Novel biologics platform for targeting tumors driven by intracellular oncoproteins

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The goal of this project is to establish a new platform technology that addresses fundamental limitations of current approaches against tumors driven by intracellular oncoproteins. Many oncogenes encode activated versions of intracellular proteins. Although biologics are revolutionizing cancer therapy, they do not readily enter cells and thus are ineffective against intracellular targets. Fragments of intracellular proteins are presented by MHC molecules on cell surface, but it is challenging to recognize differences between healthy proteins and their oncogenic counterparts that are often minute. Many covalent inhibitors have been developed against intracellular oncoproteins, but most of them, like other targeted therapies, evoke resistance and fail to achieve cancer cures. By contrast, “immune therapies” (e.g., immune checkpoint inhibitors, CAR-T cells) can be curative, but most intracellular oncogene-driven tumors fail to respond to these agents. We propose a potentially transformative innovation that unites targeted therapy using covalent inhibitors with immune therapy using biologics. We will develop “HapImmune” antibodies that selectively recognize fragments of an oncoprotein covalently linked to an inhibitor and presented by MHC Class I on the surface of cancer cells. The conjugated inhibitor serves as a hapten that increases the immunogenicity of the oncoprotein fragments. Co-administration of drug and antibody will initiate killing of cancer cells by engaging immune attack, antigen spreading and ultimately durable anti-tumor immunity. Compelling preliminary data demonstrate that HapImmune antibodies can be generated against several drug-peptide conjugates. Our multi-disciplinary team with complementary expertise in cancer biology, drug discovery, and antibody engineering is well positioned to further develop and explore the applicability of the HapImmune concept for improving targeted therapy. We will execute the following two Aims: (1) We will develop antibodies that bind a covalent drug, AMG510 conjugated with a KRASG12C peptide presented on an MHC. Although AMG510 is expected to revolutionize therapy against cancers driven by KRASG12C, its efficacy is short-lived. We will examine the efficacy of such antibodies in selective killing in vitro and in vivo of cancer cells that have been pretreated with AMG510. These experiments will critically evaluate the impact of the HapImmune approach using a major current target in cancer drug discovery. (2) We will assess the broader applicability of the HapImmune approach using distinct target-drug pairs, using covalent inhibitors of EGFR and BTK. We will develop antibodies to these conjugates presented on appropriate MHC molecules and test their efficacy in cell-based assays. These experiments should provide a rigorous test of the general applicability of the HapImmune approach and our ability to develop HapImmune antibodies. If successful, this project will establish a facile pipeline to produce potentially transformative therapeutics that can be rapidly translated into clinic.