accounting; Achievement; Affinity; Antibodies; arm; Attention; Avidity; base; Binding (Molecular Function); Bispecific Antibodies; cancer cell; Cancer Etiology; Cancerous; CD94 Antigen; cell killing; Cell surface; Cell-Mediated Cytolysis; Cells; Cleaved cell; clinical efficacy; Clinical Trials; Cytolysis; Distress; Effector Cell; Engineering; Enzymes; Fc domain; fibroblast growth factor receptor 3; Grant; Health; Human; Immune; Immune system; Immunoglobulin Fragments; Immunologics; Immunotherapy; In Vitro; innovation; Killer Cells; Killings; leukemia/lymphoma; Ligands; Liquid substance; Malignant - descriptor; Malignant neoplasm of urinary bladder; Malignant Neoplasms; Mammals; Mediating; Membrane; Mica; MICA protein; Monoclonal Antibodies; Multiple Myeloma; Natural Immunity; Natural Killer Cells; Nature; neoplastic cell; novel; novel strategies; Oncogenic; oncolysis; Oncolytic; Peptide Hydrolases; Phage Display; Pharmaceutical Preparations; Phase; Protein Engineering; Proteins; public health relevance; Publishing; receptor; Recruitment Activity; Sales; scaffold; Signal Transduction; Small Business Innovation Research Grant; Staging; Stress; Surface; Surface Antigens; Synapses; System; T-Lymphocyte; Technology; Therapeutic; Therapeutic antibodies; tumor; Tumor Antigens; Virus
