Solid tumors lead to 580,000 deaths annually in the US, and safe and effective therapeutics for many late- stage solid tumors are lacking. Ovarian cancer alone kills 14,000 people each year, and many patients do not respond to currently available treatments. The tight junction protein Claudin 6 (CLDN6) is a validated therapeutic target for many solid tumor types, including ovarian, endometrial, testicular, gastric, and pancreatic cancer. CLDN6 is differentially expressed on cancer cells with almost no expression in normal, healthy tissue. Despite being an attractive target, therapeutic MAbs targeting CLDN6 are difficult to discover due to an absolute need for high specificity. There are 26 human CLDN family members in total and most are broadly expressed and highly conserved, making drug specificity when targeting the CLDNs critically important but especially challenging. The extracellular region of CLDN6 closely resemble the widely expressed CLDN9 (3 amino acids different). The few CLDN6 MAbs discovered by others have demonstrated significant binding to other CLDN family members and most have now been halted in development. Here, we will develop a CLDN6 therapeutic for solid tumors.
Public Health Relevance Statement: PROJECT NARRATIVE This proposal will contribute to public health and the treatment of human disease by resulting in a therapeutic against CLDN6 for the treatment of late-stage solid tumors. Solid tumors kill 580,000 Americans annually, and there is an unmet need for safe and effective treatments for patients with late-stage ovarian, endometrial, testicular, gastric, and pancreatic cancers.
Project Terms: Abbreviations; Amino Acids; aminoacid; Antibodies; Monoclonal Antibodies; Clinical Treatment Moab; mAbs; Biological Assay; Assay; Bioassay; Biologic Assays; Biopsy; Cessation of life; Death; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Engineering; Exhibits; Future; Human; Modern Man; In Vitro; Integral Membrane Protein; Intrinsic Membrane Protein; Transmembrane Protein; Transmembrane Protein Gene; Isoelectric Point; Lead; Pb element; heavy metal Pb; heavy metal lead; malignant stomach neoplasm; Gastric Body Cancer; Gastric Cancer; Gastric Cardia Cancer; Gastric Fundus Cancer; Gastric Pylorus Cancer; Malignant Gastric Neoplasm; Malignant Gastric Tumor; Stomach Cancer; gastric malignancy; malignant stomach tumor; stomach fundus cancer; stomach pylorus cancer; Membrane Proteins; Membrane Protein Gene; Membrane-Associated Proteins; Surface Proteins; Mus; Mice; Mice Mammals; Murine; Persons; Patients; Pharmacokinetics; Drug Kinetics; Proteins; Public Health; Risk; Safety; Specificity; Mass Photometry/Spectrum Analysis; Mass Spectrometry; Mass Spectroscopy; Mass Spectrum; Mass Spectrum Analyses; Mass Spectrum Analysis; Progenitor Cells; stem cells; T-Cells; thymus derived lymphocyte; T-Lymphocyte; Temperature; Testing; Time; Tissues; Body Tissues; Viscosity; Work; cytokine; Family member; Mediating; Risk Assessment; CD3 Antigens; CD3; CD3 Complex; CD3 molecule; OKT3 antigen; T3 Antigens; T3 Complex; T3 molecule; TimeLine; Malignant neoplasm of testis; Malignant Testicular Neoplasm; Malignant Testicular Tumor; Malignant Tumor of the Testis; Testicular Cancer; Testis Cancer; Clinical; Failure; Occluding Junctions; Zonula Occludens; Tight Junctions; Malignant Tumor of the Lung; Pulmonary Cancer; Pulmonary malignant Neoplasm; lung cancer; Malignant neoplasm of lung; Funding; Solid Tumor; Solid Neoplasm; Therapeutic; Malignant Cell; cancer cell; Malignant Pancreatic Neoplasm; Pancreas Cancer; Pancreatic Cancer; pancreatic malignancy; Malignant neoplasm of pancreas; Clinic; Tumor Volume; Endometrial Cancer; Endometrium Cancer; Endometrium Carcinoma; Endometrial Carcinoma; Heterograft; Heterologous Transplantation; Xenograft; Xenotransplantation; xeno-transplant; xeno-transplantation; Xenograft procedure; extracellular; American; light scattering; membrane structure; Membrane; Tumor Cell; neoplastic cell; cell killing; PBMC; Peripheral Blood Mononuclear Cell; melting; biological sensor; Biosensor; Toxicities; Toxic effect; Proteome; Modeling; Adverse effects; claudin 6; ovarian neoplasm; Ovarian Tumor; Ovary Neoplasms; Ovary Tumor; Malignant Ovarian Neoplasm; Malignant Ovarian Tumor; Malignant Tumor of the Ovary; Ovary Cancer; ovarian cancer; Malignant neoplasm of ovary; T-Cell Proliferation; T-Cell Activation; Molecular Interaction; Binding; CD34; HPCA1; CD34 gene; Address; Affinity; Data; in vivo; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Xenograft Model; xenograft transplant model; xenotransplant model; Development; developmental; pre-clinical; preclinical; clinical efficacy; Cancer cell line; cancer type; Therapeutic Monoclonal Antibodies; MAb Therapeutics; monoclonal antibody drugs; therapeutic mAbs; Cell model; Cellular model; human disease; therapeutic target; tumor; effective therapy; effective treatment; efficacy testing; targeted treatment; targeted drug therapy; targeted drug treatments; targeted therapeutic; targeted therapeutic agents; targeted therapy; differential expression; differentially expressed; transcriptional differences; humanized mouse; humanized mice; experimental study; experiment; experimental research; clinical development; cytokine release syndrome; cytokine storm; Tumor-infiltrating immune cells; Immune infiltrates; T cell infiltration; T cell tumor trafficking; immune cell infiltrate; immune infiltration; intratumoral immune cell; tumor immune cell; therapeutically effective; biopharmaceutical industry; biopharmaceutical company
