Wednesday, April 2, 2025
4/2/2025
Development of a new tool to treat small cell lung cancer - Here we propose to develop a new tool to treat small cell lung cancer (SCLC) based on an abnormal post- translational modification, isoaspartylation (a type of protein damage involving kinking of the protein backbone) of the ELAVL4 protein. ELAVL4 is expressed on the outside of SCLC tumors. Isoaspartylation is a modification that gives rise to an antibody-based immune response in SCLC patients. In the case of ELAVL4, a naturally- occurring low level antibody response in ~15% of SCLC patients to ELAVL4 is associated with improved response to therapy and significantly improved survival. In addition, rare SCLC patients with spontaneous high- titer anti-ELAVL4 antibody responses show complete regression of this normally highly lethal cancer. However, while the cancer in the latter patients can be completely eradicated, epitope spreading (common with isoaspartylation) leads to the immune response attacking the native protein, causing destruction of healthy neuronal tissues (which express native ELAVL4), and ultimately patient death. The off-target effect in the latter patients is a highly undesirable side effect of an immune response which started against SCLC. However, the efficacy of the immune response in eradicating a highly metastatic cancer shows the power of anti-ELAVL antibodies. Using a genetically-engineered SCLC mouse model that accurately recapitulates human SCLC (including the anti-ELAVL4 response), we recently showed that immunizing SCLC-carrying mice with isoAsp- ELAVL4 significantly improves survival. This indicates that an artificially-induced immune response against ELAVL4 can be therapeutic. However, immunization risks epitope spreading and neuronal toxicity. These can be avoided by instead generating a monoclonal antibody (mAb) specific for isoaspartylated ELAVL4. Such an antibody could be used on its own, could be functionalized, used as part of bi/tri-specific antibodies, or grafted onto T-cells to develop CAR-T therapy. The goal of this project is to generate an isoaspartyl-ELAVL4-specific mouse mAb as a new therapeutic tool for SCLC and to test its therapeutic efficacy in the murine SCLC model. We have 2 specific aims: 1) To generate a mouse monoclonal antibody specifically targeting isoaspartylated ELAVL4 by immunizing with a synthetically-produced isoAsp-ELAVL4 peptide followed by affinity optimization. The binding kinetics and affinity of candidate mAbs for isoAsp-ELAVL4 will be measured to obtain a mAb with optimal binding kinetics (faston, slowoff). 2) To test the therapeutic efficacy of an anti-isoAsp- ELAVL4 monoclonal antibody in the mouse SCLC model. SCLC will be induced in mice with homozygously floxed Tp53 and Rb1 by intratracheal instillation of Adenovirus carrying Cre recombinase, a model we have used extensively. We will produce and purify the optimal anti-isoAsp-ELAVL4 mAb from Aim 1 and test its therapeutic efficacy using survival as an endpoint. If successful, the antibody would be humanized for clinical trials of SCLC patients. Patients with other cancers (e.g. neuroblastoma, breast, ovarian, and prostate cancer) can also exhibit ELAVL4 autoantibodies, hinting at the potential of using this strategy to treat other cancers.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).